Wengen Chen, MD, PhD

A noninvasive technique to detect vulnerable atherosclerotic plaque is critically needed. Formation of atherosclerotic plaque is a dynamic inflammatory process that involves interactions between atherogenic lipoproteins and macrophages. As vulnerable plaques are usually numerous, extending beyond the culprit plaque and involving multiple vessels, targeting a single plaque underestimates the complexity and extent of disease. Thus, an ideal imaging modality should be able to identify the vulnerable arterial bed and, therefore, the vulnerable patient, to prevent the serious complications of atherosclerosis.

Various methods, including ultrasonography, multislice CT, and MRI, have been employed for this purpose. Most of these techniques have inherent limitations, however, and some are limited in their ability to detect inflammatory plaques.1-3 FDG-PET/CT, a combined functional and structural whole-body imaging modality, holds the most potential for this purpose.

FDG uptake in large arteries detected by PET was noted as early as 1987 in patients with vasculitis.4 Work from investigators at the University of Pennsylvania first linked FDG uptake in the great vessels to atherosclerosis.5 In a retrospective study, we assessed FDG uptake in the abdominal aorta, iliac, and proximal femoral arteries in 156 patients who had undergone PET imaging for other purposes. Vascular FDG uptake was present in 50% of these patients.

Further work demonstrated that age and hypercholesterolemia were correlated consistently with FDG uptake in these three arteries.6 Others confirmed these findings, with one study also noting hypertension as a risk factor.7,8 Recent work further demonstrated that increased FDG uptake in carotid atherosclerosis was related to serum matrix metalloproteinase-1 level.9 High tissue matrix metalloproteinase activity has been associated with advanced atherosclerosis and plaque rupture.

FDG uptake is usually identified in different segments of large arteries, including the ascending aorta (Figure 1A), aortic arch (Figure 1B), descending thoracic aorta, and abdominal aorta (Figure 2), as well as the iliac (Figure 2), femoral, and carotid arteries. In severe atherosclerosis, FDG uptake can be visualized in most of the arterial system.

Dunphy et al reported that FDG uptake was more common in the aorta, compared with coronary and carotid arteries, and most prevalent in the proximal aortic segments.10 Increased FDG uptake was more common in the thoracic aorta than in the abdominal aorta.7,10

Tatsumi et al, in a 2003 study, described FDG uptake in 59% of thoracic aortas, but large arteries below the diaphragm were not assessed in this study.8 In our study, published in 2001, FDG uptake was noted in the abdominal aorta in 16% of patients and was more diffuse than in other segments.5

FDG uptake reflects active plaque inflammation, while calcification detected by CT usually indicates an advanced stage of the disease. Thus, it is not surprising to note disparities between FDG uptake on PET images and the degree of calcification in the arteries on CT images. Congruent FDG uptake and calcification were observed in only 2% to 14% of the sites in different studies.7,8,10 Researchers following 50 patients found changes in vascular wall abnormalities in 48% of PET-positive sites, compared with only 4% of PET-negative sites.11

Accumulated data from human studies suggest that FDG-PET imaging can potentially measure the inflammatory component in atherosclerotic plaque. In a pilot study on eight patients with carotid stenosis, Rudd et al used autoradiography to show that tritiated deoxyglucose accumulated in plaque macrophages when incubated with fresh carotid endarterectomy specimens in vitro.12 FDG uptake was higher in symptomatic lesions than in the contralateral asymptomatic lesions. Recent work extended this finding by showing a significant correlation in 17 patients between FDG-PET signal from the carotid plaques and macrophage staining from the corresponding histological sections of specimens following endarterectomy.13

One study evaluated 12 patients with recent transient ischemic attack and severe carotid artery stenosis in the ipsilateral carotid artery who were awaiting endarterectomy of the most severely stenotic lesion. Seven of the 12 patients had high FDG uptake in the lesion targeted for endarterectomy, and three of the other five patients had FDG uptake in nonstenotic lesions located in a vascular territory that was considered reasonably appropriate for the presenting symptoms.14 These findings suggest that FDG-PET may assess the degree of inflammation in the stenotic and nonstenotic culprit lesions and could potentially be used to identify lesions that are responsible for embolic events.

