SPECT Imaging in Vascular Disease

Eur J Vasc Endovasc Surg 35, 507e513 (2008) doi:10.1016/j.ejvs.2007.11.016, available online at http://www.sciencedirect.com on

REVIEW

Application of PET/SPECT Imaging in Vascular Disease M.G. van der Vaart,1 R. Meerwaldt,2 R.H.J.A. Slart,3 G.M. van Dam,1 R.A. Tio4 and C.J. Zeebregts1* Departments of 1Surgery, 3Nuclear Medicine and Molecular Imaging, and 4Cardiology, University Medical Center Groningen, Groningen, The Netherlands, and 2Department of Surgery, Isala Clinics, Zwolle, The Netherlands Background. Nuclear medicine imaging differs from other imaging modalities by showing physiological processes instead of anatomical details. Objective. To describe the current applications of positron emission tomography (PET) and single photon emission computed tomography (SPECT) as a diagnostic tool for vascular disease as relevant to vascular surgeons. Methods. A literature search identified articles focussing on vascular disease and PET or SPECT using the Pubmed database. Manual cross referencing was also performed. Results. PET and SPECT may be used to assess plaque vulnerability, biology of aneurysm progression, prosthetic graft infection, and vasculitis. The ability to combine computerized tomography scanning or magnetic resonance imaging with PET or SPECT adds detailed anatomical information and enhances the potential of nuclear medicine imaging in the investigation of vascular disease. Discussion. Considerable further information will be needed to define whether and where PET or SPECT will fit in a clinical strategy. The necessary validation studies represent an exciting challenge for the future but also may require the development of interdisciplinary imaging groups to integrate expertise and optimize nuclear diagnostic potential. Ó 2007 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. Keywords: Positron emission tomography; Single photon emission computed tomography; Atherosclerosis; Vasculitis; Prosthesis infection.

Introduction Conventional imaging of atherosclerosis is based on detecting the degree of luminal stenosis, which may not be the best indicator of lesion activity or of clinical risk.1 Similar maximum aneurysm diameter may not be the only factor important in determining clinical outcome.2 For example not all patients with a carotid stenosis greater than 70% develop strokes, nor do all aortic aneurysm > 6 cm rupture. Alternative imaging strategies, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT), may improve prediction of clinical

*Corresponding author. C. J. Zeebregts, MD, PhD, Department of Surgery, Division of Vascular Surgery, University Medical Center Groningen, P.O. Box 30 001, 9700 RB Groningen, The Netherlands. E-mail address: [email protected]

events. In this manuscript the current applications of PET and SPECT, as a diagnostic tool for both central and peripheral vascular disease are discussed. Basic Principles Nuclear imaging differs from many other imaging modalities by focusing on physiologic processes instead of anatomy. Images obtained by nuclear medicine can be combined with those from other imaging modalities, such as computer tomography (CT), to highlight locations of interest. PET involves imaging based on the detection of gamma radiation from the emission of positrons. Radionuclides used in PET scanning are typically isotopes with short half lives such as 11C (w20 min), 13N (~10 min), 15O (w2 min), and 18F (w110 min). Due to their short half lives, most radionuclides must be produced in a cyclotron

1078–5884/000507 + 07 $34.00/0 Ó 2007 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

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which is usually located in the proximity of the scanner in order to prevent extended delivery-times to the PET scanner. These radionuclides are incorporated into compounds normally used by the human body such as glucose, fatty acids, or antibodies and then injected as radiopharmaceuticals to visualize active processes. The acquired picture depends on several important basic factors such as the resolution of the detecting system e.g. the PET camera, the radiopharmaceutical used and the degree of uptake in the target organ or tissue.3 PET scanners have a spatial resolution of 2 mm at present and are mostly combined with an incorporated CT system. SPECT is similar to PET in detecting gamma radiation. There are some differences between SPECT and PET. The spatial resolution of SPECT is about 10 mm, i.e. lower than PET, but SPECT can also be equipped as a hybrid SPECT-CT system. Radioactive substances typically used in SPECT include 99mTechnetium, 123 Iodine, and 111mIndium. In general these radioactive substances have longer decay times than those used in PET and can also be labeled with pharmaceuticals. Other differences include the higher costs of the PET camera, the double headed camera in SPECT whereas PET is based on a ring system, the absolute quantification in PET compared to semi-quantification in SPECT, and the need of a cyclotron for most PET radiopharmaceuticals. Most common uses of PET and SPECT to date have been in the field of oncology (tumor detection, staging, and monitoring treatment effect), assessment of cardiac viability and left ventricular function.4,5 Interestingly, when performing whole body PET for tumor imaging, increased uptake was observed in large arteries.6 It was hypothesized that this increased uptake in arteries was related to the severity of atherosclerosis.

