Pre-administration of caffeine anhydrous food supplement potentially improves suppression of physiologic myocardial [18F]FDG uptake: a feasibility study.

Pre-administration of caffeine anhydrous food supplement potentially improves suppression of physiologic myocardial [18F]FDG uptake: a feasibility study. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Pre-administration of caffeine anhydrous food supplement potentially improves suppression of physiologic myocardial [ 18 F]FDG uptake: a feasibility study. Christina Petronella Wilhelmina Cox, Quido Gisou de Lussanet de la Sablonière, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7739411/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Positron emission tomography/Computed tomography (PET/CT) with [ 18 F]FDG has an increasingly relevant role in diagnosing and treatment management of myocardial inflammation and infection. A major confounding factor in cardiac [ 18 F]FDG PET/CT is physiological myocardial glucose uptake, which could obscure pathologic myocardial uptake in disease affected myocardium (e.g., inflammatory conditions). Despite generally accepted conventional measures such as dietary manipulation, extended fasting, and possibly additional intravenous heparin, confounding physiological myocardial [ 18 F]FDG uptake still occurs in 5–20% of the patients, and further improvement of the protocol is needed. It is proposed that these patients may benefit from additional pre-administration of caffeine anhydrous as a food supplement. Caffeine acts as an adenosine receptor antagonist, stimulating lipolysis in adipose tissue and promoting adrenergic release of epinephrine. This stimulates β AR-mediated lipolysis in adipose tissue and β AR-mediated inhibition of insulin-independent glucose transporter (GLUT) 4 expression and translocation, which reduces insulin-dependent GLUT4 myocardial [ 18 F]FDG uptake. This study aims to investigate the feasibility of using additional caffeine anhydrous pre-administration on myocardial [ 18 F]FDG uptake suppression. Results Additional administration of caffeine anhydrous before [ 18 F]FDG injection resulted in complete myocardial suppression in five out of eight patients (63%), and a near-complete suppression in two patients (25%). In all patients, there was a significant ( p 0.05) were observed in visual and semi-quantitative measurements of extra-cardiac image quality and extra-cardiac sarcoid lesions. All monitored patient parameters remained stable, except for an expected significant ( p < 0.001) decrease in mean heart rate before [ 18 F]FDG injection. Conclusion Pre-administration of additional caffeine anhydrous food supplement has the potency to safely improve myocardial [ 18 F]FDG uptake suppression in patients who experience inadequate myocardial [ 18 F]FDG uptake suppression following a standard HFNC diet and more than 12 hours of fasting. This potential improvement could contribute to better diagnosis and consequent treatment management of cardiac inflammation and infection in these patients. The feasibility of administering additional caffeine anhydrous is further supported by the maintenance of visual and semi-quantitative image quality, as well as good tolerability among the participants. Trial registration ISCTRP, NLOMON51725. Registered 22 December 2022, https//trialsearch.who.int/Trial2.aspx?TrialID=NLOMON51725 18F-FDG Positron emission tomography computed tomography GLUT4 myocardial metabolism inflammation caffeine sarcoidosis Figures Figure 1 Figure 2 Figure 3 Background Positron emission tomography computed tomography (PET/CT) with 18F-2-fluoro-2-deoxyglucose ([ 18 F]FDG) has an increasingly important role in diagnosing and managing cardiac inflammation and infection [ 1 ]. Cells involved in the inflammatory process exhibit increased glycolysis and, consequently, enhanced [ 18 F]FDG uptake, primarily facilitated by insulin-independent glucose transporters (GLUT)1 and GLUT3 [ 2 ]. A significant challenge in cardiac [ 18 F]FDG PET/CT is the physiological glucose uptake by the myocardium, mainly mediated by insulin-dependent GLUT4, and to a lesser extent by GLUT1 [ 3 – 5 ]. This can complicate the differentiation between normal diffuse physiological uptake and focal or focal on diffuse uptake due to inflammatory tissue [ 6 , 7 ]. This issue can be addressed by manipulating insulin-dependent GLUT4 uptake through high-fat and no- (HFNC) or low- (HFLC) carbohydrate diets for 12 to 24 hours, followed by at least 12 hours of fasting, as recommended by the 2025 Society of Nuclear Medicine and Molecular Imaging (SNMMI)/European Association of Nuclear Medicine (EANM) guideline [ 8 ]. Additionally, administering unfractionated heparin (50 IU/kg) 15 minutes before [ 18 F]FDG injection may further suppress physiological uptake by stimulating lipolysis in the capillary endothelium, leading to a temporary increase in serum free fatty acid (FFA) levels [ 9 – 11 ]. However, some studies have questioned the added benefit of heparin [ 12 – 15 ]. Despite these protocols, 5–20% of patients still exhibit inadequate myocardial uptake suppression, indicating a need for further refinement of the protocol [ 7 ]. Caffeine anhydrous (≤ 5 mg/kg) acts as an adenosine receptor antagonist that stimulates lipolysis in adipose tissue and promotes the adrenergic release of epinephrine, a β- adrenergic receptor ( β AR) agonist, which stimulates β AR-mediated lipolysis in adipose tissue and reduces glucose uptake by β AR-mediated inhibition of GLUT4 expression and translocation to the cell membrane [ 16 – 21 ]. Therefore, caffeine anhydrous may reduce physiological myocardial [ 18 F]FDG uptake. This study aims to investigate the feasibility of using a caffeine anhydrous food supplement to suppress myocardial [ 18 F]FDG uptake. Methods Patients The medical ethical committee of our institution allowed for eight adult patients (four females, four males: mean age 50.4 ± 13.4 years), who in routine