Positron Emission Tomography-Computed ... - Semantic Scholar

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MIYAGAWA M et al.

REVIEW

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp

Positron Emission Tomography-Computed Tomography for Imaging of Inflammatory Cardiovascular Diseases – Sarcoidosis, Large-Vessel Arteritis, and Atherosclerosis – Masao Miyagawa, MD, PhD; Rami Yokoyama, MD; Yoshiko Nishiyama, MD; Akiyoshi Ogimoto, MD, PhD; Jitsuo Higaki, MD, PhD; Teruhito Mochizuki, MD, PhD

Inflammation is a determinant of atherosclerotic plaque rupture, the event usually responsible for myocardial infarction and stroke. Possible causes of inflammatory cardiomyopathy include myocarditis, eosinophilic disease, and sarcoidosis. Although conventional imaging techniques can identify the site and severity of luminal stenosis, they do not provide information regarding inflammatory status. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for imaging of inflammatory cardiovascular diseases has been rapidly evolving. Integrated PET/computed tomography (CT) is becoming the method of choice for quantification of arterial inflammation across multiple vessels. Moreover, PET/CT provides information about the activation status of inflammatory cells in the vessel wall, thus allowing early diagnosis and risk stratification of patients. The Japanese health insurance system approved reimbursement for FDG-PET use to detect inflammation sites in cardiac sarcoidosis as of April 2012. This approval has necessitated a more detailed assessment of the clinical value of FDG-PET. Standardized preparation, imaging, and image interpretation protocols should be established to sufficiently suppress physiological FDG uptake in the normal myocardium, and thereby facilitate detection of early-stage cardiac inflammatory lesions with more favorable specificity. This review summarizes the background, clinical utility, state-of-the-art advances, and potential future applications of FDG-PET for imaging inflammatory cardiovascular diseases including cardiac sarcoidosis, largevessel arteritis, and atherosclerosis. (Circ J 2014; 78: 1302 – 1310) Key Words: Atherosclerosis; Cardiac sarcoidosis; Inflammation; Large-vessel arteritis; Positron emission tomography/computed tomography (PET/CT) imaging

18F

-fluorodeoxyglucose (FDG) positron emission tomography (PET) is a noninvasive molecular imaging technique that is highly sensitive to metabolically active processes that use glucose as a source of energy. This is because FDG is a glucose analog that is taken up by living cells via cell membrane glucose transporters (GLUT) and subsequently phosphorylated intracellularly by hexokinase (Figure 1).1 In oncology, FDG uptake by tumor cells makes PET the gold-standard technique for investigating metastases.2,3 This technique has also been proposed for imaging inflammation, partly because FDG has been noted at sites of inflammation during routine FDG-PET imaging of cancer patients.4 Since then, the use of FDG-PET for imaging of inflammatory cardiovascular diseases has been rapidly evolving. Fusion PET/ computed tomography (CT) imaging, which integrates metabolic imaging with morphologic imaging, is becoming the scintigraphic method of choice. With further validation, PET/ CT may become a first-line tool Moreover, arterial FDG-PET/ CT has been suggested as a promising biomarker for the meta-

bolic activity of atherosclerosis.5 In addition to identifying symptomatic lesions,6 this technique may also help in monitoring the response of atherosclerosis to therapy.7 Future applications might include the prediction of plaque rupture and clinical events. This review describes the background and current and potential future applications of this emerging biomarker of cardiac risk. Special attention is paid to the following inflammatory cardiac diseases, cardiac sarcoidosis (CS), large-vessel arteritis, and atherosclerosis.

Myocardial Inflammation and Infectious Diseases Possible causes of inflammatory cardiomyopathy include myocarditis, eosinophilic disease, and sarcoidosis.8 Accurate diagnosis typically requires the correlation of imaging findings with laboratory data. Echocardiographic findings are nonspecific and used primarily to evaluate underlying cardiac function and wall thickness, whereas PET and magnetic resonance imaging (MRI) allow more direct assessment of an infiltrative

Received February 27, 2014; revised manuscript received April 13, 2014; accepted April 15, 2014; released online May 9, 2014 Department of Radiology (M.M., R.Y., Y.N., T.M.), Department of Cardiology, Pulmonology, Hypertension & Nephrology (A.O., J.H.), Ehime University Graduate School of Medicine, Toon, Japan Mailing address: Masao Miyagawa, MD, PhD, Department of Radiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon 791-0295, Japan. E-mail: [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-14-0250 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Circulation Journal Vol.78, June 2014

FDG-PET/CT in Inflammatory CVD

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Figure 1. (Upper) 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) 3D maximum intensity projection (MIP) image of a patient with cardiac sarcoidosis (CS). Increased accumulation of FDG is shown in the multiple hilar and mediastinal lymph nodes and the heart. Fusion PET/CT: axial image of fused PET/CT scan at the mid-ventricular level depicts focal accumulation of FDG (white circle) in the muscular interventricular septum. Histology: cardiac involvement of sarcoidosis was confirmed by endomyocardial biopsy. Physiology: in the inflammatory cells, cellular activation increases both GLUT1 and GLUT3 but not GLUT4 expression. After entry into cells, FDG becomes phosphorylated to FDG-6-phosphate by hexokinase. Activated macrophages have 10-fold higher levels of hexokinase activity than resting cells. FDG-6-phosphate cannot be metabolized further along the glycolytic pathway and therefore accumulates within cells in direct proportion to their metabolic activity. This phenomenon is referred to as metabolic trapping. (Lower) After meals: 6 h after a meal, FDG MIP and fused PET/CT images of a normal volunteer depict diffuse FDG accumulation in the left ventricular myocardium. Prolonged fasting: after >18 h overnight fasting, there is no accumulation in the myocardium except for residual ventricular cardiac blood pool activity. Physiology: glucose utilization in the normal myocardial cells is enhanced in the presence of increased blood glucose and insulin levels after a meal. In contrast, it is suppressed as free fatty acid levels in the blood increase during a continued fasting state (glucose-fatty acid cycle). This suppression is mediated by insulin-dependent GLUT4. 18F-FDG-6-P, 18F-FDG-6-phosphate; Glucose-6-P, glucose-6-phosphate; GLUT, glucose transporter protein; TCA, tricarboxylic acid cycle.

