Sarcoidosis is a systemic disease of unknown cause that can affect any organ.1 Cardiac sarcoidosis (CS) produces symptoms in only 5% of patients with sarcoidosis,2 but it has been found in 27% of these patients at autopsy.3 Cardiac sarcoidosis is potentially fatal and has a wide spectrum of clinical manifestations, including conduction abnormality and sudden death. The diagnosis of CS is therefore challenging and lacking a criterion standard. Endomyocardial biopsy has a sensitivity of only 20% to 30% because it often misses areas of CS involvement, and usually the left ventricle is not accessible for biopsy.4 Currently, the Guidelines of the Japanese Ministry of Health and Welfare (JMHWG), as revised by the Japanese Society of Sarcoidosis and Other Granulomatous Disorders in 2006, is used as a worldwide standard for clinical diagnosis of CS.5 However, the JMHWG has not been clinically validated and has an imperfect diagnostic accuracy.6,7
FDG PET/CT can identify hypermetabolic, active inflammation status in CS that usually presents in the early phase of disease process and is amenable to intervention. However, the background physiological FDG activity in normal myocardium could interfere with the detection of active CS and is the major hurdle in utilizing FDG PET/CT to diagnose CS.8 Thus, FDG PET/CT has been recommended by health insurance companies only as alternative test to diagnose CS. It has been reported that FDG PET/CT has similar sensitivity to cardiac MRI in diagnosing CS, but lower specificity.9 The JMHWG is updating its guidelines for the diagnosis of CS and will probably add positive FDG PET findings as one of the criteria for the diagnosis of CS.10 Different strategies, including 12- to 18-hour pretest fasting, pretest administration of unfractionated heparin, and overnight high-fat, low-carbohydrate-diet modification, have been proposed to minimize physiological cardiac FDG activity but only with suboptimal results.10–16 Furthermore, these data come from a relative small number of patients and over a relatively long period with inherited imaging techniques that were variable. The current overnight diet protocol is based on the Randle cycle, where fatty acid loading within myocardial cells suppresses glucose metabolism.17 In view of current literature and previous suboptimal results,11,13,16 we hypothesized that a simple, prolonged 72-hour pretest high-fat, high-protein, and very-low-carbohydrate (HFHPVLC) diet, a “sarcoid diet,” could effectively suppress background FDG uptake in the myocardium, whereas active CS would be shown as focal uptake of FDG. Here we summarize our FDG PET/CT experience with this 72-hour pretest HFHPVLC diet protocol in detecting active CS.
METHODS AND MATERIALS
This institutional review board–approved retrospective study included 215 consecutive FDG PET/CT tests from a total of 207 patients with an established diagnosis of sarcoidosis and clinical suspicion for CS between July 2014 and December 2015. Our institutional pretest diet preparation protocol was initially a 1-day HFHPVLC diet before FDG PET/CT and was later switched to a 72-hour HFHPVLC diet preparation for these sarcoid patients with suspected cardiac involvement. Based on the pretest diet preparation protocol, these patients were classified into 2 groups. Group 1 included 12 FDG PET/CT scans from 12 patients, with 24-hour or less pretest HFHPVLC diet preparation. Group 2 included 203 FDG PET/CT scans with a 72-hour HFHPVLC diet before FDG-PET/CT. All patients were given detailed instructions about the diet preparation, and an additional questionnaire was obtained just before the test to verify diet adherence. After the PET/CT scan, patients were asked to remain in the nuclear medicine clinic for an interview by the physician. When the patient’s FDG PET/CT showed visualized cardiac FDG uptake, regardless of focal or diffuse uptake pattern, the nuclear medicine physician would further communicate with the patient to inquire the details of the patient’s diet preparation. Thus, any noncompliance with diet preparation was documented prospectively on the day of the scan. In this retrospective study, nonadherent patients and patients with diagnosis of cancer were excluded. All patients had follow-up for at least 6 months after imaging. The available medical records and imaging data for each patient were retrospectively analyzed. The patients’ characteristics are summarized in Table 1.
