Concurrent Molecular Magnetic Resonance Imaging of Inflammatory Activity and Extracellular Matrix Degradation for the Prediction of Aneurysm Rupture

Circ Cardiovasc Imaging. 2019 Mar;12(3):e008707. doi: 10.1161/CIRCIMAGING.118.008707.

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.

Keywords: aneurysm; extracellular matrix; inflammation; macrophage; magnetic resonance imaging.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II
  • Animals
  • Aorta, Abdominal / diagnostic imaging*
  • Aorta, Abdominal / metabolism
  • Aorta, Abdominal / pathology
  • Aortic Aneurysm, Abdominal / chemically induced
  • Aortic Aneurysm, Abdominal / diagnostic imaging
  • Aortic Aneurysm, Abdominal / metabolism
  • Aortic Aneurysm, Abdominal / pathology
  • Aortic Rupture / chemically induced
  • Aortic Rupture / diagnostic imaging
  • Aortic Rupture / metabolism
  • Aortic Rupture / pathology
  • Contrast Media / administration & dosage*
  • Disease Models, Animal
  • Disease Progression
  • Elastin / metabolism*
  • Extracellular Matrix / metabolism*
  • Extracellular Matrix / pathology
  • Feasibility Studies
  • Ferrosoferric Oxide / administration & dosage*
  • Gadolinium DTPA / administration & dosage*
  • Gadolinium DTPA / analogs & derivatives
  • Inflammation Mediators / metabolism*
  • Magnetic Resonance Imaging*
  • Male
  • Mice, Knockout, ApoE
  • Molecular Imaging / methods*
  • Predictive Value of Tests
  • Reproducibility of Results
  • Time Factors

Substances

  • Contrast Media
  • Inflammation Mediators
  • Angiotensin II
  • Elastin
  • Gadolinium DTPA
  • Ferrosoferric Oxide