A prospective clinical study suggests that FDG-PET may be able to monitor drug-induced changes in plaque inflammation. The study included 43 subjects in whom FDG-PET imaging for voluntary cancer screening revealed incidental FDG uptake in the thoracic aorta and/or carotid arteries. Patients were randomly assigned to either strict dietary management or administration of simvastatin in addition to dietary management. After three months, FDG-PET showed significant decrease of FDG uptake in the atherosclerotic plaques in the simvastatin group, whereas no change occurred in the dietary management alone group.15 One effect of statins is to promote plaque stability by decreasing plaque macrophage content and activity.16 Findings suggest that FDG-PET can identify the decrease of plaque inflammation much earlier than the anatomic changes detected by MRI, which are reportedly detected after 12 months.17

One of the major advantages of FDG-PET is its ability to quantify the metabolic activity of the intended physiological or disease process. Atherosclerosis is a systemic inflammatory disease that involves multiple vessels, and it is important and essential to quantify the degree of inflammation in a plaque regionally and also on a larger scale in the entire body. By quantifying plaque inflammation, it may be possible to predict the risk of plaque rupture and to monitor the effects of therapy.

The standardized uptake value (SUV), which is commonly employed for assessing disease activity with PET imaging, can provide quantitative information about the severity of the inflammatory process in the arterial wall even before it is clinically symptomatic or visualized with anatomic imaging modalities. Tatsumi et al8 used a grading score to semiquantitatively evaluate vascular FDG uptake:

grade 1: slightly higher than blood pool and mediastinal uptake;

grade 2: clearly visible and greater than grade 1 uptake but lower than liver uptake; and

grade 3: equal to or greater than liver uptake.

Bural et al from our group developed a novel quantitative method to measure the extent of atherosclerosis in the aorta by combining the SUV with CT volumetric data of the aortic wall.18 The end product is called the "atherosclerotic burden" or "atheroburden" (AB) value. This approach provides the means to integrate structural and functional data into a single quantitative parameter. Aortic wall volumes, mean SUVs, and ABs in each segment were compared in three age groups spanning over six decades in 18 patients. Significant differences in the age groups were found for both segmental ABs as well as for the entire aorta. Interestingly, the age-related progression in mean SUV and volume appeared linear, whereas the progression of AB relative to age appeared exponential, suggesting a major escalation in the overall atherosclerotic process with aging that can be determined only by this approach.

Based on the data that exist in the literature, FDG-PET imaging combined with CT holds great promise for assessing atherosclerosis in large arteries. The high sensitivity and optimal quantification would allow for early diagnosis and accurate evaluation of response to treatment of this serious and common disease.19

Dr. Chen is a research trainee in molecular imaging at the Hospital of the University of Pennsylvania, Dr. Bural is a resident in nuclear medicine at the Joint Training Program at Harvard in Boston, and Dr. Torigian is an assistant professor of radiology and Dr. Alavi is a professor of radiology and neurology and director of research education, both at the Hospital of the University of Pennsylvania.

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Wu YW, Kao HL, Chen MF, et al. Characterization of plaques using 18F-FDG PET/CT in patients with carotid atherosclerosis and correlation with matrix metalloproteinase-1. J Nucl Med 2007;48(2):227-233.

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Ben-Haim S, Kupzov E, Tamir A, et al. Changing patterns of abnormal vascular wall F-18 fluorodeoxyglucose uptake on follow-up PET/CT studies. J Nucl Cardiol 2006;13(6):791-800.

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Tawakol A, Migrino RQ, Bashian GG, et al. In vivo 18F-fluorodeoxyglucose positron emission tomography imaging provides a noninvasive measure of carotid plaque inflammation in patients. J Am Coll Cardiol 2006;48(9):1818-1824.

Davies JR, Rudd JH, Fryer TD, et al. Identification of culprit lesions after transient ischemic attack by combined 18F fluorodeoxyglucose positron-emission tomography and high-resolution magnetic resonance imaging. Stroke 2005;36(12):2642-2647.

Tahara N, Kai H, Ishibashi M, et al. Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography. J Am Coll Cardiol 2006;48(9):1825-1831.

Crisby M, Nordin-Fredriksson G, Shah PK, et al. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation 2001;103(7):926-933.

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Bural GG, Torigian DA, Chamroonrat W, et al. Quantitative assessment of the atherosclerotic burden of the aorta by combined FDG-PET and CT image analysis: a new concept. Nucl Med Biol 2006;33(8):1037-1043.

Bural GG, Torigian DA, Chamroonrat W, et al. FDG-PET is an effective imaging modality to detect and quantify age-related atherosclerosis in large arteries. Eur J Nucl Med Mol Imaging In press.

Wengen Chen, MD, PhD

Articles

FDG-PET imaging tackles large arteries with atherosclerosis