HFHPVLC Diet Protocol
The HFHPVLC diet was written in a menu of permitted and prohibited foods (Table 2) established by the nuclear medicine physician and local dietitians and was given to sarcoidosis patients before their scheduled FDG PET/CT. Instructions were also given to patients at the time of a confirmation telephone interaction. Patients were offered a direct consultation number to the nuclear medicine physician for further questions about the diet preparation. When we first started our sarcoid PET/CT protocol, we asked patients to be on the HFHPVLC diet 1 day before the scheduled FDG PET/CT and have an HFHPVLC breakfast approximately 4 hours before scanning. Approximately 4 months later, because of high percentage of nonsuppression of cardiac background FDG uptake, we modified the diet protocol by extending pretest HFHPVLC diet to 72 hours and keeping the boost HFHPVLC breakfast approximately 4 hours before scanning. Patients on steroids for treatment of sarcoidosis and on antidiabetic medication were instructed to hold off these medications for 24 hours before FDG PET/CT and were monitored with serum glucose levels.
FDG PET/CT Imaging
All FDG PET/CT examinations were performed on a GE Discovery 690 FDG PET/CT scanner (GE Medical Systems, Milwaukee, Wis) using a standard protocol. Patients took a boost HFHPVLC breakfast and fasted for subsequent 4 hours before scanning. All patients had a blood glucose level of less than 200 mg/dL at the time of FDG injection. Dedicated PET/CT scans from the skull base to the upper thighs were obtained 60 to 90 minutes after intravenous injection of 0.370 to 0.481 GBq of FDG. CT parameters were as follows: 120 kV, 120 mAs, pitch 0.813, 16 × 1.5-mm collimation, slice thickness of 3 mm with increment of 1.5 mm. CT scan was used for the attenuation correction. PET parameters were as follows: 2 min/bed for the noncardiac fields and 10 min/bed for fields covering the heart.
Based on data from literature,9,11–16,18 we visually classified the pattern of cardiac FDG uptake into the following (Fig. 1): “none” and “ringlike diffuse at base” (negative for CS),18 “focal” (positive for CS),19 and “diffuse” (indeterminate for CS). Quantitative cardiac FDG uptake was measured as SUVmax in the myocardium and compared with SUVmean in the ascending aorta as mediastinal blood pool background. The heart-to-blood pool SUV ratio (SUVmax/SUVmean) was calculated. All the FDG PET/CT studies were retrospectively read, or reread, by 3 imaging physicians (Y.L.: board-certified nuclear medicine physician with 5-year posttraining experience, C.G.: board-eligible senior radiology resident; K.X.: board-certified radiologist with 8-year posttraining experience) independently, and results were categorized into the 4 groups mentioned previously. Final diagnoses were made with consensus among imaging physicians (Y.L., C.G., K.X.) and a referring clinician (N.J.S.) in view of all available comprehensive clinical information and diagnostic test results, including 12-lead ECG, cardiac MRI, echocardiogram, and nuclear stress test, with reference to the modified Japanese Ministry of Health and Welfare criteria.
Differences in indeterminate/nondiagnostic rate between group 1 and group 2 were calculated and tested for significance using Fisher exact test. Statistical analyses were performed using SAS software, version 9.2. P < 0.05 was considered statistically significant.
The characteristics of the patients in each group are described in Table 1. The mean age, sex, race, body weight, and BMI were not significantly different between the 2 groups. All these 207 patients had established diagnosis of sarcoidosis in the past and were on treatment for sarcoidosis, mainly with steroid, some with other commonly used antirheumatic drugs, including methotrexate, hydroxychloroquine, leflunomide, azathioprine, or tumor necrosis factor α antagonist such as infliximab or adalimumab. These sarcoid patients all had clinical suspicion for CS, such as symptoms of chest pain, palpitation, or abnormalities on ECG or echocardiogram (ie, atrial-ventricular block, decreased left ventricular ejection fraction, or abnormal wall motion). One patient had history of myocardial biopsy-proven CS; a total of 5 patients including the one with positive myocardial biopsy results had received implantable cardioverter-defibrillator (ICD) for an existing diagnosis of CS.
FDG PET/CT Analysis
The quantitative measurements of FDG PET/CT are shown in Table 3. The pretest blood glucose level, wait time, and background FDG uptake in the mediastinal blood pool and liver were similar between the 2 groups.
