Julia Brangsch1,2, Carolin Reimann1,2, Jan O Kaufmann1,3,4, Lisa C Adams1, David C Onthank5, Christa Thöne-Reineke2, Simon P Robinson5, Rebecca Buchholz6, Uwe Karst6, Rene M Botnar7,8,9, Bernd Hamm1, Marcus R Makowski1,7,8. 1. Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany (J.B., C.R., J.O.K., L.C.A., B.H., M.R.M.). 2. Department of Veterinary Medicine, Institute of Animal Welfare, Animal Behavior and Laboratory Animal Science, Freie Universität Berlin, Germany (J.B., C.R., C.T.-R.). 3. Federal Institute for Materials Research and Testing (BAM), Division 1.5 Protein Analysis, Berlin, Germany (J.O.K.). 4. Department of Chemistry, Humboldt-Universität zu Berlin, Germany (J.O.K.). 5. Lantheus Medical Imaging, North Billerica, MA (D.C.O., S.P.R.). 6. Institute of Inorganic and Analytical Chemistry, Westfälische Wilhelms-Universität Münster, Germany (R.B., U.K.). 7. School of Biomedical Engineering and Imaging Sciences (R.M.B., M.R.M.), King's College London, United Kingdom. 8. BHF Centre of Excellence (R.M.B., M.R.M.), King's College London, United Kingdom. 9. Escuela de Ingeniería, Pontificia Universidad Católica de Chile, Santiago (R.M.B.).
Abstract
BACKGROUND: Molecular magnetic resonance imaging is a promising modality for the characterization of abdominal aortic aneurysms (AAAs). The combination of different molecular imaging biomarkers may improve the assessment of the risk of rupture. This study investigates the feasibility of imaging inflammatory activity and extracellular matrix degradation by concurrent dual-probe molecular magnetic resonance imaging in an AAA mouse model. METHODS: Osmotic minipumps with a continuous infusion of Ang II (angiotensin II; 1000 ng/[kg·min]) to induce AAAs were implanted in apolipoprotein-deficient mice (N=58). Animals were assigned to 2 groups. In group 1 (longitudinal group, n=13), imaging was performed once after 1 week with a clinical dose of a macrophage-specific iron oxide-based probe (ferumoxytol, 4 mgFe/kg, surrogate marker for inflammatory activity) and an elastin-specific gadolinium-based probe (0.2 mmol/kg, surrogate marker for extracellular matrix degradation). Animals were then monitored with death as end point. In group 2 (week-by-week-group), imaging with both probes was performed after 1, 2, 3, and 4 weeks (n=9 per group). Both probes were evaluated in 1 magnetic resonance session. RESULTS: The combined assessment of inflammatory activity and extracellular matrix degradation was the strongest predictor of AAA rupture (sensitivity 100%; specificity 89%; area under the curve, 0.99). Information from each single probe alone resulted in lower predictive accuracy. In vivo measurements for the elastin- and iron oxide-probe were in good agreement with ex vivo histopathology (Prussian blue-stain: R2=0.96, P<0.001; Elastica van Giesson stain: R2=0.79, P<0.001). Contrast-to-noise ratio measurements for the iron oxide and elastin-probe were in good agreement with inductively coupled mass spectroscopy ( R2=0.88, R2=0.75, P<0.001) and laser ablation coupled to inductively coupled plasma-mass spectrometry. CONCLUSIONS: This study demonstrates the potential of the concurrent assessment of inflammatory activity and extracellular matrix degradation by dual-probe molecular magnetic resonance imaging in an AAA mouse model. Based on the combined information from both molecular probes, the rupture of AAAs could reliably be predicted.
