Combined PET/DCE-MRI in a Rabbit Model of Atherosclerosis: Integrated Quantification of Plaque Inflammation, Permeability, and Burden During Treatment With a Leukotriene A4 Hydrolase Inhibitor

JACC Cardiovasc Imaging. 2018 Feb;11(2 Pt 2):291-301. doi: 10.1016/j.jcmg.2017.11.030.

Abstract

Objectives: The authors sought to develop combined positron emission tomography (PET) dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) to quantify plaque inflammation, permeability, and burden to evaluate the efficacy of a leukotriene A4 hydrolase (LTA4H) inhibitor in a rabbit model of atherosclerosis.

Background: Multimodality PET/MRI allows combining the quantification of atherosclerotic plaque inflammation, neovascularization, permeability, and burden by combined 18F-fluorodeoxyglucose (18F-FDG) PET, DCE-MRI, and morphological MRI. The authors describe a novel, integrated PET-DCE/MRI protocol to noninvasively quantify these parameters in aortic plaques of a rabbit model of atherosclerosis. As proof-of-concept, the authors apply this protocol to assess the efficacy of the novel LTA4H inhibitor BI691751.

Methods: New Zealand White male rabbits (N = 49) were imaged with integrated PET-DCE/MRI after atherosclerosis induction and 1 and 3 months after randomization into 3 groups: 1) placebo; 2) high-dose BI691751; and 3) low-dose BI691751. All animals were euthanized at the end of the study.

Results: Among the several metrics that were quantified, only maximum standardized uptake value and target-to-background ratio by 18F-FDG PET showed a modest, but significant, reduction in plaque inflammation in rabbits treated with low-dose BI691751 (p = 0.03), whereas no difference was detected in the high-fat diet and in the high-dose BI691751 groups. No differences in vessel wall area by MRI and area under the curve by DCE-MRI were detected in any of the groups. No differences in neovessel and macrophage density were found at the end of study among groups.

Conclusions: The authors present a comprehensive, integrated 18F-FDG PET and DCE-MRI imaging protocol to noninvasively quantify plaque inflammation, neovasculature, permeability, and burden in a rabbit model of atherosclerosis on a simultaneous PET/MRI scanner. A modest reduction was found in plaque inflammation by 18F-FDG PET in the group treated with a low dose of the LTA4H inhibitor BI691751.

Keywords: atherosclerosis; burden; imaging; inflammation; permeability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Aortic Diseases / diagnostic imaging
  • Aortic Diseases / drug therapy*
  • Aortic Diseases / enzymology
  • Aortic Diseases / pathology
  • Atherosclerosis / diagnostic imaging
  • Atherosclerosis / drug therapy*
  • Atherosclerosis / enzymology
  • Atherosclerosis / pathology
  • Biomarkers / blood
  • Capillary Permeability / drug effects*
  • Contrast Media / administration & dosage
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology*
  • Epoxide Hydrolases / antagonists & inhibitors*
  • Epoxide Hydrolases / metabolism
  • Fluorodeoxyglucose F18 / administration & dosage
  • Gadolinium DTPA / administration & dosage
  • Inflammation / diagnostic imaging
  • Inflammation / drug therapy*
  • Inflammation / enzymology
  • Inflammation / pathology
  • Magnetic Resonance Imaging*
  • Male
  • Multimodal Imaging
  • Plaque, Atherosclerotic*
  • Positron-Emission Tomography*
  • Predictive Value of Tests
  • Rabbits
  • Radiopharmaceuticals / administration & dosage

Substances

  • Anti-Inflammatory Agents
  • Biomarkers
  • Contrast Media
  • Enzyme Inhibitors
  • Radiopharmaceuticals
  • Fluorodeoxyglucose F18
  • Epoxide Hydrolases
  • Gadolinium DTPA
  • leukotriene A4 hydrolase