Results of visual assessment are described in Table 4. Eliminating the “focal on diffuse” category for PET visual analysis and using only “focal” as positive for CS and “none” and “ringlike at base” as negative for CS, we reached 100% interobserver agreement upon visual analyses of the sarcoid PET/CT scans. In group 1 patients, there were 1 (1/12, 8.3%) positive, 5 (5/12, 41.7%) indeterminate, and 6 (6/12, 50.0%) negative for CS. In group 2 patients, 10 patients were excluded (6 patients because of noncompliance diet, 2 patients with concurrent cancer diagnosis, and 2 patients because of insulin or steroid use within 4 hours before PET/CT). The remaining 185 patients had 193 PET/CT tests (8 repeats), of which there were 19 (19/193, 9.8%) positive, 7 indeterminate (7/193, 3.6%), and 167 (167/193, 86.6%) negative for CS. The indeterminate rate was significantly lower (P < 0.001) in group 2 (7/193, 3.6%) than in group 1 (5/12, 41.7%).
In group 1, the PET/CT diagnoses of 1 positive and 6 negative cases were consistent with the final comprehensive clinical diagnosis. One of the 5 indeterminate cases was deemed as positive for CS, with support from nuclear stress test results and low LVEF on echocardiogram, whereas the other 4 cases were deemed as negative for CS.
In group 2, there were 167 cases diagnosed on PET/CT as negative for active CS including 3 patients who had ICD in place. One of the 3 ICD patients was negative for CS due to treatment effect (D–F, Fig. 2). Four of the 167 cases were repeating PET/CT because of their scans being consistently negative for active CS. The 19 positive cases including 2 patients who received ICD for an existing diagnose of CS (A–C, Figs. 2 and 3) were in keeping with the final clinical diagnosis. The total 19 positive cases were from 16 patients; 4 patients had follow-up PET/CT. In the follow-up PET/CT studies, 1 patient’s CS has resolved upon adalimumab therapy20 (Fig. 2), 2 patients had partial response to therapy with decreased FDG intensity and extent on follow-up PET/CT (Fig. 4), whereas the other patient had no response to steroid therapy with progression of CS (Fig. 3). Among the 7 indeterminate cases, 2 cases had a final diagnosis of positive for CS, and the other 5 cases were negative for CS.
Under fasting conditions, the normal myocardium predominantly utilizes lipid as its main energy sources.21 Nevertheless, myocardial FDG uptake is often unpredictable, prominent, and diffuse, rendering diagnosing active CS on FDG PET/CT very difficult. Suppression of glucose (and hence FDG) uptake in the myocardium can be achieved by dietary preparation. Currently, 3 methods have been used for this purpose: prolonged fasting,22 intravenous administration of unfractionated heparin to activate lipoprotein and hepatic lipases,23,24 and pretest dietary modification.11,25 All have been associated with suboptimal results, and most data were derived from small groups of patients.
Intense myocardial FDG uptake can be observed even under prolonged fasting conditions of more than 18 hours.12 Also, it is generally not practical to have patients fasting for more than 18 hours before FDG PET/CT. Heparin preadministration is not a well-established method and needs further study to develop an appropriate protocol. Also, pretest heparin administration will need more medical surveillance and sometimes might cause unexpected complications especially in patients with bleeding risk. Physiological myocardial FDG uptake was not fully suppressed in up to 47% (14/30) of cases26 in a protocol with a dose of 50 IU/kg heparin 15 minutes before FDG administration. Low insulin levels and high fatty acid levels will theoretically produce the least amount of glucose metabolism, thus suppression of background FDG uptake in myocardium. This is what the HFHPVLC diet is aiming to accomplish. Current diet preparation protocol is only for 24 hours or less.11,27 Harisankar et al13 showed that dietary modification with high-fat diet the night before and 4 hours prior to FDG injection had 53% (31/60) complete suppression of background FDG uptake in the myocardium and was superior to the 32% (16/50) of prolonged fasting (>12 hours) group.