clinical care were deemed to have had inadequate myocardial [ 18 F]FDG suppression with the standard HFNC diet and > 12 hours of fasting on their routine [ 18 F]FDG PET/CT, to be included prospectively between February 2023 and August 2024. Exclusion criteria were pregnancy or breastfeeding; history of heart failure; uncontrolled or untreated hypertension; hypersensitivity to caffeine, use of β -blockers, adenosine, stiripentol, or melatonin; started or changed anti-inflammatory therapy between routine and study PET/CT. An exception was made for patient number 5, who was diagnosed with cardiac sarcoidosis. However, high left ventricle (LV) [ 18 F]FDG uptake in the routine PET/CT hindered therapy evaluation, suggesting this patient might benefit from the study. The study was approved by the Medical Ethical Committee of the Erasmus Medical Center (MEC-2022-0053), written informed consent was obtained from all the patients, and procedures were in accordance with the Declaration of Helsinki of 1964, as revised in 2013. Study [F]FDG PET/CT procedure For this study, an [ 18 F]FDG PET/CT with additional caffeine anhydrous was performed 27.8 ± 16.1 (range 7–56) days after the routine [ 18 F]FDG PET/CT. Patients were instructed to eat and drink only the HFNC products that were listed in their medical records for the routine scan and to keep track of these items in a food diary. Furthermore, it was agreed that the fasting time should be similar to the one before the previous routine scan. At the study day, patients were asked to drink 1 litre of water for 2.5 hours prior to [ 18 F]FDG injection. After placing an intravenous (IV) cannula, patients received an oral food supplement tablet containing 200 mg caffeine anhydrous (Pure caffeine, Myprotein, Manchester, United Kingdom), which is considered safe for adults [ 22 ]. According to our local protocol, 232 ± 87 MBq (routine) and 230 ± 84 MBq (study)[ 18 F]FDG was injected 59 ± 2 minutes after caffeine intake followed by rest in a warm, dimly lit room. After 58 ± 3 minutes (routine and study), patients were scanned on a Siemens Biograph mCT PET/CT scanner (Siemens Healthineers, Erlangen, Germany). First, a low-dose CT was acquired for attenuation correction and localization purposes with 120 kV; 40 Quality reference mAs; 0.5 seconds rotation time; pitch of 0.8 mm; slice thickness of 2 mm; Siemens B19f low-dose for emission computed tomography kernel, and a reconstructed slice thickness of 2 mm. Followed by PET acquisition for 3 (≤ 100 kg) or 4 (> 101 kg) minutes per bedposition, which was reconstructed with ordered subset expectation maximization 3D with all standard corrections; point spread function; time of flight; 3 iterations, 21 subsets on a matrix of 400×400 with a voxel size of 2.0×2.0×2.0 and 3 mm (visual analysis) or 5 mm (semi-quantitative analysis (EANM Research Ltd. 2 (EARL2) compliant) Gaussian post-reconstruction filter. Image analysis Two experienced nuclear medicine physicians (TM and QL), blinded for patient data and preparation method, assessed the scans in two randomly divided groups, in two separate sessions (at least two weeks apart) using Hermia Gold Smart Workstation version 2.17 (Hermes Medical Solutions, Stockholm, Sweden). First, they scored myocardial [ 18 F]FDG uptake in the entire myocardium using a 5-point scale according to Scholtens et al. [ 9 ] ranging from 0 to 4: 0 (Myocardium less than left ventricular blood pool); 1 (Myocardium equal to left ventricular blood pool); 2 (Myocardium greater than left ventricular blood pool but less than liver); 3 (Myocardium focally greater than liver); 4 (Myocardium diffusely greater than liver). These scores were dichotomized into adequate (0, 1, and 2) and inadequate (3 and 4) myocardial [ 18 F]FDG suppression for the final analysis. Additionally, segments with inadequate (3 or 4) myocardial [ 18 F]FDG suppression were marked on a 17-segment model. In case of disagreement between the physicians, the scoring and segments were established through a consensus evaluation. Furthermore, the extra-cardiac image quality was scored using a 4-point scale according to Halpern et al.[ 23 ] ranging from 1 to 4: 1 (Non-diagnostic); 2 (Poor); 3 (Moderate); 4 (Good). Extra-cardiac semi-quantitative image quality was determined using VUE PACS version 12 (Philips Medical Systems Nederland BV, Best, The Netherlands) by a third experienced nuclear medicine physician (LG). Volume of interest measurements were applied to determine the mean standard uptake value (SUVmean) of right ventricle bloodpool (Ø=1.5cm) and right liver lobe (Ø=3.0cm). The threshold segmentation tool, with a 50% segmentation range of the maximum value point inside the volume boundaries, was used to measure SUVmean and max values in up to 5 lesions per patient. Patient Monitoring Venous blood was sampled from the IV-cannula for blood glucose (mmol/L) and FFA (mmol/L) analysis before caffeine intake and before [ 18 F]FDG injection. Heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were measured before caffeine intake, before [ 18 F]FDG injection, and after PET/CT. A symptom and mood questionnaire (supplementary material) was carried out at three time points: before caffeine intake, before [ 18 F]FDG injection, and after PET/CT. The symptom and mood questionnaire was adapted from the Symptom-Q questionnaire, which assesses keto-induction symptoms and incorporates a simplified 5-point scale indicator of mood state, both developed by Harvey et al.