there is a delicate balance between degradation and the stabilization response mediated by smooth muscle cells.11e14 If PET and SPECT are to gain a position as a clinical instrument in search of the vulnerable plaque, specific tracers are needed to image components which play an important role in the formation and progression of vulnerable plaques. Table 1 lists several tracers which can be used to image plaque vulnerability. The most widely available tracer for analysis of plaque inflammation is FDG. FDG is a glucose analogue that is taken up by glucose-using cells and phosphorylated by hexokinase. However, no further intracellular metabolization takes place, which results in an accumulation of the tracer intracellularly.15 FDG is known to accumulate in inflammatory lesions, a key feature of atherosclerosis. Other radiolabeled tracers are available for imaging features of the vulnerable plaque, such as oxidized LDL accumulation and apoptosis (Table 1).16e22 Detection of plaque vulnerability The indication for intervention in patients with internal carotid artery stenosis is currently determined by the duplex ultrasound grade of the stenosis in most centers. However, plaque vulnerability and risk of rupture is usually a consequence of inflammatory reactions within the plaque. Imaging of plaque inflammation by PET/SPECT may add important diagnostic information for both tailoring and monitoring treatment. Davies et al. showed in their pilot study that carotid plaques can be imaged with FDG-PET in patients with carotid stenosis. Interestingly, symptomatic plaques accumulate more FDG compared to asymptomatic lesions.23 The estimated net FDG accumulation rate (plaque/integral plasma) in symptomatic lesions

Imaging of Plaque Vulnerability Plaque formation and vulnerability Angiography is still regarded as the gold standard for evaluation of progression in atherosclerotic disease.7 However, angiography does not always identify atherosclerotic plaques at risk of cap rupture.7 Atherosclerosis is a multifactor disease combining metabolic burden, e.g. accumulation of oxidized low-density lipoproteins (LDL), with inflammatory reactions such as activation of chemotactic proteins and monocytes recruitment.8e11 Apoptosis of macrophages and production of proteinases may lead to plaque destabilisation and rupture. However, not every lesion advances into a vulnerable plaque as Eur J Vasc Endovasc Surg Vol 35, May 2008

Table 1. Targets for nuclear medicine imaging and the tracers that can be used within the field of vascular disease Target of imaging

Tracer

Inflammation Macrophages

18

Oxidized LDL Matrix metalloproteinase Angiogenesis Apoptosis

FDG F-choline Tc-MCP-1 125 I-MCP-1 99m Tc-oxLDL 125 I-MDA2 123 I-HO-CGS 27023A 123 I-VEGF165 99m Tc-annexin-V 18

99m

FDG ¼ fluorodeoxyglucose, MCP-1 ¼ monocyte chemotactic protein-1, Tc ¼ technetium, I ¼ Iodine, MDA ¼ malondialdehyde, 123 I-HO-CGS 27023A ¼ MMP inhibitor, VEGF ¼ vascular endothelial growth factor.

PET/SPECT Imaging in Vascular Disease

was 27% higher than in contralateral asymptomatic lesions. There was no measurable FDG uptake in normal carotid arteries. Autoradiography of excised plaques confirmed accumulation of deoxyglucose in macrophage-rich areas of the plaque. In an effort to link FDG PET to vulnerable plaques, Arauz et al. performed PET analyses on patients with recent symptomatic carotid lesions.24 They found strong FDG uptake in 11 out of 13 symptomatic patients. Despite treatment, 6 patients suffered from a stroke, death or re-stenosis, during follow-up. All of these 6 patients had strong FDG uptake. However, the small group size and diverse treatment options make it impossible to draw any real conclusion. SPECT analysis of radiolabeled cytokines may further image plaque inflammation. For instance, 99m Tc-IL2 targets high-affinity interleukin 2 receptors, and, thereby, could be an useful monitor of carotid plaques inflammation and vulnerability.20,25 The accumulation of 99mTc-IL2 in carotid plaques is correlated with the amount of IL2Rþ cells and is influenced by lipid-lowering treatment with statins. Metabolic stress is another important aspect of plaque formation and vulnerability. Radiolabeled (oxidized) LDL may be used to study in vivo distribution and metabolism of native LDL. Lees et al. found focal accumulation in vivo of 99mtechnetium (Tc) labelled LDL in four out of 17 patients with atherosclerotic disease using a gamma scintillation camera.26 The carotid specimens that had shown accumulation of 99mtechnetium on SPECT analyses, were found to have high levels of foam cells and macrophages and poorly organized intramural blood consistent with plaque haemorrhage. In contrast, lesions which weren’t visible on SPECT analysis were found to be mature and fibrocalcified plaques on histological examination. Iuliano et al. developed a technique to oxidize autologous LDL and analyzed its biodistribution in relation to carotid stenosis.27 The authors found that the uptake of 99mTc-oxLDL by carotid plaques was significantly higher compared to that in normal carotid arteries ( p < 0.02). Uptake of 99mTc-oxLDL above that measured in normal carotid arteries was observed in 10 out of 11 patients with symptomatic carotid stenosis (91%, confidence interval 58.7 to 99.8). There was no correlation between the degree of stenosis and degree of 99mTc-oxLDL uptake in the plaque lesion.27,28 Clinical data on the imaging of plaque vulnerability at other sites is limited. Most studies describe the use radiolabeled tracers in animal experiments comparing imaging results with histopathological analyses of macrophages burden and apoptosis.17,19,29,30