process within the myocardium. The most common causes of myocarditis are infections, especially viral infections, autoimmune processes, and exposure to cardiotoxic agents. Myocarditis may be identified by PET/ CT through the presence of increased metabolic activity in the myocardium. Myocarditis that results from radiation treatment or chemotherapy may also be detected. The increased metabolic activity is related to a combination of microvascular damage, myocyte damage, and changes in fatty acid metabolism.9 Localized radiation myocarditis and the consequent increased FDG activity generally require a radiation dose greater than 35 Gy.10 The pattern of FDG activity in radiation-induced myocardial damage should correlate with the area of the heart involved in the radiation field. Chemotherapy-related adverse cardiac effects vary, clinically evident heart failure occurs in 1–5% of patients undergoing chemotherapy, and another 5–20%

experience an asymptomatic decline in left ventricular function.11 Cardiotoxic effects have been most notably associated with exposure to anthracyclines.12 Diastolic and systolic ventricular dysfunction and congestive heart failure can occur as long-term sequelae of chemotherapy. Infectious myocarditis is an important complication encountered in oncologic patients because of their compromised immune status. A wide range of virus types have been associated with viral infections and the development of dilated cardiomyopathy, which can occur as a result of viral myocarditis.13 One case report described a diffusely increased and heterogeneous pattern of FDG activity in the heart of a patient with suspected Epstein-Barr viral myocarditis.14 To prevent the development of cardiomyopathy, endomyocardial biopsy may be considered in patients with suspected viral myocarditis.

Circulation Journal Vol.78, June 2014

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Table 1. Revised Guidelines for Diagnosing Cardiac Sarcoidosis 2006 (Japan Society of Sarcoidosis and Other Granulomatous Disorders)26,27 Histologic diagnosis group S is confirmed when endomyocardial biopsy specimens demonstrate noncaseating epithelioid cell granulomas with histological or clinical C diagnosis of extracardiac sarcoidosis Clinical diagnosis group lthough endomyocardial biopsy specimens do not demonstrate noncaseating epithelioid cell granulomas, extracardiac sarcoidosis is A diagnosed histologically or clinically and satisfies the following conditions and more than 1 of 6 basic diagnostic criteria. 1. More than 2 of the 4 major criteria are satisfied. 2. 1 of 4 major criteria and more than 2 of 5 minor criteria are satisfied. Major criteria (a) Advanced AV block. (b) Basal thinning of the interventricular septum. (c) Positive 67Ga uptake in the heart. (d) Depressed left ventricular ejection fraction (5　　

Okumura et al29

2004

With sarcoidosis

1993

22

>12

Ishimaru et al30

2005

With sarcoidosis

1993

32

>6　　

Langah et al31

2009

With suspected CS

1993

76

>18

Tahara et al32

2010

With suspected CS

2006

24

>12

Manabe et al33

2013

With suspected CS

1993

67

>6　　

Mc Ardle et al34

2013

With suspected CS

2006

134

>12

Blankstein et al35

2014

With suspected CS

1993

118

>3　　

Study

Sensitivity (%)

Specificity (%)

Brief description

Yamagishi et al28

82

NA

First systemic research with 13N-NH3

Okumura et al29

100

91

PET is more sensitive than 67Ga scintigraphy

Ishimaru et al30

100

82

Pre-administered heparin before 18F-FDG injection

Langah et al31

85

90

PET/CT with prolonged fasting >18 h

Tahara et al32

100

46→97

Analysis using the coefficient of variation improved specificity

Manabe et al33

96

62

100

83

Mc Ardle et

al34

Blankstein et al35

71**

45**

18F-FDG

uptake was related to ECG abnormalities

With a high-fat, low-carbohydrate diet on the day before PET With a high-fat, high protein, low-carbohydrate diet

*Clinical guidelines for the diagnosis of CS were first published by the JMHW in 1993.25 In 2006, the joint committee of the Japan Society of Sarcoidosis and Other Granulomatous Disorders, and the Japanese College of Cardiology published a revised version (see Table 1). **Results of 18F-FDG in combination with rubidium-82 on PET/CT were compared with JMHW criteria.35 CS, cardiac sarcoidosis; JMHW, Japanese Ministry of Health and Welfare.

