Department of Epidemiology, Atherothrombosis and Imaging, Centro Nacional de Investigaciones Cardiovasculares.
Circ Cardiovasc Imaging. 2014 Mar;7(2):312-20. doi: 10.1161/CIRCIMAGING.113.001084. Epub 2014 Feb 7.
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.
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(+)).
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.
缺氧是影响动脉粥样硬化进展的重要微环境因素，可诱导泡沫细胞形成、浸润巨噬细胞的代谢适应和斑块新生血管形成。因此，成像斑块缺氧可以作为病变风险的标志物。
通过致动脉粥样硬化饮食和双球囊内皮剥脱术在 18 只兔子中诱导高级主动脉粥样硬化。动物在饮食开始后 6 至 8 个月（动脉粥样硬化诱导）和 12 至 16 个月（进展）进行（18）F-氟米索硝唑正电子发射断层扫描和（18）F-氟脱氧葡萄糖正电子发射断层扫描成像。4 只喂饲标准食物的兔子作为对照。使用标准化摄取值测量腹主动脉的放射性示踪剂摄取。成像后，通过免疫组织化学评估斑块缺氧（咪硝唑）、巨噬细胞（RAM-11）、新生血管（CD31）和缺氧诱导因子-1α。（18）F-氟米索硝唑摄取随饮食时间增加（非动脉粥样硬化动物的标准化摄取值平均值为 0.10±0.01，在诱导时为 0.20±0.03[P=0.002]，在进展时为 0.25±0.03[P<0.001]）。离体正电子发射断层扫描成像证实了动脉粥样硬化兔子主动脉的（18）F-氟米索硝唑摄取。（18）F-氟脱氧葡萄糖摄取也在动脉粥样硬化动物中增加，诱导时的标准化摄取值平均值为 0.43±0.02，而非动脉粥样硬化动物为 0.35±0.02（P=0.031），进展时无进一步增加。通过免疫组织化学，缺氧主要位于动脉粥样硬化核心内富含巨噬细胞的区域，而靠近管腔的巨噬细胞则无缺氧。斑块内新生血管主要存在于富含巨噬细胞的缺氧区域（咪硝唑（+）/缺氧诱导因子-1α（+）/RAM-11（+））。
斑块缺氧随疾病进展而增加，存在于与新生血管形成相关的富含巨噬细胞的区域。（18）F-氟米索硝唑正电子发射断层扫描成像成为检测动脉粥样硬化病变的新工具。
