Non-invasive imaging of atherosclerotic plaque macrophage in a rabbit model with F-18 FDG PET: a histopathological correlation

Zhuangyu Zhang, Josef Machac, Gerard Helft, Stephen G Worthley, Cheuk Tang, Azfar G Zaman, Oswaldo J Rodriguez, Monte S Buchsbaum, Valentin Fuster, Juan J Badimon, Zhuangyu Zhang, Josef Machac, Gerard Helft, Stephen G Worthley, Cheuk Tang, Azfar G Zaman, Oswaldo J Rodriguez, Monte S Buchsbaum, Valentin Fuster, Juan J Badimon

Abstract

Background: Coronary atherosclerosis and its thrombotic complications are the major cause of mortality and morbidity throughout the industrialized world. Thrombosis on disrupted atherosclerotic plaques plays a key role in the onset of acute coronary syndromes. Macrophages density is one of the most critical compositions of plaque in both plaque vulnerability and thrombogenicity upon rupture. It has been shown that macrophages have a high uptake of 18F-FDG (FDG). We studied the correlation of FDG uptake with histopathological macrophage accumulation in atherosclerotic plaques in a rabbit model.

Methods: Atherosclerosis was induced in rabbits (n = 6) by a combination of atherogenic diet and balloon denudation of the aorta. PET imaging was performed at baseline and 2 months after atherogenic diet and coregistered with magnetic resonance (MR) imaging. Normal (n = 3) rabbits served as controls. FDG uptake by the thoracic aorta was expressed as concentration (muCi/ml) and the ratio of aortic uptake-to-blood radioactivity. FDG uptake and RAM-11 antibody positive areas were analyzed in descending aorta.

Results: Atherosclerotic aortas showed significantly higher uptake of FDG than normal aortas. The correlation of aortic FDG uptake with macrophage areas assessed by histopathology was statistically significant although it was not high (r = 0.48, p < 0.0001). When uptake was expressed as the ratio of aortic uptake-to-blood activity, it correlated better (r = 0.80, p < 0.0001) with the macrophage areas, due to the correction for residual blood FDG activity.

Conclusion: PET FDG activity correlated with macrophage content within aortic atherosclerosis. This imaging approach might serve as a useful non-invasive imaging technique and potentially permit monitoring of relative changes in inflammation within the atherosclerotic lesion.

Figures

Figure 1
Figure 1
Atherosclerotic Rabbit Aorta: RAM-11 staining.
Figure 2
Figure 2
Coregistration of MRI and PET images. Coregistration of MRI and FDG PET images of a control (top) and an atherosclerotic rabbit (bottom). Each row shows the fused dataset progressing from an anatomical MRI to a sole functional FDG PET image of the same animal in the same location. ROIs of the aorta (indicated with a blue circle and arrow) were identified on the MRI. The software automatically extracted the PET values from the same location in the PET image.
Figure 3
Figure 3
In vivo PET images. In vivo PET sagittal (top) and coronal (bottom) images showing the uptake of FDG in the thoracic aorta in a control rabbit (A), in a rabbit with mild atherosclerosis (B).
Figure 4
Figure 4
The correlation of macrophage areas and FDG uptake. Linear regression analyses showing the correlation of macrophage areas and FDG uptake in the segments (n = 72) of descending thoracic aorta of the rabbits, expressed as concentration (μCi/ml) (A) (r = 0.48, p < 0.0001) and ratio of aortic uptake-to-blood activity (B) (r = 0.80, p < 0.0001).