CS Sarcoidosis is a multisystem granulomatous disease of unknown etiology occurring in 10.9 per 100,000 Caucasians and 35.5 per 100,000 African Americans.15 Cardiac involvement is clinically evident in only 5% of patients with sarcoidosis,16 but myocardial lesions are found at autopsy in 25–79% of patients.17,18 Importantly, sudden death is the leading cause of

mortality in patients with sarcoidosis in Japan and probably the second most common after pulmonary complications in the United States.19,20 Therefore, it has been postulated that cardiac involvement in patients with sarcoidosis is often clinically unrecognized and is a primary cause of death.20 Recently, CS has started being recognized as a cause of heart failure and arrhythmias. However, CS is difficult to detect, in part because of the



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Figure 2. (A) Gallium-67 scintigraphy of a woman in her 50 s with advanced atrioventricular block noted on ECG. Abnormal accumulation in the heart was not evident on whole-body gallium-67 scintigraphy (arrow). Coronary angiography revealed no significant stenosis with depressed left ventricular ejection fraction of 43%. (B) FDG-PET image (3D maximum intensity projection) of the same patient. PET imaging performed after administration of heparin in combination with 18-h fast depicted focal FDG accumulation in the heart (arrow). Extracardiac FDG uptake was also evident in the lymph nodes, spleen and bone marrow. Sarcoidosis was histologically confirmed by endomyocardial biopsy. FDG-PET, 18F-fluorodeoxyglucose positron emission tomography.

Figure 3. FDG-PET before and after steroid therapy. (A) FDG-PET image (3D maximum intensity projection) before therapy (same as Figure 2B). (B) After administration of 30 mg/day prednisone for 8 weeks, abnormal accumulation of FDG almost disappeared, with improvement of symptoms. FDG-PET, 18F-fluorodeoxyglucose positron emission tomography.

patchy nature of the disease.21 As a result, endomyocardial biopsy has a sensitivity of only 20–30%, because it often misses areas of cardiac involvement.17,22 Early intervention using corticosteroids improves prognosis, at least in some patients with CS.22–24 Therefore, early diagnosis is essential, but the diagnostic strategy for CS has not been fully established. Japanese Guidelines for the Diagnosis of CS Clinical guidelines for the diagnosis of CS were first published by the Japanese Ministry of Health and Welfare (JMHW) in 1993 and have been used most frequently as the clinical gold standard for the diagnosis of CS and as the reference for comparison of various imaging techniques.25 In 2006, the Joint Committee of the Japan Society of Sarcoidosis and Other Granulomatous Disorders, and the Japanese College of Cardiology published a revised version of the guidelines in which gadolinium-enhanced

MRI was added as a minor criterion for the clinical diagnosis (Table 1).26,27 Cardiac abnormal accumulation on FDG-PET was not added in the diagnostic criteria but just included in the additional statements. Several imaging studies of diagnosing CS utilizing FDG-PET and cardiac MRI has been published to date, but almost all of them were validated according to the JMHW’s original guidelines. It is only recently that we have found the published data about the diagnostic accuracy of FDG-PET based on the JMHW revised guidelines in 2006 (Table 2).28–35 In the United States, a modified Delphi study highlighted the dilemma that expert physicians on sarcoidosis face in their approach to CS and the lack of agreement among even the experts regarding key aspects of diagnosis and management.36,37 Meanwhile, the Japanese health insurance system approved


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Figure 4. (Left) Myocardial FDG-PET images (left ventricular short axis, vertical long axis, and horizontal long axis images) (same as Figure 2B). (Right) Polar map display of the standard 17 segments of the left ventricular myocardium. Accumulation of FDG is higher in the inferior and antero-apical walls with maximum standard uptake value (SUVmax) of 6.9 in segment 4 (basal inferior segment). FDG-PET, 18F-fluorodeoxyglucose positron emission tomography.

reimbursement coverage for FDG-PET to detect inflammation sites in CS as of April 2012. This approval has led to the need for a more detailed assessment of the clinical value of FDGPET. FDG-PET in the Diagnosis of CS Long-used gallium 67 (Ga-67) scintigraphy is being replaced by FDG-PET mainly because of its low diagnostic sensitivity, which does not exceed 36% owing to low image resolution (Figure 2). FDG-PET has a markedly higher sensitivity (71–100%) for diagnosing CS than does Ga-67 scintigraphy. It also has greater sensitivity than other radioisotope imaging modalities such as thallium-201 or technetium-99 m perfusion single photon emission computed tomography (SPECT) for diagnosing CS.28–30 Two studies of the diagnostic accuracy of FDG-PET have been published and were based on the JMHW revised guidelines in 2006 (Table 2). Tahara et al reported that they utilized visual analysis using FDG-PET images and the sensitivity and specificity for diagnosing CS were 100% and 46%, respectively, but after the quantitative analysis utilizing the coefficient of variation of standardized uptake value for segmental FDG uptake, they achieved a specificity of 97%.32 Mc Ardle et al described the sensitivity and specificity for diagnosing CS as 100% and 83%, respectively, and CS patients with ventricular tachycardia (VT) displayed higher cardiac uptake of FDG when compared with those with advanced atrioventricular block.34 Accumulating evidence indicates that cardiac MRI is another noninvasive imaging technique that is useful in diagnosing and monitoring CS.38 Both FDG-PET and MRI are considered highly sensitive, although there have been few direct comparisons of them.39 In summary, MRI detects regions of fibrosis with