[ 24 ]. All symptom scores were summed to calculate an overall sum of symptoms score (SOSS) between 0 and 48 for subsequent analysis [ 24 ]. Statistical analysis All statistical analyses were performed using Graphpad PRISM version 9. To compare myocardial [ 18 F]FDG uptake suppression between the two scans, a McNemar test (α = 0.05) was conducted. A Shapiro-Wilk test (α = 0.05) was used to assess normality and select the correct test for the following analyses. A paired t-test (α = 0.05) or a Wilcoxon signed-rank test (α = 0.05) was performed to compare differences in continuous variables. An analysis of variance (ANOVA) repeated measurement test (α = 0.05) (including Mauchly’s test of sphericity with a Greenhouse-Geisser correction for nonsphericity) or a Friedman test (α = 0.05) followed by Dunnett’s or Dunn’s multiple comparisons post hoc test was used to identify significant differences across the three time points for HR, SBP, DBP, SOSS scores and mood state scores. The sample size calculation was based on [ 18 F]FDG PET/CT in oncology [ 25 ] as the only existing test-retest [ 18 F]FDG PET/CT study in cardiac inflammatory [ 26 ] provided no useful information for sample size calculation. Therefore, we assumed that the test-retest SUV measurements in inflammatory extra-cardiac lesions are in line with SUV measurements in oncology. The equality formula for a pair of continuous data proposed by Chow et al [ 27 ] was used for sample size calculation. A power analysis with a 5% two-sided alpha of type I error ( Zα/2 = 1.960) and 90% statistical power ( Zβ = 1.28) was performed. For σ, a SUVmean standard deviation (SD) of 12.5% was used. In sample size calculations for oncology, under ideal conditions, this is around 10% [ 25 ]. However, in the current study, patient preparation between the scans was different, and patient adherence to the diet and fasting may have differed, even with prior agreements on food products and fasting time. For ϵ, a clinically meaningful SUVmean change of 15% will be used based on the recent information statement from the SNMMI, American Society of Nuclear Cardiology (ASNC), and EANM [ 28 ]. The sample size calculation resulted in a sample size of 8 patients for this feasibility study. Results Patient characteristics & diagnostics The patient characteristics are presented in Table 1 . As shown, the mean fasting time was significantly ( p = 0.037) longer for the study (14h16m ± 01h07m) PET/CT than for the routine (13h32m ± 00:31m) PET/CT. Six patients were habitual users of caffeine-containing substances and had abstained for at least 13 hours. Six patients had extra-cardiac sarcoidosis, one had sarcoidosis-like disease, and one had clinical suspicion of sarcoidosis. Except for patient 5, no signs of LV cardiac involvement were found in patients with other tests before routine PET/CT. Three patients (1,3, and 6) showed inadequate physiological [ 18 F]FDG uptake suppression on previous PET/CT scans. Table 1 Patient characteristics Patient Sex m/f Age (years) Fasting time Routine/ Study PET/CT (hour) Habitual caffeine user (yes/no)/ hours abstained for study PET/CT Diagnosis Treatment ECG/ Holter/ Ultrasound/ MRI/ PET findings before routine PET/CT 1 f 47 13:40/ 13:40 Yes/ 13:40 Sarcoid-like disease Golimumab ECG/Holter/ Ultrasound and PET: all normal PET/CT uptake LV physiological pattern, despite HFNC + > 12h fasting 2 f 77 13:10/ 13:05 Yes/ 13:05 Clinical suspicion of sarcoidosis Methotrexate ECG/Holter/Ultrasound/ MRI: PET: all normal 3 f 36 13:50/ 15:15 Yes/ > 24:00 Sarcoidosis Influximab ECG/PET: all normal PET/CT slightly higher uptake LV physiological pattern, despite HFNC + > 12-hour fasting 4 f 51 14:20/ 15:00 Yes/ 15:00 Sarcoidosis - ECG: RBTB PET: normal 5 m 55 14:10/ 16:10 No Sarcoidosis Methotrexate EGC: RBTB Ultrasound: Normal MRI: focal LGE mid-myocardial basal infero-lateral PET/CT: Uptake LV basal inferolateral, possibly cardiac sarcoidosis with low-carbohydrate diet and unknown fasting time 6 m 50 13:05/ 14:40 Yes/ > 24:00 Sarcoidosis Prednisone ECG: normal PET: high LV cardiac uptake ->no diet and prolonged fasting, possibly physiological 7 m 54 12:45/ 12:55 No Sarcoidosis Hydroxy-chloroquine ECG: normal 8 m 33 13:20 13:30 Yes/ 17:30 Sarcoidosis - ECG/ Ultrasound: normal ECG: Electrocardiogram; LV: left ventricle; HFNC: High-fat no-carbohydrate; MRI: Magnetic resonance imaging; RBTB: Right bundle branch block; LGE: Late Gadolinium enhancement Myocardial [F]FDG suppression image analysis Figure 1 compares the transversal slice with the highest myocardial [ 18 F]FDG of the routine PET/CT with the corresponding slice of the study PET/CT. A substantial decrease in myocardial [ 18 F]FDG uptake is observed in the majority of patients after the second PET/CT with additional caffeine anhydrous one hour before [ 18 F]FDG injection. The number of patients with adequate myocardial [ 18 F]FDG uptake suppression increased from one patient (see discussion) in the routine PET/CT group to five patients in the study PET/CT group. Figure 2 illustrates that the study protocol led to a significant ( p < 0.001) reduction in the total number of segments with inadequate suppression (median = 1) compared to the routine protocol (median = 4). The number of inadequately suppressed segments decreased from 9 to 2 segments in patient 2, who showed focal uptake, and from 13 to 4 segments in patient 8, who exhibited diffuse uptake. These inadequate suppressed segments were located in the basal and mid postero-antero-lateral areas (segments 5,6,11, and 12). In patient 6, all segments presented diffuse uptake in both scans, although it was markedly less intense on the study PET/CT. Furthermore, both scans of patient 3 scored adequate myocardial [ 18 F]FDG uptake suppression in the blinded review. Figure 1 Comparison between the transversal slice with the highest myocardial [ 18 F]FDG of the routine PET/CT (upper row) with the corresponding slice of the study PET/CT (lower row) shows that a remarkable decrease of myocardial [ 18 F]FDG uptake and number of inadequate suppressed segments can be seen in the majority of patients after caffeine anhydrous Figure 2 Comparison of segments with inadequate myocardial [ 18 F]FDG suppression demonstrates that the study protocol (B) resulted in a significant (p < 0.001) lower total number of segments with inadequate suppression (median = 1) than the routine protocol (A) (median = 4) Extra-cardiac