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Imaging of Aneurysms The risk of rupture of aneurysms such as abdominal aortic aneurysm (AAA) increases with the diameter of the aneurysm. However, rupture also occurs in small AAAs, and it would therefore be useful to define predictors of accelerated growth or increased rupture risk. The risk of rupture may be related to the level of MMP activation in the smooth muscle cells of the aneurysm wall. Sakalihasan et al. showed a possible association between increased FDG uptake and AAA expansion and rupture.31e33 In their prospective study 10 out of 26 patients with an AAA had increased FDG uptake. Ninety percent of them required urgent surgery within 30 days for rupture or symptomatic complications. In those without increased FDG uptake, none needed urgent surgery. Recently, thrombus in the AAA was found to be biologically active and involved in permanent platelet activation and apoptosis.34,35 Annexin V specifically binds with high affinity to PS, which is exposed to the surface of apoptotic cells and activated platelets. 99m Tc-annexin-V has previously been used for in vivo scintigraphy of apoptotic cells both in animals and humans.29 Sarda-Mantel et al. showed that 99mTcannexin-V activity was located in the thrombus area where activated platelets and leukocytes accumulated.36,37 Similar patterns were also found in all of the human AAA thrombi harvested during surgery. 99m Tc-annexin-V imaging may assess mural thrombus renewal activity.

Imaging of Graft Infection Vascular prosthesis infection is a serious complication with high morbidity and mortality.38 Vascular graft infections are usually detected by CT or MRI, but there is growing interest in PET as a modality for imaging infection. Increased FDG uptake may be seen in areas of activated granulocytes. Fig. 1 shows the fused PET/CT images in a patient with an infected aortoiliac prosthetic graft. Previous studies demonstrated the value of PET in analyzing suspected aortic graft infections.39 FDG-PET was performed in a study of 33 consecutive patients with a suspected arterial prosthetic graft infection. Based upon surgical, microbiological, and clinical follow-up, 11 patients were considered to have a graft infection. PET had a sensitivity of 91% and specificity of 95%, which was higher than CT findings. Importantly, previous studies have also shown false-positive accumulation of FDG during vascular prosthetic graft replacement. This falsepositive accumulation may be related to the reaction Eur J Vasc Endovasc Surg Vol 35, May 2008

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Fig. 1. Fifty-eight-year-old male patient, who suffered Q-fever (Coxiella burnetii) causing an infected aorto-iliac Dacron prosthesis, which had been inserted seven months before during exclusion of an inflammatory abdominal aortic aneurysm (A. CT image, B. PET image, and C. Fused PET-CT).

of the body to foreign material or postoperative inflammation. Many others have reported case series of PET scanning in patients with graft infection and aorta-enteric fistula.38,40,41 Interestingly, mild increased FDG uptake in cardiovascular prosthesis years after surgery is not always related to infection. Duet et al. recently presented a case with a high level of FDG uptake over a prosthesis a few days before the occurrence of an acute graftrelated thrombosis.42 The patient had undergone vascular prosthetic surgery 5.5 years previously. In their opinion the intense uptake could no longer be related to the postoperative development of a pseudointima, a physiologic process due to inflammation and cell colonization occurring within the graft. In their report, infection was ruled out by bacteriologic graft analysis. Therefore, they suggested that, some time after bypass surgery, FDG uptake over a vascular prosthesis seen on PET/CT could also suggest lesions at risk of future acute cardiovascular events.