delayed gadolinium enhancement, but fails to detect myocardial inflammation and hence, active sarcoidosis. PET has the advantage of being able to image patients with implanted pacemakers or defibrillators and those with impaired renal function.40 In addition, whole-body PET may identify extracardiac FDG-avid lesions, which may be more accessible to biopsy than the myocardium. The metabolic signal of inflammation is a marker of disease activity and can be used to guide the need for and response to corticosteroid therapies (Figure 3). Minimizing Physiological FDG Uptake in the Normal Myocardium In the past decade, FDG-PET has substantially enhanced the detection of CS. However, great variability in specificity (45–91%) has been reported. Low specificity may be related to nonspecific myocardial uptake of FDG in the normal heart or early-stage or isolated inflammatory lesions in the heart of patients who do not meet the diagnostic guidelines of CS. Therefore, standardized preparation protocols should be established to sufficiently suppress physiological FDG uptake in the normal myocardium, which is likely to facilitate detection of early-stage cardiac inflammatory lesions with high specificity. Cells involved in infection and inflammation, especially neutrophils and monocytes/macrophages, express high levels of GLUT1 and GLUT3 in the cell membrane, and hexokinase.41,42 The identification of sites of inflammation is related to the glycolytic activity of the cells involved in the inflammatory response. It is important to determine whether FDG uptake in inflammatory lesions can be distinguished from physiological FDG uptake in the myocardium (Figure 1). However, glucose utilization in normal myocardial cells is enhanced in the pres-



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Figure 5. (A) FDG-PET image (3D maximum intensity projection) of a woman in her 60 s showing increased metabolic activity along the wall of the thoracic aorta, the bilateral subclavian and the common carotid arteries (arrows). Coronal PET (B) and PET/ CT fusion images (C) of the abdominal aorta also demonstrate increased metabolic activity along the vessel wall. Histologic examination of the superficial temporal artery indicated giant cell arteritis. FDG-PET, 18F-fluorodeoxyglucose positron emission tomography.

ence of increased blood glucose and insulin levels after a meal, whereas it is suppressed as free fatty acid levels in the blood increase during continued fasting.43,44 This suppression is mediated by insulin-dependent GLUT4. Hence, separately visualizing increased FDG uptake in lesions through GLUT1/GLUT3 is possible if GLUT4 is adequately suppressed in normal myocardial cells. This suppression is the key factor in CS diagnosis, which may be achievable with prolonged overnight fasting and low-carbohydrate/high-fat diet regimens prior to imaging.45–47 Intravenous administration of low-dose heparin prior to scanning also increases fatty acid uptake, which may result in improved image quality.48–50 Finally, The Japanese Society of Nuclear Cardiology has published “recommendations standardized for FDG-PET imaging for CS”.51 For example, adopting a standardized segmentation and nomenclature system of the heart would allow relevant comparison of FDG-PET findings from different institutions (Figure 4).52 FDG-PET is expected to facilitate early diagnosis with high accuracy, to preserve cardiac function, and to avoid fatal arrhythmias, thereby achieving better and longer survival of patients with CS. If optimal risk stratification of CS becomes possible, better treatment and clinical outcomes are likely to be achieved in the future. Atherosclerosis Atherosclerotic disease may produce no uptake, mild diffuse uptake, or focally increased uptake along the vessel wall on FDG-PET. To perform vascular PET studies, a 90-min circulation time for FDG is advised, to allow sufficient FDG accumulation in the arterial wall and to permit reduction of blood levels of FDG by decay and excretion. When FDG uptake is seen, it is most commonly identified in large vessels >1 cm in diameter. The sensitivity of FDG-PET for diagnosis of small vessels such as the carotid or coronary arteries has been low

because of the limits of spatial resolution with PET.53,54 Recent technological advancements with PET/CT have facilitated radiotracer uptake in smaller vessels. In 2002, an initial study suggested a potential relationship between focal FDG uptake and symptomatic cerebrovascular disease in patients with carotid atherosclerosis.5 A correlation was confirmed between FDG uptake and macrophage density in inflamed human carotid endarterectomy specimens from symptomatic patients.55 The FDG signal also correlates with the levels of several circulating inflammatory biomarkers.56 Recently, for instance, FDG uptake was positively correlated with the expression levels of CD68, a marker of atherosclerotic plaque inflammation.57 In cancer patients, higher FDG uptake in major arteries emerged as the strongest predictor of a subsequent vascular event.58 A strong association between carotid artery FDG uptake and Framingham risk score has been reported, supporting the value of vascular FDG-PET imaging for identification of the vulnerable patient.59 Moreover, characterization of atherosclerosis with PET/CT may help identify patients at risk for a cardiac event.60 Focal, intense activity of FDG-PET within atherosclerotic plaques has been proposed as a marker of lesions that are vulnerable to possible disruption, lesions with increased FDG uptake have more inflammatory cells.61 In longer-term observations, there seems to be a degree of progression of FDG uptake in arterial segments, with smaller changes noted in calcified segments.62,63 This situation may be related to active, FDG-avid plaques becoming burned out, with calcification as a manifestation of this late phase of atherosclerosis. Vasculitis Takayasu arteritis is most prevalent in Asian populations. In Japan, an estimated 150 new cases occur each year,64 whereas in the United States and Europe the annual incidence is 1–3


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Figure 6. A woman in her 70 s underwent FDG-PET/CT as a preoperative examination of colon cancer. The level of blood glucose at the time of FDG injection was 180 mg/dl because of uncontrolled diabetes mellitus with a high level of C-reactive protein (4.9 mg/ dl). Transaxial (A) and sagittal (B) fused FDG-PET/CT scan shows faint but significant increased metabolic activity (with SUVmax of 2.7) in the inferior wall of the aortic arch (white arrows). Three days after surgery, she had massive hematemesis with septic fever. Emergency contrast-enhanced CT (C,D) revealed a mycotic aneurysm of the thoracic aorta (red arrows). CT, computed tomography; FDG-PET, 18F-fluorodeoxyglucose positron emission tomography.

