In Vivo Assessment of Aortic Aneurysm Wall Integrity Using Elastin-Specific Molecular Magnetic Resonance Imaging

Botnar, René M.; Wiethoff, Andrea J.; Ebersberger, Ullrich; Lacerda, Sara; Blume, Ulrike; Warley, Alice; Jansen, Christian; Onthank, David; Cesati, Richard R.; Razavi, Reza; Marber, Michael; Hamm, Bernd; Schaeffter, Tobias; Robinson, Simon P.; Makowski, Marcus R.

doi:10.1161/circimaging.113.001131

Cited by 49 publications

(43 citation statements)

References 45 publications

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“…3 ECM destruction leads to proteolysis of elastin, the predominant ECM protein in the aortic wall. 4 Elastin proteolysis releases elastin-derived peptides (EDPs), including peptides with the xGxxPG motif, a commonly repeated sequence in elastin. 5 Of those EDPs released by elastin degradation, the VGVAPG repeat sequence in the human tropoelastin molecule has been shown to have the highest affinity for elastin-binding protein.…”

Section: Introductionmentioning

confidence: 99%

Elastin-Derived Peptides Promote Abdominal Aortic Aneurysm Formation by Modulating M1/M2 Macrophage Polarization

Dale

Xiong

Carson

et al. 2016

The Journal of Immunology

109

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Abdominal aortic aneurysm (AAA) is a dynamic vascular disease characterized by inflammatory cell invasion and extracellular matrix (ECM) degradation. Damage to elastin in the ECM results in release of elastin-derived peptides (EDPs), which are chemotactic for inflammatory cells such as monocytes. Their effect on macrophage polarization is less well known. Pro-inflammatory M1 macrophages initially are recruited to sites of injury but, if their effects are prolonged, they can lead to chronic inflammation that prevents normal tissue repair. Conversely, anti-inflammatory M2 macrophages reduce inflammation and aid in wound healing. Thus, a proper M1/M2 ratio is vital for tissue homeostasis. AAA tissue reveals a high M1/M2 ratio where pro-inflammatory cells and their associated markers dominate. In the present study, in vitro treatment of bone marrow-derived macrophages with EDPs induced M1 macrophage polarization. By using C57Bl/6 mice, antibody-mediated neutralization of EDPs reduced aortic dilation, matrix metalloproteinase activity, and pro-inflammatory cytokine expression at early and late time points after aneurysm induction. Furthermore, direct manipulation of the M1/M2 balance altered aortic dilation. Injection of M2 polarized macrophages reduced aortic dilation after aneurysm induction. EDPs promoted a pro-inflammatory environment in aortic tissue by inducing M1 polarization and neutralization of EDPs attenuated aortic dilation. The M1/M2 imbalance is vital to aneurysm formation.

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Section: Introductionmentioning

confidence: 99%

Elastin-Derived Peptides Promote Abdominal Aortic Aneurysm Formation by Modulating M1/M2 Macrophage Polarization

Dale

Xiong

Carson

et al. 2016

The Journal of Immunology

109

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“…Considering the equivocal clinical usefulness of the mere assessment of vascular wall inflammation for the diagnostic and prognostic evaluation of AAA that was previously suggested and that is further shown by the present study of Barwick et al [8], the development of methodologies such as SPECT/CT, PET/CT and MRI allowing simultaneous anatomical and molecular imaging of the AAA wall with agents targeting potentially more specific biomarkers of prone-torupture AAA than FDG [22][23][24] might therefore be a relevant area of research for the ultimate noninvasive prediction of AAA growth and rupture.…”

mentioning

confidence: 63%

Equivocal usefulness of FDG for the noninvasive imaging of abdominal aortic aneurysms