et al. showed in a study of 69 patients with vasculitis (giant cell arteritis, polymyalgia rheumatica) and 44 controls (temporal artery biopsies) an increased uptake of FDG in patients with vasculitis.48 Thoracic vascular uptake of FDG had a positive predictive value of 93% and a negative predictive value of 80%. FDG PET has the advantage of identifying all sites of inflammation within one scan. Several case reports

Imaging of Vasculitis and Aortitis Vasculitis and mycotic aneurysms are examples of other vascular challenges where PET may aid in the assessment. In 1999, the first use of PET in vasculitis was reported.43 Fig. 2 shows the PET/CT fused images of a patient with giant-cell arteritis. The increased FDG uptake analyzed by PET, seems to be a specific finding in vasculitis such as giant cell arteritis.44e47 The temporal arteries cannot be visualized due to their small diameters and superficial localization. Blockmans Eur J Vasc Endovasc Surg Vol 35, May 2008

Fig. 2. PET/CT fused images of a 57-year-old male patient with giant-cell arteritis, showing vasculitis of the greater vessels, with extensive 18F-FDG at the level of the carotids, subclavian arteries, thoracic and abdominal aorta, and in both femoral arteries (from left to right: transverse, sagittal and coronal view, respectively).

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and small case series have been published that confirm the initial findings of FDG uptake in vasculitis.49e51 However, it is important to realize that other vascular diseases such as arteriosclerosis might produce falsepositive results. Yun et al. analyzed the presence of FDG uptake in 137 patients who underwent PET predominantly for malignant diseases.6 More than 50% showed increased uptake in one or more large vessels. On the other hand, increased uptake in vessels not prone to atherosclerosis, such as the subclavian artery, increases the specificity for true vasculitis. De Leeuw et al. showed the therapeutic effect of corticosteroids on vasculitis. Vasculitis activity disappeared on FDG PET after steroid treatment.52 Mycotic aneurysms are a rare entity, but may pose a challenging problem in diagnosing.53 Survival is markedly increased by prompt diagnosis and surgical treatment. In early reports, most infected aneurysms were related to valvular infection, however nowadays most mycotic aneurysms are aortitis related.54 Bacterial seeding of the aortic wall can occur by hematogenous spread, lymphatic spread or direct extension from an adjacent infected focus.55e57 The intimal lining of the aorta is generally highly resistant to infection. However, even normal aortic intima can be subject to bacterial invasion. Secondary degeneration of the arterial wall may result in aneurysm formation and rupture. Rupture may occur as early as one week after the onset of aortitis.57 In the absence of the classical signs (fever, pulsatile mass, positive blood culture), the diagnosis of mycotic aneurysm is difficult. A CT scan might provide an early diagnosis, showing irregular peripheral enhancement of the aneurysm wall.58 Davison recently presented a case where the diagnosis was confirmed by different imaging modalities, including FDG PET.59 Combined PET/CT demonstrated increased FDG metabolism within the wall of the aneurysm. Others have shown comparable results for FDG PET and aneurysms, and PET/CT may be a new addition to the work-up for suspected mycotic aneurysm due to aortitis.60

Conclusion The ability to non-invasively image physiological and biochemical processes opens clinically relevant diagnostic applications and fascinating possibilities for basic scientific research. Imaging of plaque vulnerability, graft infection and vasculitis by nuclear medicine techniques may add in diagnosis and management. Further information will be needed to define whether and where PET or SPECT will fit in a clinical strategy. Especially, the predictive value

for vascular events has to be substantiated. The increasing infrastructure of hybrid PET-CT or SPECTCT scanners and new tracers has set the stage for more widespread use. Optimal radioactive tracers are needed, with high sensitivity, specificity and high background to target ratio. Importantly, cost, product availability, reimbursement, and patient referral will be important factors defining future use of nuclear imaging in vascular disease. The necessary validation studies represent an exciting challenge for the future but also may require the development of interdisciplinary imaging groups to integrate expertise and optimize nuclear diagnostic potential.

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58 EWART JM, BURKE ML, BUNT TJ. Spontaneous abdominal aortic infections. Essentials of diagnosis and management. Am Surg 1983;49(1):37e50. 59 DAVISON JM, MONTILLA-SOLER JL, BROUSSARD E, WILSON R, CAP A, ALLEN T. F-18 FDG PET-CT imaging of a mycotic aneurysm. Clin Nucl Med 2005;30(7):483e487. 60 TAKAHASHI M, MOMOSE T, KAMEYAMA M, OHTOMO K. Abnormal accumulation of [18F]Fluorodeoxyglucose in the aortic wall related to inflammatory changes: three case reports. Ann Nucl Med 2006;20(5):361e364. Accepted 27 November 2007 Available online 3 January 2008

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