cases per million population.65 The disease predominantly affects younger female patients between the ages of 10 and 40 years. FDG-PET is able to detect large-vessel inflammation in patients with Takayasu arteritis.66 Several groups have also noted FDG uptake in inflammatory arterial conditions, including giant cell arteritis and polymyalgia rheumatism.67 In contrast to Takayasu arteritis, giant cell arteritis most commonly affects people older than 50 years (Figure 5). FDG-PET has a reported sensitivity of 77–92% and a specificity of 89– 100% for the detection of large-vessel vasculitis among untreated patients with elevated levels of inflammatory markers. PET/CT may also be useful for monitoring the response to treatment because it can depict metabolic changes before anatomic changes are identifiable on CT or MRI.68,69 Finally, infected aneurysms (or mycotic aneurysm) are uncommon but can affect any artery. Higher FDG uptake in the major arterial walls is reported to be found in patients with a final diagnosis of mycotic aneurysm.70 An mycotic aneurysm can rapidly develop or enlarge (Figure 6) and symptomatic mycotic aneurysms require urgent open surgery in combination with antibiotic therapy. Delayed treatment often has a poor outcome, with high morbidity and mortality.

Future Directions FDG-PET is widely used worldwide for the imaging of atherosclerosis because of its superior sensitivity. However, it lacks

molecular specificity for therapeutically targeting atherosclerosis or aortitis. Recent preliminary data on PET imaging research have revealed that some radiotracers such as 2-deoxy2-[18F]fluoro-d-mannose ([18F]FDM) and 68Ga-DOTATATE are promising agents that may detect atherosclerotic plaques more specifically than FDG.71,72 Another recent interesting line of investigation has been exploring the possibility of using 18F- sodium fluoride (NaF) PET for imaging active mineral deposition in atherosclerotic plaques.73 By providing molecular information about the activity of the calcification process, 18F-NaF uniquely depicts pathophysiologic aspects of atherosclerotic plaque formation.74 Therefore, 18F-NaF PET/CT is the first noninvasive imaging method to identify and localize ruptured and high-risk coronary plaques.75 Finally, hybrid PET/MRI systems have been introduced into medical imaging most recently. The benefits of using PET/MRI over PET/CT are currently being investigated in the cardiology field.76 Hybrid PET/MRI may also be useful for assessing disease activity and guiding therapy for CS. In addition, extensive characterization of atherosclerotic plaques might be possible with PET/MRI. It may have the potential to improve the identification of high-risk lesions in patients with atherosclerotic disease. Disclosures Funding Sources: None. Conflict of Interest Statement: None.



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References 1. Shepherd PR, Kahn BB. Glucose transporters and insulin action, implications for insulin resistance and diabetes mellitus. N Engl J Med 1999; 341: 248 – 257. 2. Hillner BE, Siegel BA, Liu D, Shields AF, Gareen IF, Hanna L, et al. Impact of positron emission tomography/computed tomography and positron emission tomography (PET) alone on expected management of patients with cancer: Initial results from the National Oncologic PET Registry. J Clin Oncol 2008; 26: 2155 – 2161. 3. Shankar LK, Hoffman JM, Bacharach S, Graham MM, Karp J, Lamertsma AA, et al. Consensus recommendations for the use of 18F-FDG PET as an indicator of therapeutic response in patients in National Cancer Institute Trials. J Nucl Med 2006; 47: 1059 – 1066. 4. Jamar F, Buscombe J, Chiti A, Christian PE, Delbeke D, Donohoe KJ, et al. EANM/SNMMI guideline for 18F-FDG use in inflammation and infection. J Nucl Med 2013; 54: 647 – 658. 5. Rudd JH, Warburton EA, Fryer TD, Jones HA, Clark JC, Antoun N, et al. Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography. Circulation 2002; 105: 2708 – 2711. 6. Davies JR, Rudd JH, Fryer TD, Graves MJ, Clark JC, Kirkpatrick PJ, 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: 2642 – 2647. 7. Tahara N, Kai H, Ishibashi M, Nakaura H, Kaida H, Baba K, et al. Simvastatin attenuates plaque inflammation: Evaluation by fluorodeoxyglucose positron emission tomography. J Am Coll Cardiol 2006; 48: 1825 – 1831. 8. James OG, Christensen JD, Wong TZ, Borges-Neto S, Koweek LM. Utility of FDG PET/CT in inflammatory cardiovascular disease. Radiographics 2011; 31: 1271 – 1286. 9. Jingu K, Kaneta T, Nemoto K, Ichinose A, Oikawa M, Takai Y, et al. The utility of 18F-fluorodeoxyglucose positron emission tomography for early diagnosis of radiation-induced myocardial damage. Int J Radiat Oncol Biol Phys 2006; 66: 845 – 851. 10. Zöphel K, Hölzel C, Dawel M, Hölscher T, Evers C, Kotzerke J. PET/CT demonstrates increased myocardial FDG uptake following irradiation therapy. Eur J Nucl Med Mol Imaging 2007; 34: 1322 – 1323. 11. Albini A, Pennesi G, Donatelli F, Cammarota R, De Flora S, Noonan DM. Cardiotoxicity of anticancer drugs: The need for cardio-oncology and cardio-oncological prevention. J Natl Cancer Inst 2010; 102: 14 – 25. 12. Miyagawa M, Tanada S, Hamamoto K. Scintigraphic evaluation of myocardial uptake of thallium-201 and technetium-99 m pyrophosphate utilizing a rat model of chronic doxorubicin cardiotoxicity. Eur J Nucl Med 1991; 18: 332 – 338. 13. Kühl U, Pauschinger M, Noutsias M, Seeberg B, Bock T, Lassner D, et al. High prevalence of viral genomes and multiple viral infections in the myocardium of adults with “idiopathic” left ventricular dysfunction. Circulation 2005; 111: 887 – 893. 14. Takano H, Nakagawa K, Ishio N, Daimon M, Daimon M, Kobayashi Y, et al. Active myocarditis in a patient with chronic active EpsteinBarr virus infection. Int J Cardiol 2008; 130: e11 – e13, doi:10.1016/j. ijcard.2007.07.040. 15. Youssef G, Leung E, Mylonas I, Nery P, Williams K, Wisenberg G, et al. The use of 18F-FDG PET in the diagnosis of cardiac sarcoidosis, a systematic review and metaanalysis including the Ontario experience. J Nucl Med 2012; 53: 241 – 248. 16. Hunninghake GW, Costabel U, Ando M, Baughman R, Cordier JF, du Bois R, et al. ATS/ERS/WASOG statement on sarcoidosis: American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and Other Granulomatous Disorders. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16: 149 – 173. 17. Silverman KJ, Hutchins GM, Bulkley BH. Cardiac sarcoid: A clinicopathologic study of 84 unselected patients with systemic sarcoidosis. Circulation 1978; 58: 1204 – 1211. 18. Matsui Y, Iwai K, Tachibana T, Fruie T, Shigematsu N, Izumi T, et al. Clinicopathological study of fatal myocardial sarcoidosis. Ann NY Acad Sci 1976; 278: 455 – 469. 19. Iwai K, Sekiguti M, Hosoda Y, DeRemee RA, Tazelaar HD, Sharma OP, et al. Racial difference in cardiac sarcoidosis incidence observed at autopsy. Sarcoidosis 1994; 11: 26 – 31. 20. Iannuzzi MC, Fontana JR. Sarcoidosis: Clinical presentation, immunopathogenesis, and therapeutics. JAMA 2011; 305: 391 – 399. 21. Uemura A, Morimoto S, Hiramitsu S, Kato Y, Ito T, Hishida H. Histologic diagnostic rate of cardiac sarcoidosis: Evaluation of endomyocardial biopsies. Am Heart J 1999; 138: 299 – 302.