image quality analysis The results of the extra-cardiac image quality analysis are presented in Table 2 . The visual and semi-quantitative extra-cardiac image quality did not show significant differences between the two groups. However, SUVmax and SUVmean values of 20 lesions were significantly ( p ≤ 0.02) lower in the study PET/CT. The mean change of SUVmean change of -9% between the scans is below the clinically meaningful SUVmean change threshold of 15%. Table 2 Mean ± SD values of visual and semi-quantitative extra-cardiac image quality analysis Routine PET/CT Study PET/CT Visual extra-cardiac image quality score 3.0 ± 0.0 3.0 ± 0.0 SUVmean bloodpool 1.8 ± 0.2 1.7 ± 0.3 SUVmean liver 2.5 ± 0.3 2.5 ± 0.3 SUVmax lesions 6.8 ± 2.1 6.1 ± 2.2* SUVmean lesions 4.5 ± 1.4 4.1 ± 1.5* Significant differences (p < 0.05) are indicated with an asterisk Patient monitoring The results of the blood glucose and FFA measurements before caffeine and [ 18 F]FDG are displayed in Table 3. As can be seen, mean blood glucose and FFA levels were not significantly ( p = 0.191) different between the measurements. However, a large intraindividual variability in the changes of FFA levels following caffeine intake can be seen in Fig. 3 . Table 3: Mean ± SD values of blood glucose and FFA measurements Routine PET/CT before [18F]-FDG Study PET/CT before caffeine Routine PET/CT before [ 18 F]-FDG Blood glucose (mmol/L) 5.9±0.5 5.6±0.5 5.6±0.6 FFA (mmol/L) 0.67±0.30 0.67±0.24 Significant differences (p≤0.05) are indicated with an asterisk Table 4 reports the hemodynamic monitoring parameters. During the hour after caffeine intake, mean HR decreased significantly, and mean SBP and mean DBP increased slightly. After PET/CT, the mean HR returned to before caffeine values, while the mean DBP remained slightly higher (+ 4.1 mmHg) and mean SBP was significantly higher (+ 8.8 mmHg). As shown in the lower part of the table, the SOSS and mood state scores remained stable following caffeine anhydrous intake. Table 4 Mean ± SD values of patient monitoring parameters for before caffeine intake versus before [18F]FDG and after PET/CT Patient monitoring parameter Before caffeine Before [ 18 F]FDG After PET/CT Heart rate (HR) 73.6 ± 13.9 65.6 ± 11.6** 70.4 ± 12.2 Systolic blood pressure (SBP) 127.6 ± 10.8 134.6 ± 14.8 136.4 ± 12.8* Diastolic blood pressure (DBP) 81.5 ± 9.5 83.1 ± 7.2 85.6 ± 6.5 Overall sum of symptoms scores (SOSS) 4.5 ± 4.0 3.4 ± 3.8 2.9 ± 2.8 Mood state score 2.0 ± 0.8 1.9 ± 0.6 1.9 ± 0.6 Significant differences compared to pre-caffeine values are indicated with * p < 0.05 or ** p < 0.01 Discussion To our knowledge, this feasibility study is the first to demonstrate that administering additional caffeine anhydrous food supplement safely significantly (p < 0.001) improves myocardial [ 18 F]FDG uptake suppression in patients who experience inadequate myocardial [ 18 F]FDG uptake suppression following a standard HFNC diet and more than 12 hours of fasting. The feasibility of administering additional caffeine anhydrous is further supported by the maintenance of visual and semi-quantitative image quality, as well as good tolerability among the participants. Despite the good results in most patients, a certain degree of inadequate suppression was still observed in a fairly distinctive pattern, located exclusively in the basal and mid postero-antero-lateral areas, which are known to commonly exhibit physiological diffuse or focal uptake [ 9 , 12 , 29 – 31 ]. Follow-up diagnostic exams after the study PET/CT (such as ECG, Holter, ultrasound, and MRI), under the same treatment conditions, confirmed the absence of myocardial inflammation or ischemia in all but one patient. The one patient (patient 6) who exhibited inadequate suppression on both PET/CT scans, albeit still a reduced intensity of diffuse uptake on the study PET/CT with additional caffeine anhydrous administration, was ultimately diagnosed with extensive cardiac sarcoidosis after being referred for a new ECG and MRI. Additionally, this one patient with less intense yet persistent myocardial uptake also had extensive pulmonary disease, which may have resulted in increased myocardial [ 18 F]FDG uptake due to upregulated GLUT1 and downregulated fatty acid transporters in the myocardium [ 13 ]. That one patient (patient 3) was included based on the original medical report stating insufficient myocardial suppression, but scored as adequate suppression on both scans upon blinded review in this study is regarded inherent to differences in an individual case in a clinical setting versus scoring a series of studies in a research setting. Previous studies [ 9 , 32 ] have noted that subjective scoring in patients with myocardial uptake similar to liver uptake can lead to interobserver disagreement. While semi-quantitative measurements are more objective, cardiac segmentation can be challenging for patients with focal or no uptake [ 33 ], making such assessments unfeasible for the current study. Caffeine anhydrous did not impact the extra-cardiac visual image quality and lesion SUV measurements, as it specifically affects GLUT4 [ 16 , 17 ] and not GLUT1 and 3, which are involved in inflammation. The mean change in SUVmean between routine and study PET/CT was − 9%, which is below the clinically meaningful SUVmean change of 15% [ 28 ]. However, this significant ( p ≤ 0.02) decrease was primarily due to nonspecific lesions in patient 1. After exclusion of this patient, the mean change in SUVmean dropped to -1.8%, with no significant ( p = 0.289) differences between the scans. The hemodynamic trends showed an increase in SBP and DBP due to vasoconstriction due to adenosine receptor blockage, along with a baroreceptor-mediated decrease HR during the first hour. These findings are consistent with previous studies involving similar caffeine intake levels [ 34 , 35 ]. After the PET/CT, SBP was significantly higher, largely due to patient 2, whose SBP increased by