Currently, the largest cohort of patients with suspected CS undergoing PET reported to date was from Brigham and Women’s Hospital (BWH) and included 118 patients over a 5-year period who underwent “a high-fat, high-protein, low-carbohydrate diet followed by a fast of at least 3 hours” prior to FDG PET for inflammation evaluation and 82Rb PET to assess perfusion defects.28 The authors categorized the PET images as normal perfusion and metabolism, abnormal perfusion or metabolism, or abnormal perfusion and metabolism. Although they reported a poor correlation between Japanese Ministry of Health and Welfare criteria and cardiac PET results (positive and negative for abnormalities in perfusion and/or metabolism), they did not mention definitive cardiac PET criteria in diagnosing CS. Their proposed interpretations of the representative cardiac FDG uptake patterns as “focal,” “focal increased,” and “focal on diffuse” are somewhat difficult for physicians outside their group to follow, which may cause interobserver disagreement when the same criteria are to be applied by other physicians. The authors’ interpretations on cardiac PET results also appear difficult to understand. For example, these authors interpreted 15 FDG PET scans with diffuse cardiac uptake as “due to failure to suppress FDG from normal myocardium,” which we would be categorized as “nondiagnostic for CS,” but they read as “normal metabolism” and included these cases in the PET-negative group. Moreover, they interpreted the 6 scans with “focal on diffuse” uptake as “areas of inability to suppress FDG from normal myocardium versus diffuse inflammation” but categorized them into “abnormal metabolism” and “PET positive.” In our study, we did not classify a “focal on diffuse” pattern as proposed by these and other authors,10,16,26 because we thought this interpretation was inherently subjective and could easily be confused with the “diffuse” pattern. And there are no convincing data verifying the utility of this uptake pattern for active CS. We think the diffuse uptake is most likely due to suboptimal suppression of background cardiac FDG uptake. Eliminating the “focal on diffuse” visual classification rendered the interpretation of cardiac FDG PET/CT easy to follow. Based on cardiac FDG PET/CT alone, when grouping the “diffuse” cardiac FDG uptake as nondiagnostic for CS, the indeterminate rate for BWH group data would be 12.7% (15/118), when added on 6 “focal on diffuse” scans, the indeterminate rate would be 15.3% (18/118), which is significantly higher than the 3.6% (7/193) in our group 2 (P < 0.01). We believe that this is largely due to the different diet preparation protocol, as patients in our group 2 adhered to 72-hour HFHPVLCL diet, whereas the BWH group proposed only “a diet with 3 hours’ fast.”
We chose to use a prolonged 72-hour HFHPVLC diet preparation protocol mainly based on the published literature and our initial observation from group 1 patients’ suboptimal suppression of cardiac FDG uptake when on a 24-hour diet preparation. Furthermore, the 72-hour HFHPVLC diet preparation protocol is easy for patient to follow. As expected, the indeterminate rate in group 2 patients on the prolonged 72-hour diet regimen is significantly lower than that in group 1 patients with a 24-hour or less diet preparation protocol (3.6% vs 41.7%, P < 0.001). We categorized a “ringlike diffuse at base” as negative for CS, because it is a common variant seen in normal healthy volunteers.18 Nonetheless, there was only 2.1% (4/193) of patients with such pattern in our 72-hour HFHPVLC diet preparation group. Furthermore, these 4 patients had no cardiac event, with a final diagnosis negative for CS during the 6 months’ clinical follow-up.
Although this is a retrospective study with single-center experience, it is the largest cohort of patients with suspected CS undergoing FDG PET/CT reported to date. And this is the first study using prolonged 72-hour HFHPVLC diet preparation protocol for patients with suspected CS receiving FDG PET/CT. Eliminating the controversial “focal on diffuse” pattern for positive CS diagnosis could help to minimize the potential interobserver variability and improve diagnosis confidence. Our results showed the positive CS diagnosed on FDG PET/CT has high concordance with the final clinical diagnosis and corresponding abnormal cardiac MRI findings. We were unable to identify the true diagnostic accuracy of PET/CT for CS because there is no reliable reference standard for CS. The positive CS cases diagnosed with our FDG PET/CT protocol were consistent with clinical diagnosis, and most had concordant cardiac MRI findings. Moreover, FDG PET/CT can be reliably used to assess treatment response in patients with ICD for CS, when cardiac MRI is contraindicated.
In conclusion, the 72-hour HFHPVLC diet preparation for patients with suspected CS undergoing FDG PET/CT can successfully suppress background FDG uptake in the myocardium and minimize the rate of indeterminate/nondiagnostic findings.
The authors thank Dr Heiko Schoder, Molecular Imaging and Therapy Service at Memorial Sloan-Kettering Cancer Center, for his helpful comments and suggestions on this study.