22. Lorell B, Alderman EL, Mason JW. Cardiac sarcoidosis: Diagnosis with endomyocardial biopsy and treatment with corticosteroids. Am J Cardiol 1978; 42: 143 – 146. 23. Ishikawa T, Kondoh H, Nakagawa S, Koiwaya Y, Tanaka K. Steroid therapy in cardiac sarcoidosis: Increased left ventricular contractility concomitant with electrocardiographic improvement after prednisolone. Chest 1984; 85: 445 – 447. 24. Yazaki Y, Isobe M, Hiroe M, Morimoto S, Hiramitsu S, Nakano T, et al. Prognostic determinants of long-term survival in Japanese patients with cardiac sarcoidosis treated with prednisone. Am J Cardiol 2001; 88: 1006 – 1010. 25. Hiraga H, Iwai K, Hiroe M. Guidelines for diagnosis of cardiac sarcoidosis, study report on diffuse pulmonary diseases. Tokyo: The Japanese Ministry of Health and Welfare, 1993; 23 – 24 (in Japanese). 26. Diagnostic standard and guidelines for sarcoidosis. Jpn J Sarcoidosis Granulomatous Disorders 2007; 27: 89 – 102 (in Japanese). 27. Soejima K, Yada H. The work-up and management of patients with apparent or subclinical cardiac sarcoidosis, with emphasis on the associated heart rhythm abnormalities. J Cardiovasc Electrophysiol 2009; 20: 578 – 583. 28. Yamagishi H, Shirai N, Takagi M, Yoshiyama M, Akioka K, Takeuchi K, et al. Identification of cardiac sarcoidosis with (13)NNH(3)/(18) F-FDG PET. J Nucl Med 2003; 44: 1030 – 1036. 29. Okumura W, Iwasaki T, Toyama T, Iso T, Arai M, Oriuchi N, et al. Usefulness of fasting 18F-FDG PET in identification of cardiac sarcoidosis. J Nucl Med 2004; 45: 1989 – 1998. 30. Ishimaru S, Tsujino I, Takei T, Tsukamoto E, Sakaue S, Kamigaki M, et al. Focal uptake on 18F-fluoro-2-deoxyglucose positron emission tomography images indicates cardiac involvement of sarcoidosis. Eur Heart J 2005; 26: 1538 – 1543. 31. Langah R, Spicer K, Gebregziabher M, Gordon L. Effectiveness of prolonged fasting 18F-FDG PET-CT in the detection of cardiac sarcoidosis. J Nucl Cardiol 2009; 16: 801 – 810. 32. Tahara N, Tahara A, Nitta Y, Kodama N, Mizoguchi M, Kaida H, et al. Heterogeneous myocardial FDG uptake and the disease activity in cardiac sarcoidosis. JACC Cardiovasc Imaging 2010; 3: 1219 – 1228. 33. Manabe O, Ohira H, Yoshinaga K, Sato T, Klaipetch A, OyamaManabe N, et al. Elevated 18F-fluorodoexyglucose uptake in the interventricular septum is associated with atrioventricular block in patients with suspected cardiac involvement sarcoidosis. Eur J Nucl Med Mol Imaging 2013; 40: 1558 – 1566. 34. Mc Ardle BA, Birnie DH, Klein R, de Kemp RA, Leung E, Renaud J, et al. Is there an association between clinical presentation and the location and extent of myocardial involvement of cardiac sarcoidosis as assessed by 18F-fluorodoexyglucose positron emission tomography? Circ Cardiovasc Imaging 2013; 6: 617 – 626. 35. Blankstein R, Osborne M, Naya M, Waller A, Kim CK, Murthy VL, et al. Cardiac positron emission tomography enhances prognostic assessments of patients with suspected cardiac sarcoidosis. J Am Coll Cardiol 2014; 63: 329 – 336. 36. Hamzeh NY, Wamboldt FS, Weinberger HD. Management of cardiac sarcoidosis in the United States: A Delphi study. Chest 2012; 141: 154 – 162. 37. Schatka I, Bengel FM. Advanced imaging of cardiac sarcoidosis. J Nucl Med 2014; 55: 99 – 106. 38. Patel MR, Cawley PJ, Heitner JF, Klem I, Parker MA, Jaroudi WA, et al. Detection of myocardial damage in patients with sarcoidosis. Circulation 2009; 120: 1969 – 1977. 39. Ohira H, Tsujino I, Ishimaru S, Oyama N, Takei T, Tsukamoto E, et al. Myocardial imaging with 18F-fluoro-2-deoxyglucose positron emission tomography and magnetic resonance imaging in sarcoidosis. Eur J Nucl Med Mol Imaging 2008; 35: 933 – 941. 40. Casset-Senon D, Philippe L, Renard JP, Cosnay P. Recurrent ventricular tachycardia in cardiac sarcoidosis: Usefulness of fluorodeoxyglucose positron emission tomography for adequate management of corticoid therapy after placement of an implantable cardioverter defibrillator. J Nucl Cardiol 2008; 15: 282 – 285. 41. Yamada S, Kubota K, Kubota R, Ido T, Tamahashi N. High accumulation of fluorine-18-fluorodeoxyglucose in turpentine-induced inflammatory tissue. J Nucl Med 1995; 36: 1301 – 1306. 42. Mochizuki T, Tsukamoto E, Kuge Y, Kanegae K, Zhao S, Hikosaka K, et al. FDG uptake and glucose transporter subtype expressions in experimental tumor and inflammation models. J Nucl Med 2001; 42: 1551 – 1555. 43. Nuutila P, Koivisto VA, Knuuti J, Ruotsalainen U, Teras M, Haaparanta M, et al. Glucose-free fatty acid cycle operates in human heart and skeletal muscle in vivo. J Clin Invest 1992; 89: 1767 – 1774. 44. Fox JJ, Strauss HW. One step closer to imaging vulnerable plaque in the coronary arteries. J Nucl Med 2009; 50: 497 – 500.