approximately 12 mmHg following the [ 18 F]FDG injection. This observation supports findings of previous studies in older patients [ 36 , 37 ], and after excluding patient 2, there was no significant difference ( p = 0.174) in SBP. Further monitoring of the patients revealed no negative symptoms or mood effects, which is consistent with findings of the European Food Safety Authority [ 22 ]. In contrast to previous studies with comparable caffeine dosage [ 38 , 39 ], current study showed both increased and decreased FFA levels after caffeine ingestion. A possible explanation might be that persons with a high baseline FFA level due to the HFNC diet might reached their maximum FFA level within the hour after caffeine ingestion in combination with a higher energy expenditure [ 40 ]. However, no other study investigated the FFA response to caffeine after a HFNC diet and this requires further investigation. A strength of this study is its design, where each patient serves as their own control. Notably, there is only one other extensive controlled study that compares the standard preparation with the addition of heparin within the same patient, conducted by Gormsen et al. [ 13 ]. Unfortunately, studies of this design are limited in the number of participants due to ethical regulations. However, our appropriately calculated sample size provides generalizable results. In contrast to these two smaller studies, several larger studies [ 9 – 12 , 14 , 15 ] that focus on strategies to suppress myocardial [ 18 F]FDG uptake are primarily case-control or retrospective studies. These studies are influenced by individual differences in myocardial substrate metabolism. Additionally, they did not confirm adherence to diet and/or report precise fasting times, which may have introduced bias. A limitation of the current study is the absence of measurements for ketosis with beta-hydroxybutyrate (BHB). Previous studies [ 14 , 41 – 43 ] have shown a relationship between BHB levels and the suppression of myocardial [ 18 F]FDG uptake. However, some patients with low BHB still demonstrated adequate myocardial [ 18 F]FDG uptake suppression and vice versa [ 42 ]. This suggests that myocardial substrate metabolism is quite complex, with significant interindividual variations, indicating that further research is needed. A weakness of the current study it that, despite providing comprehensive instructions and emphasizing the importance of using the same food products and adhering to the specific time for the pre-fast meal through both email and telephone communication with all patients, there was some slight variability in food products and fasting times. This inconsistency may have introduced bias in the amount of myocardial [ 18 F]FDG uptake suppression. However, this occurrence of bias varies among patients. For instance, in patient 3, the PET/CT scan conducted using the standard preparation before the routine PET/CT scan showed inadequate suppression, despite a longer fasting period (15.40 hours) compared to both the routine and study PET/CT scans. Another weakness of this study is that patients were allowed to consume caffeine-containing drinks until 11 hours before taking the caffeine anhydrous food supplement, as per the routine study diet. This might have led to some tolerance in habitual heavy users, like patient 8. Unlike the other patients, this patient exhibited minimal changes in HR and BP, suggesting the presence of caffeine tolerance [ 44 ]. It is recommended that patients abstain from caffeine for at least 24 hours to improve their response to acute caffeine intake [ 34 , 44 ]. Additionally, it’s important to note that coffee cannot replace caffeine anhydrous, as other organic compounds like chlorogenic acids in coffee can interfere with caffeine's binding to adenosine receptors. This can reduce its effectiveness in promoting lipolysis and inhibiting GLUT4 [ 18 F]FDG uptake [ 45 – 47 ]. Despite the small number of patients in this study, the findings support the hypothesis that an additional food supplement of caffeine anhydrous improves [ 18 F]FDG uptake suppression in patients who do not achieve adequate [ 18 F]FDG uptake suppression following standard preparation. To validate these results, further research is needed with larger patient groups, and at least 24 hours of caffeine abstinence. Alternatively, there is an ongoing search for PET tracers that are more specific than [ 18 F]FDG for myocardial inflammation. Currently, data is available on [ 68 Ga]Ga-Somatostatin analogues [ 48 ], [ 68 Ga]Ga-Pentixafor [ 48 ], and [ 68 Ga]Ga-fibroblast activation protein inhibitors [ 49 ]. To date, however, only small studies have been conducted, and larger, prospective studies are necessary to evaluate their potential effectiveness, along with addressing issues related to availability and reimbursement. Conclusion Additional caffeine anhydrous food supplement one hour before [ 18 F]FDG administration has the potency to safely improve myocardial [ 18 F]FDG uptake suppression, while maintaining extra-cardiac visual and semi-quantitative image quality in patients with inadequate suppression after standard preparation. Abbreviations GLUT glucose transporter PET/CT positron emission tomography/computed tomography [ 18 F]FDG 18F-2-fluoro-2-deoxyglucose HFNC high-fat, no-carbohydrate HFLC high-fat, low-carbohydrate SNMMI Society of Nuclear Medicine and Molecular Imaging EANM European Association of Nuclear Medicine FFA free fatty acids β AR β- adrenergic receptor LV left ventricle IV intravenously EARL2 EANM Research Ltd. 2 SUVmean mean standard uptake value HR heart rate SBP systolic blood pressure DBP diastolic blood pressure SOSS sum of symptoms score ASNC American Society of Nuclear Cardiology ECG Electrocardiogram MRI Magnetic resonance imaging RBTB Right bundle branch block LGE Late Gadolinium enhancement BHB beta-hydroxybutyrate Declarations Ethics approval and consent to participate The study was approved