title: Noninvasive assessment of hypoxia in rabbit advanced atherosclerosis using ¹⁸F-fluoromisonidazole positron emission tomographic imaging.
abstract: BACKGROUND
  Hypoxia is an important microenvironmental factor influencing atherosclerosis progression by inducing foam-cell formation, metabolic adaptation of infiltrated macrophages, and plaque neovascularization. Therefore, imaging plaque hypoxia could serve as a marker of lesions at risk.
  
  
  RESULTS
  Advanced aortic atherosclerosis was induced in 18 rabbits by atherogenic diet and double balloon endothelial denudation. Animals underwent (18)F-fluoromisonidazole positron emission tomographic and (18)F-fluorodeoxyglucose positron emission tomographic imaging after 6 to 8 months (atherosclerosis induction) and 12 to 16 months (progression) of diet initiation. Four rabbits fed standard chow served as controls. Radiotracer uptake of the abdominal aorta was measured using standardized uptake values. After imaging, plaque hypoxia (pimonidazole), macrophages (RAM-11), neovessels (CD31), and hypoxia-inducible factor-1α were assessed by immunohistochemistry.(18)F-fluoromisonidazole uptake increased with time on diet (standardized uptake value mean, 0.10±0.01 in nonatherosclerotic animals versus 0.20±0.03 [P=0.002] at induction and 0.25±0.03 [P<0.001] at progression). Ex vivo positron emission tomographic imaging corroborated the (18)F-fluoromisonidazole uptake by the aorta of atherosclerotic rabbits. (18)F-fluorodeoxyglucose uptake also augmented in atherosclerotic animals, with an standardized uptake value mean of 0.43±0.02 at induction versus 0.35±0.02 in nonatherosclerotic animals (P=0.031) and no further increase at progression. By immunohistochemistry, hypoxia was mainly located in the macrophage-rich areas within the atheromatous core, whereas the macrophages close to the lumen were hypoxia-negative. Intraplaque neovessels were found predominantly in macrophage-rich hypoxic regions (pimonidazole(+)/hypoxia-inducible factor-1α(+)/RAM-11(+)).
  
  
  CONCLUSIONS
  Plaque hypoxia increases with disease progression and is present in macrophage-rich areas associated with neovascularization. (18)F-fluoromisonidazole positron emission tomographic imaging emerges as a new tool for the detection of atherosclerotic lesions.
authors: Department of Epidemiology, Atherothrombosis and Imaging, Centro Nacional de Investigaciones Cardiovasculares.
authors: Jesus
authors: J
authors: Mateo
authors: David
authors: D
authors: Izquierdo-Garcia
authors: Juan J
authors: JJ
authors: Badimon
authors: Zahi A
authors: ZA
authors: Fayad
authors: Valentin
authors: V
authors: Fuster
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000000981:diagnostic imaging*; D001018:Aortic Diseases / Q000000981:diagnostic imaging*; D050197:Atherosclerosis / Q000150:complications / Q000000981:diagnostic imaging*; D004195:Disease Models, Animal; D018450:Disease Progression; D005462:Fluorine Radioisotopes; D000860:Hypoxia / Q000000981:diagnostic imaging* / Q000209:etiology; D008297:Male; D008920:Misonidazole / Q000031:analogs & derivatives*; D049268:Positron-Emission Tomography / Q000379:methods*; D011817:Rabbits; D011838:Radiation-Sensitizing Agents; D015203:Reproducibility of Results; D012720:Severity of Illness Index
chemical_list: D005462:Fluorine Radioisotopes; D011838:Radiation-Sensitizing Agents; C031843:fluoromisonidazole; D008920:Misonidazole
keywords: atherosclerosis; hypoxia; neovascularization; positron emission tomography