Riou

Vanzetto

Broisat

et al. 2014

Eur J Nucl Med Mol Imaging

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Abdominal aortic aneurysms (AAA) usually progress asymptomatically and are undetected until rupture occurs. Once ruptured, the mortality rate of AAA is about 80 %. Among all patients with ruptured AAA, about one-third die without reaching hospital, and about another quarter reach hospital but die prior to surgical intervention. Among the remaining patients (about 40 %) surviving AAA rupture long enough to benefit from surgical intervention, the perioperative mortality has historically reached about 50 % [1], a value that has however recently decreased owing to the introduction of endovascular repair [2]. On the other hand, elective AAA repair has a much lower in-hospital mortality rate, with recently reported values of 1.3 % and 4.7 % for endovascular and open surgical repair, respectively [3], thereby strongly emphasizing the need for screening and identification of those patients with prone-to-rupture AAA.The crude estimate of AAA diameter remains the most widely used predictive risk factor for AAA rupture and the sole therapeutic management criterion. Indeed, in both the 2014 European Society of Cardiology and the 2011 American College of Cardiology/American Heart Association guidelines, aortic repair is a class I indication if the AAA diameter exceeds 55 mm [4,5]. However, the limitations of this parameter are well acknowledged, and it is therefore unanimously agreed that a more robust noninvasive predictor of the individual risk of AAA rupture is required. Although being much less documented than atherogenesis, the current knowledge regarding the pathophysiology of AAA indicates that parietal inflammation, matrix degradation and smooth muscle cell apoptosis are required for AAA pathogenesis [6]. FDG has been suggested as a potentially useful agent for the molecular imaging of vascular inflammation due to the elevated carbohydrate metabolism of extravasated inflammatory cells [7]. As such, the tracer has been extensively evaluated in both the experimental and clinical settings for the noninvasive imaging of inflammatory processes in vulnerable atherosclerotic lesions as well as in AAA.In the multicentre study by Barwick and colleagues published in this issue of the European Journal of Nuclear Medicine & Molecular Imaging [8], the authors used PET imaging of FDG uptake to retrospectively compare the metabolic activity in the abdominal aortic wall of 151 patients with AAA (mean aortic diameter, 50±13 mm) with that of 159 individuals with no AAA (mean aortic diameter, 21±3 mm) and matched for age, sex, diabetes, smoking status, statin use and indication for PET/CT. This cohort is the largest so far used for the comparison of FDG uptake between AAA and normal vessels in well-matched patients. FDG uptake was analysed by semiquantitative visual scoring as well as quantitatively using SUVmax and target to background ratios utilizing mediastinal blood pool or descending thoracic aorta activities for normalization. Although the retrospective nature and the design of the study limit the conclusions that can be drawn w...

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“…all animals were sacrificed for further histopathological analysis after the final imaging sessions. For the imaging session, mice were anesthetized with an intramuscular application [21, 22] of the same combination of Medetomidin, Fentanyl, Midazolam as mentioned above. In all mice with abdominal aortic aneurysm, an exsanguination in anterior perfusion with phosphate buffered saline (100 mm Hg) was performed following the MR imaging session.…”

Section: Methodsmentioning

confidence: 99%

In vivo MR-angiography for the assessment of aortic aneurysms in an experimental mouse model on a clinical MRI scanner: Comparison with high-frequency ultrasound and histology

et al. 2017

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BackgroundMR-angiography currently represents one of the clinical reference-standards for the assessment of aortic-dimensions. For experimental research in mice, dedicated preclinical high-field MRI scanners are used in most studies. This type of MRI scanner is not available in most institutions. The aim of this study was to evaluate the potential of MR-angiography performed on a clinical MR scanner for the assessment of aortic aneurysms in an experimental mouse model, compared to a preclinical high-resolution ultrasound imaging system and histopathology.MethodsAll in vivo MR imaging was performed with a clinical 3T MRI system (Philips Achieva) equipped with a clinical gradient system in combination with a single-loop surface-coil (47 mm). All MR sequences were based on clinically used sequences. For ultrasound, a dedicated preclinical high-resolution system (30 MHz linear transducer, Vevo770, VisualSonics) was used. All imaging was performed with an ApoE knockout mouse-model for aortic aneurysms. Histopathology was performed as reference-standard at all stages of aneurysm development.ResultsMR-angiography on a clinical 3T system enabled the clear visualization of the aortic lumen and aneurysmal dilation at different stages of aneurysm development. A close correlation (R2 = 0.98; p < 0.001) with histological area measurements was found. Additionally, a good agreement between MR and ultrasound area measurements in systole (R2 = 0.91; p < 0.001) and diastole (R2 = 0.94; p < 0.001) were measured. Regarding interobserver reproducibility, MRI measurements yielded a smaller 95% confidence interval and a closer interreader correlation compared to ultrasound measurements (-0.37–0.46; R2 = 0.97 vs. -0.78–0.88; R2 = 0.87).ConclusionThis study demonstrates that MR-angiography, performed on a clinical 3T MR scanner, enables the reliable detection and quantification of the aortic dilatation at different stages of aneurysm development in an experimental mouse model.

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In Vivo Assessment of Aortic Aneurysm Wall Integrity Using Elastin-Specific Molecular Magnetic Resonance Imaging

Cited by 49 publications

References 45 publications

Elastin-Derived Peptides Promote Abdominal Aortic Aneurysm Formation by Modulating M1/M2 Macrophage Polarization

Elastin-Derived Peptides Promote Abdominal Aortic Aneurysm Formation by Modulating M1/M2 Macrophage Polarization

Equivocal usefulness of FDG for the noninvasive imaging of abdominal aortic aneurysms

In vivo MR-angiography for the assessment of aortic aneurysms in an experimental mouse model on a clinical MRI scanner: Comparison with high-frequency ultrasound and histology

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