by the Medical Ethical Committee of the Erasmus Medical Centre (reference number: MEC-2022-0053). Consent for publication Patients signed informed consent regarding publishing their data and images. Competing interests The authors have no competing interests to declare that are relevant to the content of this article. Funding The authors did not receive support from any organization for the submitted work. This project was funded by the department of Radiology & Nuclear medicine, Erasmus MC, Rotterdam, The Netherlands Authors' contributions CC, TB, and FV contributed to the study concepts and to the study design. CC contributed to the data collection. QL and TM contributed to the visual analysis. LG contributed to the semi-quantitative analysis. CC contributed to the data analysis and statistical analysis. CC, TB, TM, FV, QL, and LG contributed to the data interpretation, to the manuscript preparation, to the manuscript editing, and reviewing. All authors read and approved the final manuscript. Acknowledgements Not applicable References 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(4):647–58. Wang ZG, Yu MM, Han Y, Wu FY, Yang GJ, Li DC, Liu SM. Correlation of Glut-1 and Glut-3 expression with F-18 FDG uptake in pulmonary inflammatory lesions. Med (Baltim). 2016;95(48):e5462. Olson AL, Pessin JE. Structure, function, and regulation of the mammalian facilitative glucose transporter gene family. Annu Rev Nutr. 1996;16:235–56. Depre C, Vanoverschelde JL, Taegtmeyer H. Glucose for the heart. Circulation. 1999;99(4):578–88. van den Brom C, Bulte C, Loer S, Bouwman RA, Boer C. Diabetes, perioperative ischaemia and volatile anaesthetics: Consequences of derangements in myocardial substrate metabolism. Cardiovasc Diabetol. 2013;12:42. Glaudemans AW, Israel O, Slart RH. Pitfalls and Limitations of Radionuclide and Hybrid Imaging in Infection and Inflammation. Semin Nucl Med. 2015;45(6):500–12. Osborne MT, Hulten EA, Murthy VL, Skali H, Taqueti VR, Dorbala S, et al. Patient preparation for cardiac fluorine-18 fluorodeoxyglucose positron emission tomography imaging of inflammation. J Nucl Cardiol. 2017;24(1):86–99. Abikhzer G, Treglia G, Pelletier-Galarneau M, Buscombe J, Chiti A, Dibble EH, et al. EANM/SNMMI guideline/procedure standard for [18F]FDG hybrid PET use in infection and inflammation in adults v2.0. Eur J Nucl Med Mol Imaging. 2025;52(2):510–38. Scholtens AM, Verberne HJ, Budde RP, Lam MG. Additional Heparin Preadministration Improves Cardiac Glucose Metabolism Suppression over Low-Carbohydrate Diet Alone in ¹⁸F-FDG PET Imaging. J Nucl Med. 2016;57(4):568–73. Scholtens AM, van den Berk AM, van der Sluis NL, Esser JP, Lammers GK, de Klerk JMH, et al. Suppression of myocardial glucose metabolism in FDG PET/CT: impact of dose variation in heparin bolus pre-administration. Eur J Nucl Med Mol Imaging. 2020;47(11):2698–702. Masuda A, Naya M, Manabe O, Magota K, Yoshinaga K, Tsutsui H, Tamaki N. Administration of unfractionated heparin with prolonged fasting could reduce physiological 18F-fluorodeoxyglucose uptake in the heart. Acta Radiol. 2016;57(6):661–8. Morooka M, Moroi M, Uno K, Ito K, Wu J, Nakagawa T, et al. Long fasting is effective in inhibiting physiological myocardial 18F-FDG uptake and for evaluating active lesions of cardiac sarcoidosis. EJNMMI Res. 2014;4(1):1. Gormsen LC, Christensen NL, Bendstrup E, Tolbod LP, Nielsen SS. Complete somatostatin-induced insulin suppression combined with heparin loading does not significantly suppress myocardial 18F-FDG uptake in patients with suspected cardiac sarcoidosis. J Nucl Cardiol. 2013;20(6):1108–15. Hartikainen S, Vepsäläinen V, Lyyra-Laitinen T, Hedman M, Laitinen T, Tompuri T. Heparin does not improve myocardial glucose metabolism suppression in [18 F]FDG PET/CT in patients with low β-hydroxybutyrate level. EJNMMI Res. 2024;14. Manabe O, Yoshinaga K, Ohira H, Masuda A, Sato T, Tsujino I, et al. The effects of 18-h fasting with low-carbohydrate diet preparation on suppressed physiological myocardial (18)F-fluorodeoxyglucose (FDG) uptake and possible minimal effects of unfractionated heparin use in patients with suspected cardiac involvement sarcoidosis. J Nucl Cardiol. 2016;23(2):244–52. Thong FS, Graham TE. Caffeine-induced impairment of glucose tolerance is abolished by beta-adrenergic receptor blockade in humans. J Appl Physiol (1985). 2002;92(6):2347–52. Mulder AH, Tack CJ, Olthaar AJ, Smits P, Sweep FC, Bosch RR. Adrenergic receptor stimulation attenuates insulin-stimulated glucose uptake in 3T3-L1 adipocytes by inhibiting GLUT4 translocation. Am J Physiol Endocrinol Metab. 2005;289(4):E627–33. Deibert Dc Fau - DeFronzo RA, DeFronzo RA. Epinephrine-induced insulin resistance in man. (0021-9738 (Print)). Battram DS, Graham TE, Dela F. Caffeine's impairment of insulin-mediated glucose disposal cannot be solely attributed to adrenaline in humans. J Physiol. 2007;583(Pt 3):1069–77. Mangmool S, Denkaew T, Parichatikanond W, Kurose H. β-Adrenergic Receptor and Insulin Resistance in the Heart. Biomol Ther (Seoul). 2017;25(1):44–56. Mangmool S, Denkaew T, Phosri S, Pinthong D, Parichatikanond W, Shimauchi T, Nishida M. Sustained βAR Stimulation Mediates Cardiac Insulin Resistance in a PKA-Dependent Manner. Mol Endocrinol. 2016;30(1):118–32. Panel EN. Scientific Opinion on the safety of caffeine. EFSA J. 2015;13(5). Halpern BS, Dahlbom M, Auerbach MA, Schiepers C, Fueger BJ, Weber WA, et al. Optimizing imaging protocols for overweight and obese patients: a lutetium orthosilicate PET/CT study. J Nucl Med. 2005;46(4):603–7. Harvey C, Schofield G, Zinn C, Thornley S. Can a 'carbohydrate tolerance questionnaire' predict outcomes from diets differing in carbohydrate content? A pilot study. J Holist Perform. 2019. Doot RK, Kurland BF, Kinahan PE, Mankoff DA. Design considerations for using PET as a response measure in single site and multicenter clinical trials. Acad Radiol. 