Introduction
18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) plays an important role in the detection of active inflammatory lesions in cardiac involvement sarcoidosis (CS).
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4 Recently, the Heart Rhythm Society (HRS) issued a consensus statement on the diagnosis and management of arrhythmias associated with CS.
5 In this statement, FDG PET was recommended for advanced cardiac imaging in CS diagnosis. A FDG PET preparation protocol and image interpretation should therefore be improved and standardized. The Japanese Society of Nuclear Cardiology (JSNC) has also issued FDG PET imaging guidelines for diagnosis CS.
1 The positive uptake pattern is defined using visual assessment in HRS and JSNC guidelines. By adding a quantitative parameter over the standard visual analysis, FDG PET may improve the ability to diagnose patients with CS. For the evaluation of FDG uptake, volume-based parameters were proposed to estimate disease progression in the assessment of malignant tumors.
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7 Ahmadian et al also applied FDG volume measurement for patients with cardiac sarcoidosis.
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Sarcoidosis is a systemic granulomatous disease with unknown etiology.
9 Manifestation of sarcoidosis varies from an asymptomatic state to a progressive disease, and CS has the greatest life-threatening potential in sarcoidosis patients.
10 Therefore, the precise diagnosis of CS is important to sarcoidosis patients. The heart uses a variety of energy sources such as free fatty acids (FFA), glucose, lactate, and ketone bodies.
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12 FDG is an analog of glucose. Theoretically, glucose use during a fasting state is limited but diffuse left ventricle (LV) wall FDG uptake is sometimes reported even under fasting conditions.
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13 In addition, FDG uptake in the entire LV wall is generally considered to be physiologically normal.
1 This physiological uptake makes it difficult to distinguish between active inflammation and physiological distribution.
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14 Myocardial FDG uptake is known to be correlated inversely with serum FFA concentration but not with serum insulin concentration.
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17 Several recent studies have focused on reducing physiological FDG uptake through such measures as performing extended fasting, following a particular regime (a low-carbohydrate diet or a high-fat diet), or receiving unfractionated heparin (UFH), and they have examined the usefulness of provoking a shift from glucose metabolism to FFA metabolism.
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20 However, there have been limited data to evaluate the association between certain details of FFA level and diffuse LV FDG uptake under a longer fasting period and LCD in patients with suspected CS. In addition, the effect of UFH in reducing diffuse LV FDG uptake has not been established. The aims of this study were to examine the effect of the preparations on diffuse LV FDG uptake and to evaluate the association between diffuse LV FDG uptake and FFA levels before and after UFH injection. We also tried to evaluate the cardiac FDG uptake volume and compare that evaluation to the visual assessment.
Discussion
The minimum 18-h fasting with LCD preparation reduced FPG, increased FFA before UFH administration, and led to significantly suppressed diffuse LV FDG uptake, according to not only visual evaluation but also volume-based analysis, in comparison with results of shorter fasting without LCD protocol. UFH administration led to increases in FFA levels; however, the FFA levels after UFH administration might not play a significant role in reducing diffuse LV FDG uptake.
FDG is an analog of glucose and FDG PET is known to be useful for detecting inflammatory lesions. Sarcoidosis lesions include inflammatory cell infiltration by such things as lymphocytes and macrophages, which utilize glucose for their energy source. FDG PET can therefore be used to identify active sarcoidosis lesions.
2 However, diffuse FDG uptake in the entire LV wall is generally considered to be physiologically normal.
1 In the current study, the association between fasting conditions and diffuse LV FDG uptake was significant. Minimum 18-h fasting with LCD preparation led to significantly suppressed diffuse LV FDG uptake compared to results with the shorter fasting protocol. These data may imply the importance of a gradual myocardial metabolic shift from glucose use to fatty acid use in fasting FDG imaging. The myocardium could derive energy from a variety of sources such as FFA, glucose, lactate, and ketone bodies.
11 Several factors were known to affect the utilization of an individual substrate, including the plasma insulin concentration, availability of alternative substrates, and myocardial blood flow supply.
25 The heart preferentially utilizes substrates that yield energy from FFA and lactate, while glycolysis normally produces only about 30% of substrates for the citric acid cycle.
26 In particular, the heart prefers to use FFA for energy production, and under these conditions, myocardial glucose uptake is low with fasting.
15 In the absence of dietary glucose intake and carbohydrate intake due to prolonged fasting, the myocardium physiologically adapts and makes a metabolic shift from glucose use to fatty acid use. Under the long fasting condition, glucose production and glucose oxidation should be decreased. In contrast, FFA is mobilized from adipose tissue and the increased FFA becomes an alternative fuel in the myocardium.
27 Wisneski et al demonstrated the presence of a significant inverse correlation between the arterial FFA level and myocardial glucose uptake in normal healthy subjects.
28 Specifically, after a carbohydrate meal, FFA uptake and oxidation decrease, and glucose and lactate extraction increase.
29 It has been suggested that this shift in fuel preference is caused by the changes in substrate and leads to the suppression of physiological glucose metabolism. In fact, the current data showed higher plasma FFA levels in the group of patients undergoing long fasting with LCD. This increasing FFA use may be significantly reduced by cardiac glucose metabolism. Thus, long fasting with LCD preparation significantly reduces physiological FDG uptake. In addition, even with shorter fasting, some patients in the current study showed significantly reduced physiological myocardial FDG uptake. These patients also showed significantly higher plasma FFA levels than did patients with diffuse LV FDG uptake. This result may indicate the importance of increasing plasma FFA levels for fasting cardiac FDG PET imaging or of measuring plasma FFA before the fasting FDG PET study.