1310

MIYAGAWA M et al.

45. Simoes MV, Egert S, Ziegler S, Miyagawa M, Reder S, Lehner T, et al. Delayed response of insulin-stimulated fluorine-18 deoxyglucose uptake in glucose transporter-4-null mice hearts. J Am Coll Cardiol 2004; 43: 1690 – 1697. 46. Wykrzykowska J, Lehman S, Williams G, Parker JA, Palmer MR, Varkey S, et al. Imaging of inflamed and vulnerable plaque in coronary arteries with 18F-FDG PET/CT in patients with suppression of myocardial uptake using a low-carbohydrate, high-fat preparation. J Nucl Med 2009; 50: 563 – 568. 47. Harisankar CN, Mittal BR, Agrawal KL, Abrar ML, Bhattacharya A. Utility of high fat and low carbohydrate diet in suppressing myocardial FDG uptake. J Nucl Cardiol 2011; 18: 926 – 936. 48. Asmal AC, Leary WP, Thandroyen F, Botha J, Wattrus S. A doseresponse study of the anticoagulant and lipolytic activities of heparin in normal subjects. Br J Clin Pharmacol 1979; 7: 531 – 533. 49. Persson E. Lipoprotein lipase, hepatic lipase and plasma lipolytic activity: Effects of heparin and a low molecular weight heparin fragment (Fragmin). Acta Med Scand Suppl 1988; 724: 1 – 56. 50. Shulman GI, Rothman DL, Jue T, Stein P, DeFronzo RA, Shulman RG. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N Engl J Med 1990; 322: 223 – 228. 51. Ishida Y, Yoshinaga K, Miyagawa M, Moroi M, Kondoh C, Kiso K, et al. Recommendations for 18F-fluorodeoxyglucose positron emission tomography imaging for cardiac sarcoidosis: Japanese Society of Nuclear Cardiology Recommendations. Ann Nucl Med 2014 January 25, doi:10.1007/s12149-014-0806-0. 52. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 2002; 105: 539 – 542. 53. Brodmann M, Lipp RW, Passath A, Seinost G, Pabst E, Pilger E. The role of 2-18F-fluoro-2-deoxy-d-glucose positron emission tomography in the diagnosis of giant cell arteritis of the temporal arteries. Rheumatology 2004; 43: 241 – 242. 54. Ohira H, McArdle B, Cocker MS, deKemp RA, DaSilva JN, Beanlands RS. Current and future clinical applications of cardiac positron emission tomography. Circ J 2013; 77: 836 – 848. 55. Tawakol A, Migrino RQ, Bashian GG, Bedri S, Vermylen D, Cury RC, 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: 1818 – 1824. 56. Wu YW, Kao HL, Chen MF, Lee BC, Tseng WY, Jeng JS, 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: 227 – 233. 57. Pedersen SF, Graebe M, Fisker Hag AM, Højgaard L, Sillesen H, Kjaer A. 18F-FDG imaging of human atherosclerotic carotid plaques reflects gene expression of the key hypoxia marker HIF-1α. Am J Nucl Med Mol Imaging 2013; 3: 384 – 392. 58. Rominger A, Saam T, Wolpers S, Cyran CC, Schmidt M, Foerster S, et al. 18F-FDG PET/CT identifies patients at risk for future vascular events in an otherwise asymptomatic cohort with neoplastic disease. J Nucl Med 2009; 50: 1611 – 1620. 59. Noh TS, Moon SH, Cho YS, Hong SP, Lee EJ, Choi JY, et al. Relation of carotid artery 18F-FDG uptake to C-reactive protein and Framingham risk score in a large cohort of asymptomatic adults. J Nucl Med 2013; 54: 2070 – 2076. 60. Rogers IS, Nasir K, Figueroa AL, Cury RC, Hoffman U, Vermylen