2012;19(2):184–90. Alvi RM, Young BD, Shahab Z, Pan H, Winkler J, Herzog E, Miller EJ. Repeatability and Optimization of FDG Positron Emission Tomography for Evaluation of Cardiac Sarcoidosis. JACC Cardiovasc Imaging. 2019;12(7 Pt 1):1284–7. Chow SC, Shao J, Wang H, Lokhnygina Y. Sample Size Calculations in Clinical Research. CRC; 2017. Sperry BW, Bateman TM, Akin EA, Bravo PE, Chen W, Dilsizian V et al. Hot spot imaging in cardiovascular diseases: an information statement from SNMMI, ASNC, and EANM. J Nucl Cardiol. 2022;30(2). Norikane T, Yamamoto Y, Takami Y, Mitamura K, Kobata T, Maeda Y, et al. Physiological myocardial 18F-FDG uptake pattern in oncologic PET/CT: comparison with findings in cardiac sarcoidosis. Asia Ocean J nuclear Med biology. 2024;12:1–10. Gropler RJ, Siegel BA, Lee KJ, Moerlein SM, Perry DJ, Bergmann SR, Geltman EM. Nonuniformity in myocardial accumulation of fluorine-18-fluorodeoxyglucose in normal fasted humans. J Nucl Med. 1990;31(11):1749–56. Maurer AH, Burshteyn M, Adler LP, Gaughan JP, Steiner RM. Variable cardiac 18FDG patterns seen in oncologic positron emission tomography computed tomography: importance for differentiating normal physiology from cardiac and paracardiac disease. J Thorac Imaging. 2012;27(4):263–8. Ohira H, Ardle BM, deKemp RA, Nery P, Juneau D, Renaud JM, et al. Inter- and Intraobserver Agreement of 18 F-FDG PET/CT Image Interpretation in Patients Referred for Assessment of Cardiac Sarcoidosis. Journal of Nuclear Medicine. 2017;58(8):1324. Josselyn N, MacLean MT, Jean C, Fuchs B, Moon BF, Hwuang E, et al. Classification of Myocardial (18)F-FDG PET Uptake Patterns Using Deep Learning. Radiol Artif Intell. 2021;3(4):e200148. Whitsett TL, Manion CV, Christensen HD. Cardiovascular effects of coffee and caffeine. Am J Cardiol. 1984;53(7):918–22. Casiglia E, Paleari CD, Petucco S, Bongiovì S, Colangeli G, Baccilieri MS, et al. Haemodynamic effects of coffee and purified caffeine in normal volunteers: a placebo-controlled clinical study. J Hum Hypertens. 1992;6(2):95–9. Arciero PJ, Ormsbee MJ. Relationship of blood pressure, behavioral mood state, and physical activity following caffeine ingestion in younger and older women. Appl Physiol Nutr Metab. 2009;34(4):754–62. Arciero PJ, Gardner AW, Benowitz NL, Poehlman ET. Relationship of blood pressure, heart rate and behavioral mood state to norepinephrine kinetics in younger and older men following caffeine ingestion. Eur J Clin Nutr. 1998;52(11):805–12. Patwardhan RV, Desmond PV, Johnson RF, Dunn GD, Robertson DH, Hoyumpa AM Jr., Schenker S. Effects of caffeine on plasma free fatty acids, urinary catecholamines, and drug binding. Clin Pharmacol Ther. 1980;28(3):398–403. Benowitz NL, Jacob P 3rd, Mayan H, Denaro C. Sympathomimetic effects of paraxanthine and caffeine in humans. Clin Pharmacol Ther. 1995;58(6):684–91. Arciero PJ, Gardner AW, Calles-Escandon J, Benowitz NL, Poehlman ET. Effects of caffeine ingestion on NE kinetics, fat oxidation, and energy expenditure in younger and older men. Am J Physiol. 1995;268(6 Pt 1):E1192–8. Alfawara MS, Ahmed AI, Saad JM, Han Y, Alahdab F, Al Rifai M, et al. The utility of beta-hydroxybutyrate in detecting myocardial glucose uptake suppression in patients undergoing inflammatory [18F]-FDG PET studies. Eur J Nucl Med Mol Imaging. 2023;50(4):1103–10. Hartikainen S, Tompuri T, Laitinen T, Laitinen T. Point-of-care β-hydroxybutyrate measurement predicts adequate glucose metabolism suppression in cardiac FDG-PET/CT. Clin Physiol Funct Imaging. 2024;44(5):349–58. Madamanchi C, Weinberg RL, Murthy VL. Utility of serum ketone levels for assessment of myocardial glucose suppression for (18)F-fluorodeoxyglucose PET in patients referred for evaluation of endocarditis. J Nucl Cardiol. 2023;30(3):928–37. Robertson D, Wade D, Workman R, Woosley RL, Oates JA. Tolerance to the humoral and hemodynamic effects of caffeine in man. J Clin Invest. 1981;67(4):1111–7. Battram DS, Arthur R, Weekes A, Graham TE. The glucose intolerance induced by caffeinated coffee ingestion is less pronounced than that due to alkaloid caffeine in men. J Nutr. 2006;136(5):1276–80. Hodgson AB, Randell RK, Jeukendrup AE. The metabolic and performance effects of caffeine compared to coffee during endurance exercise. PLoS ONE. 2013;8(4):e59561. Graham TE, Hibbert E, Sathasivam P. Metabolic and exercise endurance effects of coffee and caffeine ingestion. J Appl Physiol (1985). 1998;85(3):883–9. Lucinian YA, Martineau P, Abikhzer G, Harel F, Pelletier-Galarneau M. Novel tracers to assess myocardial inflammation with radionuclide imaging. J Nuclear Cardiol. 2024:102012. Treglia G, Albano D. FAPI PET/CT in infectious, inflammatory, and rheumatological diseases: watch it like a hawk or one swallow does not make a summer? Eur J Nucl Med Mol Imaging. 2023;50(7):1848–50. Supplementary Files Supplementarymaterial.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7739411","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":547503595,"identity":"9fc813a5-27e3-4f8e-9f58-4188d247a8ca","order_by":0,"name":"Christina Petronella Wilhelmina Cox","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuklEQVRIiWNgGAWjYNCCCmQOO1FaziBzmInRwdhGihb+BuaHj3nn2eTz959Ok/yZY8dgTkiLxAE2Y8OZ29IsZ9zI3SbNuy2ZwbKZgBYDBh42iY/bDhsw3ODdJs247QCDwWFitCTO+W8gf/7sNsmfRGv52HDAwOBA7jYJXmK0SBwG+mXGsWQDwxu5m62BfuEhqIW/vfnhY54aOwO582c33vy5zU7O4HgDAT3oQcpDQP0oGAWjYBSMAmIAAGDkOlPQ4dpWAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-5313-6727","institution":"Erasmus MC","correspondingAuthor":true,"prefix":"","firstName":"Christina","middleName":"Petronella Wilhelmina","lastName":"Cox","suffix":""},{"id":547503596,"identity":"4509c26d-62ce-4c61-8ad4-fe99000a0ea6","order_by":1,"name":"Quido Gisou de Lussanet de la Sablonière","email":"","orcid":"","institution":"Erasmus MC","correspondingAuthor":false,"prefix":"","firstName":"Quido","middleName":"Gisou de Lussanet de la","lastName":"Sablonière","suffix":""},{"id":547503597,"identity":"7c2d1485-a8ba-42b7-955a-b42bf95de4ba","order_by":2,"name":"Ties