References

    1. Davies MJ, Thomas AC. Plaque fissuring-the cause of acute myocardial infarction, sudden ischemic death, and crescendo angina. Br Heart J. 1985;53:363–373.
    1. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (1) N Eng J Med. 1992;326:242–250. 310-8.
    1. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995;92:657–671.
    1. Celermajer DS. Noninvasive detection of atherosclerosis. N Engl J Med. 1998;39:2014–5. doi: 10.1056/NEJM199812313392709.
    1. Robbie L, Libby P. Inflammation and atherothrombosis. Ann N Y Acad Sci. 2001;947:167–179.
    1. Libby P. Inflammation in atherosclerosis. Nature. 2002;420:868–874. doi: 10.1038/nature01323.
    1. van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation. 1994;89:36–44.
    1. Corti R, Fuster V, Badimon JJ. Pathogenetic concepts of acute coronary syndromes. J Am Coll Cardiol. 2003;41:7S–14S. doi: 10.1016/S0735-1097(02)02833-4.
    1. Toschi V, Gallo R, Lettino M, Fallon JT, Gertz SD, Fernandez-Ortiz A, Chesebro JH, Badimon L, Nemerson Y, Fuster V, Badimon JJ. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation. 1997;95:594–9.
    1. Kubota R, Yamada S, Kubota K, Ishiwata K, Tamahashi N, Ido T. Intratumoral distribution of fluorine-18-fluorodeoxyglucose in vivo: high accumulation in macrophages and granulation tissues studied by microautoradiography. J Nucl Med. 1992;33:1972–1980.
    1. Viles-Gonzalez JF, Poon M, Sanz J, Rius T, Nikolaou K, Fayad ZA, Fuster V, Badimon JJ. In vivo 16-slice, multidetector-row computed tomography for the assessment of experimental atherosclerosis: comparison with magnetic resonance imaging and histopathology. Circulation. 2004;14:1467–72. doi: 10.1161/01.CIR.0000141732.28175.2A.
    1. Woods R, Cherry S, Mazziotta J. Rapid automated algorithm for aligning and reslicing PET images. J Comp Assist Tomog. 1992;16:620–633.
    1. Richardson PD, Davies MJ, Born GV. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet. 1989;2:94l–4.
    1. Vallabhajosula S, Fuster V. Atherosclerosis: imaging techniques and the evolving role of nuclear medicine. J Nucl Med. 1997;38:1788–1796.
    1. Stratton JR, Dewhurst TA, Kasina S, Reno JM, Cerqueira MD, Baskin DG, Tait JF. Selective uptake of radiolabeled annexin V on acute porcine left atrial thrombi. Circulation. 1995;92:3113–3121.
    1. Bates SM, Lister-James J, Julian JA, Taillefer R, Moyer BR, Ginsberg JS. Imaging characteristics of a novel technetium Tc99m-labeled platelet glycoprotein IIb/IIIa receptor antagonist in patients with acute deep vein thrombosis or a history of deep vein thrombosis. Arch Intern Med. 2003;163:452–6. doi: 10.1001/archinte.163.4.452.
    1. Renner ED, Plagemann PG, Bernlohr RW. Permeatin of glucose by simple and facilitated diffusion by Novikoff rat hepatoma cells in suspension culture and its relationship to glucose metabolism. J Biol Chem. 1972;247:5765–5776.
    1. Weber G. Enzymology of cancer cells (second of two parts) N Engl J Med. 1977;296:541–551.
    1. Lederman RJ, Raylman RR, Fisher SJ, Kison PV, San H, Nabel EG, Wahl RL. Detection of atherosclerosis using a novel positron-sensitive probe and 18-fluorodeoxy-glucose (FDG) Nucl Med Commun. 2001;22:747–753. doi: 10.1097/00006231-200107000-00004.
    1. Ogawa M, Ishino S, Mukai T, Asano D, Teramoto N, Watabe H, Kudomi N, Shiomi M, Magata Y, Iida H, Saji H. 18F-FDG Accumulation in Atherosclerotic Plaques: Immunohistochemical and PET Imaging Study. J Nucl Med. 2004;45:1245–1250.
    1. Rudd JH, Warburton EA, Fryer TD, Jones HA, Clark JC, Antoun N, Johnstrom P, Davenport AP, Kirkpatrick PJ, Arch BN, Pickard JD, Weissberg PL. Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography. Circulation. 2002;105:2708–2711. doi: 10.1161/01.CIR.0000020548.60110.76.

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