61. 62. 63. 64.

65.

66. 67.

68.

69.

70.

71. 72.

73.

74. 75.

76.

DA, et al. Feasibility of FDG imaging of the coronary arteries: Comparison between acute coronary syndrome and stable angina. JACC Cardiovasc Imaging 2010; 3: 388 – 397. Kaikita K, Ogawa H. [18F]-Fluorodeoxyglucose, a new imaging modality for atherosclerotic plaque thrombogenicity. Circ J 2013; 77: 2479 – 2480. Ben Haim S, Kupzov E, Tamir A, Frenkel A, Israel O. Changing patterns of abnormal vascular wall F-18 fluorodeoxyglucose uptake on follow-up PET/CT studies. J Nucl Cardiol 2006; 13: 791 – 800. Wassélius J, Larsson S, Jacobsson H. Time-to-time correlation of high-risk atherosclerotic lesions identified with [(18)F]-FDG-PET/ CT. Ann Nucl Med 2009; 23: 59 – 64. Ohigashi H, Haraguchi G, Konishi M, Tezuka D, Kamiishi T, Ishihara T, et al. Improved prognosis of Takayasu arteritis over the past decade: Comprehensive analysis of 106 patients. Circ J 2012; 76: 1004 – 1011. Arend WP, Michel BA, Bloch DA, Hunder GG, Calabrese LH, Edworthy SM, et al. The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum 1990; 33: 1129 – 1134. Theron J, Tyler JL. Takayasu’s arteritis of the aortic arch: Endovascular treatment and correlation with positron emission tomography. Am J Neuroradiol 1987; 8: 621 – 626. Hautzel H, Sander O, Heinzel A, Schneider M, Müller HW. Assessment of large-vessel involvement in giant cell arteritis with 18F-FDG PET: Introducing an ROC-analysis-based cutoff ratio. J Nucl Med 2008; 49: 1107 – 1113. Webb M, Chambers A, Al-Nahhas A, Mason JC, Maudlin L, Rahman L, et al. The role of F-18-FDG-PET in characterising disease activity in Takayasu arteritis. Eur J Nucl Med Mol Imaging 2004; 31: 627 – 634. Kobayashi Y, Ishii K, Oda K, Nariai T, Tanaka Y, Ishiwata K, et al. Aortic wall inflammation due to Takayasu arteritis imaged with 18FFDG PET coregistered with enhanced CT. J Nucl Med 2005; 46: 917 – 922. Murakami M, Morikage N, Samura M, Yamashita O, Suehiro K, Hamano K. Fluorine-18-fluorodeoxyglucose positron emission tomography-computed tomography for diagnosis of infected aortic aneurysms. Ann Vasc Surg 2014; 28: 575 – 578. Tahara N, Mukherjee J, de Haas HJ, Petrov AD, Tawakol A, Haider N, et al. 2-deoxy-2-[18F]fluoro-d-mannose positron emission tomography imaging in atherosclerosis. Nat Med 2014; 20: 215 – 219. Rominger A, Saam T, Vogl E, Ubleis C, la Fougère C, Förster S, et al. In vivo imaging of macrophage activity in the coronary arteries using 68Ga-DOTATATE PET/CT: Correlation with coronary calcium burden and risk factors. J Nucl Med 2010; 51: 193 – 197. Derlin T, Tóth Z, Papp L, Wisotzki C, Apostolova I, Habermann CR, et al. Correlation of inflammation assessed by 18F-FDG PET, active mineral deposition assessed by 18F-Fluoride PET, and vascular calcification in atherosclerotic plaque, a dual-tracer PET/CT study. J Nucl Med 2011; 52: 1020 – 1027. Dweck MR, Chow MW, Joshi NV, Williams MC, Jones C, Fletcher AM, et al. Coronary arterial 18F-sodium fluoride uptake: A novel marker of plaque biology. J Am Coll Cardiol 2012; 59: 1539 – 1548. Joshi NV, Vesey AT, Williams MC, Shah AS, Calvert PA, Craighead FH, et al. 18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques, a prospective clinical trial. Lancet 2014; 383: 705 – 713. Rischpler C, Nekolla SG, Dregely I, Schwaiger M. Hybrid PET/MR imaging of the heart: Potential, initial experiences, and future prospects. J Nucl Med 2013; 54: 402 – 415.