BACKGROUND: Molecular magnetic resonance imaging is a promising modality for the characterization of abdominal aortic aneurysms (AAAs). The combination of different molecular imaging biomarkers may improve the assessment of the risk of rupture. This study investigates the feasibility of imaging inflammatory activity and extracellular matrix degradation by concurrent dual-probe molecular magnetic resonance imaging in an AAA mouse model. METHODS: Osmotic minipumps with a continuous infusion of Ang II (angiotensin II; 1000 ng/[kg·min]) to induce AAAs were implanted in apolipoprotein-deficient mice (N=58). Animals were assigned to 2 groups. In group 1 (longitudinal group, n=13), imaging was performed once after 1 week with a clinical dose of a macrophage-specific iron oxide-based probe (ferumoxytol, 4 mgFe/kg, surrogate marker for inflammatory activity) and an elastin-specific gadolinium-based probe (0.2 mmol/kg, surrogate marker for extracellular matrix degradation). Animals were then monitored with death as end point. In group 2 (week-by-week-group), imaging with both probes was performed after 1, 2, 3, and 4 weeks (n=9 per group). Both probes were evaluated in 1 magnetic resonance session. RESULTS: The combined assessment of inflammatory activity and extracellular matrix degradation was the strongest predictor of AAA rupture (sensitivity 100%; specificity 89%; area under the curve, 0.99). Information from each single probe alone resulted in lower predictive accuracy. In vivo measurements for the elastin- and iron oxide-probe were in good agreement with ex vivo histopathology (Prussian blue-stain: R2=0.96, P<0.001; Elastica van Giesson stain: R2=0.79, P<0.001). Contrast-to-noise ratio measurements for the iron oxide and elastin-probe were in good agreement with inductively coupled mass spectroscopy ( R2=0.88, R2=0.75, P<0.001) and laser ablation coupled to inductively coupled plasma-mass spectrometry. CONCLUSIONS: This study demonstrates the potential of the concurrent assessment of inflammatory activity and extracellular matrix degradation by dual-probe molecular magnetic resonance imaging in an AAA mouse model. Based on the combined information from both molecular probes, the rupture of AAAs could reliably be predicted.
Entities:
Keywords:
aneurysm; extracellular matrix; inflammation; macrophage; magnetic resonance imaging
Authors: Avan Kader; Jan O Kaufmann; Dilyana B Mangarova; Jana Moeckel; Julia Brangsch; Lisa C Adams; Jing Zhao; Carolin Reimann; Jessica Saatz; Heike Traub; Rebecca Buchholz; Uwe Karst; Bernd Hamm; Marcus R Makowski Journal: Cancers (Basel) Date: 2022-06-13 Impact factor: 6.575
Authors: Dilyana B Mangarova; Julia Brangsch; Azadeh Mohtashamdolatshahi; Olaf Kosch; Hendrik Paysen; Frank Wiekhorst; Robert Klopfleisch; Rebecca Buchholz; Uwe Karst; Matthias Taupitz; Jörg Schnorr; Bernd Hamm; Marcus R Makowski Journal: Sci Rep Date: 2020-07-24 Impact factor: 4.379
Authors: Federico Collettini; Carolin Reimann; Julia Brangsch; Julius Chapiro; Lynn Jeanette Savic; David C Onthank; Simon P Robinson; Uwe Karst; Rebecca Buchholz; Sarah Keller; Bernd Hamm; S Nahum Goldberg; Marcus R Makowski Journal: Sci Rep Date: 2021-03-25 Impact factor: 4.379
Authors: Julia Brangsch; Carolin Reimann; Jan Ole Kaufmann; Lisa Christine Adams; David Onthank; Christa Thöne-Reineke; Simon Robinson; Marco Wilke; Michael Weller; Rebecca Buchholz; Uwe Karst; Rene Botnar; Bernd Hamm; Marcus Richard Makowski Journal: Mol Imaging Date: 2020 Jan-Dec Impact factor: 4.488
Authors: Sarah Keller; Tabea Borde; Julia Brangsch; Carolin Reimann; Avan Kader; Daniel Schulze; Rebecca Buchholz; Jan O Kaufmann; Uwe Karst; Eyk Schellenberger; Bernd Hamm; Marcus R Makowski Journal: Sci Rep Date: 2020-11-27 Impact factor: 4.379
Authors: Lisa C Adams; Julia Brangsch; Carolin Reimann; Jan O Kaufmann; Rebecca Buchholz; Uwe Karst; Rene M Botnar; Bernd Hamm; Marcus R Makowski Journal: Sci Rep Date: 2020-09-16 Impact factor: 4.379