Enzyme-sensitive magnetic resonance imaging targeting myeloperoxidase identifies active inflammation in experimental
John A Ronald1, John W Chen, Yuanxin Chen
1Robarts Research Institute, London, Ontario, Canada. jronald1@stanfor.edu
Background:
Inflammation undermines the stability of atherosclerotic plaques, rendering them susceptible to acute rupture, the cataclysmic event that underlies clinical expression of this disease. Myeloperoxidase is a central inflammatory enzyme secreted by activated macrophages and is involved in multiple stages of plaque destabilization and patient outcome. We report here that a unique functional in vivo magnetic resonance agent can visualize myeloperoxidase activity in atherosclerotic plaques in a rabbit model.
Methods And Results:
We performed magnetic resonance imaging of the thoracic aorta of New Zealand White rabbits fed a cholesterol (n=14) or normal (n=4) diet up to 2 hours after injection of the myeloperoxidase sensor bis-5HT-DTPA(Gd) [MPO(Gd)], the conventional agent DTPA(Gd), or an MPO(Gd) analog, bis-tyr-DTPA(Gd), as controls. Delayed MPO(Gd) images (2 hours after injection) showed focal areas of increased contrast (>2-fold) in diseased wall but not in normal wall (P=0.84) compared with both DTPA(Gd) (n=11; P<0.001) and bis-tyr-DTPA(Gd) (n=3; P<0.05). Biochemical assays confirmed that diseased wall possessed 3-fold elevated myeloperoxidase activity compared with normal wall (P<0.01). Areas detected by MPO(Gd) imaging colocalized and correlated with myeloperoxidase-rich areas infiltrated by macrophages on histopathological evaluations (r=0.91, P<0.0001). Although macrophages were the main source of myeloperoxidase, not all macrophages secreted myeloperoxidase, which suggests that distinct subpopulations contribute differently to atherogenesis and supports our functional approach.
Conclusions:
The present study represents a unique approach in the detection of inflammation in atherosclerotic plaques by examining macrophage function and the activity of an effector enzyme to noninvasively provide both anatomic and functional information in vivo.
Insights
A novel magnetic resonance agent visualizes myeloperoxidase activity in atherosclerotic plaques. This functional imaging detects inflammation in macrophages, aiding in understanding plaque instability and rupture risk.
Area of Science:
- Cardiovascular Research
- Biomedical Imaging
- Inflammation Biology
Background:
- Inflammation destabilizes atherosclerotic plaques, increasing rupture risk.
- Myeloperoxidase (MPO), an enzyme from activated macrophages, is key in plaque progression.
- Visualizing MPO activity can reveal plaque instability.
Purpose of the Study:
- To develop and validate a novel in vivo magnetic resonance imaging (MRI) agent for detecting MPO activity in atherosclerotic plaques.
- To assess the agent's ability to differentiate between diseased and normal arterial walls.
- To correlate imaging findings with biochemical and histopathological markers of inflammation.
Main Methods:
- Magnetic resonance imaging (MRI) of New Zealand White rabbit aortas using a MPO-specific agent (MPO(Gd)) and control agents.
- Rabbits were fed cholesterol-rich or normal diets to induce atherosclerosis.
- Histopathological and biochemical analyses were performed to quantify MPO activity and macrophage infiltration.
Main Results:
- The MPO-specific agent showed significantly increased contrast (>2-fold) in diseased aortas compared to controls.
- Elevated MPO activity (3-fold) was confirmed biochemically in diseased arterial walls.
- Imaging results strongly correlated with MPO-rich areas and macrophage infiltration (r=0.91, P<0.0001).
Conclusions:
- This study introduces a unique functional MRI approach to detect inflammation in atherosclerotic plaques.
- The agent visualizes macrophage-derived MPO activity, providing both anatomic and functional information in vivo.
- This method offers a novel way to assess plaque stability and inflammatory status noninvasively.
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