Langah et al reported the effects of 18-h fasting preparation on the suppression of myocardial physiological FDG uptake.
13 They indicated that the frequency of LV FDG uptake under prolonged fasting was significantly lower than under the short fasting protocol. In their report, only one of the 10 patients (10.0%) had a diffuse pattern. Morooka et al also reported the importance of prolonged fasting for evaluating active inflammatory lesions in cardiac sarcoidosis.
30 In their study, healthy volunteers who fasted for 18 h showed reduced physiological LV FDG uptake in comparison with healthy volunteers who underwent 12 h of fasting with heparin administration. In addition, they suggested that the FFA level before UFH injection may be the important factor in inhibiting physiological LV FDG uptake. Physiological uptake was likely to be efficiently inhibited when the FFA level was more than 760 μEq/L. Our current data agree with their previous study. In this study, we applied the longer fasting protocol to CS patients and showed the usefulness of this preparation for eliminating diffuse LV FDG uptake in clinical settings. Thus, the current study added further insights to those of previous studies by Langah et al
13 and Morooka et al.
30
In the current study, the 18-h fasting group also followed LCD. LCD also has an impact on myocardial metabolism and may contribute to reducing physiological FDG uptake.
31 Kobayashi et al reported the usefulness of LCD in suppressing myocardial physiological FDG uptake in healthy subjects.
22 Kumar et al reported that both restricted diet and duration of fasting play an important role in determining the pattern and suppression of myocardial FDG uptake.
32 LCD may have played a role in reducing the physiological LV FDG uptake in the present study; however, since we did not apply LCD to the shorter fasting group, we are not able to conclude which factor played a more significant role in the current study. Further study examining the effects of LCD on myocardial physiological FDG uptake under various fasting conditions should be conducted in the future.
UFH activates lipoprotein lipase, enhances plasma lipolytic activity, and increases FFA levels.
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34 Therefore, UFH has been expected to reduce physiological LV FDG uptake. In this regard, our group applied UFH for fasting cardiac FDG PET studies in CS.
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21 However, the full effects of heparin in reducing physiological LV FDG uptake have not been established.
1 In the current study, UFH increased plasma FFA levels in both group A and group B. In addition, in the short-fast group, the difference in FFA levels after 15 min of UFH administration between patients with diffuse LV uptake and those without diffuse LV uptake was not significant. The current data agree with those of previous reports indicating that patients with increased FFA responded to UFH.
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35 Moreover, the present data may imply that acutely increasing plasma FFA by UFH may not have a significant role in reducing physiological LV FDG uptake. A recent study by Gormsen et al reported that heparin loading did not reduce myocardial FDG uptake.
36 Our data agree with previous data and also may imply the importance of longer fasting with LCD rather than heparin administration. However, the effects of heparin should also be evaluated in future studies.
Distribution of FDG uptake might change in patients with diabetes who use insulin or oral antidiabetic drugs.
37 There were four diabetic patients in this study. Two of them were in group A and the other two were in group B. Their FPG levels were lower than 114 mg/dL, and their uptake patterns were not diffuse. If their results were excluded, the conclusion remained the same.
Limitations
The present study had some limitations. We used both PET and PET/CT systems. The detector and method of attenuation correction were not same. However, the current visual analyses focused on the existence of diffuse physiological myocardial FDG uptake. This visual approach was simple and relatively independent from attenuation correction or other system specifications. A previous study by Youssef et al assessed cardiac involvement sarcoidosis using 3 different PET scanners from 3 different centers.
4 In the quantitative analysis, each system showed that the cardiac metabolic volume was significantly larger in the diffuse uptake group. The results were consistent. Thus, the effects of using different PET systems may have minimal impact on the current study similar to the previous study by Youssef et al.
Patients in group A were instructed to fast for a minimum of 6 h; however, the actual fasting time of group A was not available. For the patients in group B, fasting time was based on self-reporting. However, all patients were admitted to hospital and were provided dinner at the same time, and therefore, reported fasting times should be accurate. Obvious whole LV FDG accumulation higher than liver uptake was defined as diffuse LV FDG uptake. However, physiological uptake may sometimes be seen in only part of the LV myocardium rather than in the whole, and therefore, further investigation to reveal the relationship between other patterns of FDG uptake and fasting conditions is warranted.
Recently, prolonged fasting and diet modifications including a low-carbohydrate diet and a high-fat diet have been applied to FDG PET/CT studies in patients with CS. In the current study, we did not evaluate the effects of high-fat meals. The effects of adding a high-fat diet should be studied as the next step.
Acknowledgments
The authors thank Shigeo Oomagari, MSc; Ken-ichi Nishijima, PhD; Kumi Ajiki; and Eriko Suzuki for their support for this study. This study was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Category B, No. 23390294, Category Young Investigator, No. 23790826), and the Hokkaido Heart Association for Research (H-23) (Sapporo, Japan). Dr. Yoshinaga is supported by the Imura Clinical Research Award (Adult Vascular Disease Research Foundation).