1. Valeyre D, Prasse A, Nunes H, et al. Sarcoidosis. Lancet
2. Sharma OP, Maheshwari A, Thaker K. Myocardial sarcoidosis. Chest
3. Albert CM, Chae CU, Grodstein F, et al. Prospective study of sudden cardiac death among women in the United States. Circulation
4. Cooper LT, Baughman KL, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. Eur Heart J
5. 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
6. Patel MR, Cawley PJ, Heitner JF, et al. Detection of myocardial damage in patients with sarcoidosis. Circulation
7. Youssef G, Leung E, Mylonas I, et al. The use of 18
PET in the diagnosis of cardiac sarcoidosis
: a systematic review and metaanalysis including the Ontario experience. J Nucl Med
8. Schatka I, Bengel FM. Advanced imaging of cardiac sarcoidosis
. J Nucl Med
9. Ohira H, Tsujino I, Ishimaru S, et al. Myocardial imaging with 18
F-fluoro-2-deoxyglucose positron emission tomography and magnetic resonance imaging in sarcoidosis. Eur J Nucl Med Mol Imaging
10. Ishida Y, Yoshinaga K, Miyagawa M, et al. Recommendations for (18)F-fluorodeoxyglucose positron emission tomography imaging for cardiac sarcoidosis
: Japanese Society of Nuclear Cardiology recommendations. Ann Nucl Med
11. Williams G, Kolodny GM. Suppression of myocardial 18
uptake by preparing patients with a high-fat, low-carbohydrate diet. AJR Am J Roentgenol
12. Langah R, Spicer K, Gebregziabher M, et al. Effectiveness of prolonged fasting 18
PET-CT in the detection of cardiac sarcoidosis
. J Nucl Cardiol
13. Harisankar CN, Mittal BR, Agrawal KL, et al. Utility of high fat and low carbohydrate diet in suppressing myocardial FDG
uptake. J Nucl Cardiol
14. Morooka M, Moroi M, Uno K, et al. Long fasting is effective in inhibiting physiological myocardial 18
uptake and for evaluating active lesions of cardiac sarcoidosis
. EJNMMI Res
15. Okumura W, Iwasaki T, Toyama T, et al. Usefulness of fasting 18
PET in identification of cardiac sarcoidosis
. J Nucl Med
16. Soussan M, Brillet PY, Nunes H, et al. Clinical value of a high-fat and low-carbohydrate diet before FDG
for evaluation of patients with suspected cardiac sarcoidosis
. J Nucl Cardiol
17. Randle PJ, Garland PB, Hales CN, et al. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet
18. Ito K, Okazaki O, Morooka M, et al. Visual findings of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with cardiac sarcoidosis
. Intern Med
19. Lu Y, Sweiss NJ. MRI and FDG PET/CT
imaging manifestations of cardiac sarcoidosis
. Clin Nucl Med
20. Miller CT, Sweiss NJ, Lu Y. FDG PET/CT
evidence of effective treatment of cardiac sarcoidosis
with adalimumab. Clin Nucl Med
21. Wisneski JA, Gertz EW, Neese RA, et al. Myocardial metabolism of free fatty acids. Studies with 14
C-labeled substrates in humans. J Clin Invest
22. Gropler RJ, Siegel BA, Lee KJ, et al. Nonuniformity in myocardial accumulation of fluorine-18-fluorodeoxyglucose in normal fasted humans. J Nucl Med
23. 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
24. Nuutila P, Koivisto VA, Knuuti J, et al. Glucose-free fatty acid cycle operates in human heart and skeletal muscle in vivo. J Clin Invest
25. Ishii A, Hoshii Y, Nakashima T, et al. Sarcoidosis with pulmonary hypertension exacerbated by Takayasu-like large vessel vasculitis. Pathol Int
26. Ishimaru S, Tsujino I, Takei T, et al. Focal uptake on 18
F-fluoro-2-deoxyglucose positron emission tomography images indicates cardiac involvement of sarcoidosis. Eur Heart J
27. Wykrzykowska J, Lehman S, Williams G, et al. Imaging of inflamed and vulnerable plaque in coronary arteries with 18
in patients with suppression of myocardial uptake using a low-carbohydrate, high-fat preparation. J Nucl Med
28. Blankstein R, Osborne M, Naya M, et al. Cardiac positron emission tomography enhances prognostic assessments of patients with suspected cardiac sarcoidosis
. J Am Coll Cardiol