Andries Mulders","email":"","orcid":"","institution":"Erasmus MC","correspondingAuthor":false,"prefix":"","firstName":"Ties","middleName":"Andries","lastName":"Mulders","suffix":""},{"id":547503598,"identity":"b8bb9d66-15eb-4cc4-b291-e7ddd1254252","order_by":3,"name":"Laura Hendrika Graven","email":"","orcid":"","institution":"Erasmus MC","correspondingAuthor":false,"prefix":"","firstName":"Laura","middleName":"Hendrika","lastName":"Graven","suffix":""},{"id":547503599,"identity":"ea042751-866d-4f23-a7fd-f798e8f700ad","order_by":4,"name":"Frederik Anton Verburg","email":"","orcid":"","institution":"Erasmus MC","correspondingAuthor":false,"prefix":"","firstName":"Frederik","middleName":"Anton","lastName":"Verburg","suffix":""},{"id":547503600,"identity":"ba30c3fa-8faf-4c94-8653-2f363642214f","order_by":5,"name":"Tessa Brabander","email":"","orcid":"","institution":"Erasmus MC","correspondingAuthor":false,"prefix":"","firstName":"Tessa","middleName":"","lastName":"Brabander","suffix":""}],"badges":[],"createdAt":"2025-09-29 08:04:59","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7739411/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7739411/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":96977868,"identity":"564e7e54-117a-4f19-bb82-3cf0679392bd","added_by":"auto","created_at":"2025-11-28 08:49:18","extension":"tif","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":327006,"visible":true,"origin":"","legend":"","description":"","filename":"Fig1.tif","url":"https://assets-eu.researchsquare.com/files/rs-7739411/v1/a4f4dfd96aeec2a47086ecdc.tif"},{"id":96977864,"identity":"1246c4f7-d7b4-4ada-a79f-f28d00e92700","added_by":"auto","created_at":"2025-11-28 08:49:18","extension":"tiff","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":86034,"visible":true,"origin":"","legend":"","description":"","filename":"Fig2.tiff","url":"https://assets-eu.researchsquare.com/files/rs-7739411/v1/d6b7ae3ccf8fa44ed9928160.tiff"},{"id":97138230,"identity":"6b537e40-f8b9-4dea-a79e-240d89c100bf","added_by":"auto","created_at":"2025-12-01 09:58:40","extension":"tiff","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":228992,"visible":true,"origin":"","legend":"","description":"","filename":"Fig3.tiff","url":"https://assets-eu.researchsquare.com/files/rs-7739411/v1/c474409a0eb84089d251dd7e.tiff"},{"id":97137114,"identity":"b4c0d0b9-62c5-4173-ba7f-7df7a8120144","added_by":"auto","created_at":"2025-12-01 09:57:23","extension":"xml","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":11931,"visible":true,"origin":"","legend":"","description":"","filename":"ejreEJRED2500419.xml","url":"https://assets-eu.researchsquare.com/files/rs-7739411/v1/abfa564e50264d2dd668a411.xml"},{"id":97138872,"identity":"68311ee6-4dde-42de-b08c-b93ac734ea01","added_by":"auto","created_at":"2025-12-01 09:59:24","extension":"xml","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1066,"visible":true,"origin":"","legend":"","description":"","filename":"EJRED250041911268.go.xml","url":"https://assets-eu.researchsquare.com/files/rs-7739411/v1/8f738b85f3365eb8ae4b12c7.xml"},{"id":96977866,"identity":"c1ef1466-e9cd-42c5-97cf-64d96dc0a4d6","added_by":"auto","created_at":"2025-11-28 08:49:18","extension":"xml","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":941,"visible":true,"origin":"","legend":"","description":"","filename":"EJRED2500419Import.xml","url":"https://assets-eu.researchsquare.com/files/rs-7739411/v1/cb68f05d52020c90b5b44731.xml"},{"id":96977872,"identity":"1bdebc81-89e2-414b-9d73-911b99b3280c","added_by":"auto","created_at":"2025-11-28 08:49:18","extension":"xml","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":126780,"visible":true,"origin":"","legend":"","description":"","filename":"EJRED25004190enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7739411/v1/376a8e7d86c581a1e63f626f.xml"},{"id":96977874,"identity":"97eb162f-a5b6-443c-b0ea-e520e93ee918","added_by":"auto","created_at":"2025-11-28 08:49:18","extension":"tif","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":327006,"visible":true,"origin":"","legend":"","description":"","filename":"Fig1.tif","url":"https://assets-eu.researchsquare.com/files/rs-7739411/v1/bee25830218fe7e66a57f253.tif"},{"id":96977877,"identity":"f6969a87-2242-486e-a691-e164efcf1663","added_by":"auto","created_at":"2025-11-28 08:49:18","extension":"tiff","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":86034,"visible":true,"origin":"","legend":"","description":"","filename":"Fig2.tiff","url":"https://assets-eu.researchsquare.com/files/rs-7739411/v1/9bb65051a4ea9e718136bcce.tiff"},{"id":96977875,"identity":"66f3b74d-06ab-46dc-9c2f-30edaa0f7ae8","added_by":"auto","created_at":"2025-11-28 08:49:18","extension":"tiff","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":228992,"visible":true,"origin":"","legend":"","description":"","filename":"Fig3.tiff","url":"https://assets-eu.researchsquare.com/files/rs-7739411/v1/cf5285da2b6100ac91eae24d.tiff"},{"id":97138066,"identity":"61896c8e-c033-4e94-b9f3-e0b8bff2c294","added_by":"auto","created_at":"2025-12-01 09:58:27","extension":"jpeg","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":233193,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7739411/v1/720afc54a05e1e2fc81d200a.jpeg"},{"id":96977883,"identity":"c62dfdde-9749-4944-b0c7-df3dc8076981","added_by":"auto","created_at":"2025-11-28 08:49:18","extension":"png","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":166983,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFig1.png","url":"https://assets-eu.researchsquare.com/files/rs-7739411/v1/fc43244e5a7f08ca0be7524a.png"},{"id":96977881,"identity":"33d99c74-bb05-403c-a795-7f144037b352","added_by":"auto","created_at":"2025-11-28 08:49:18","extension":"png","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":24232,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFig2.png","url":"https://assets-eu.researchsquare.com/files/rs-7739411/v1/4914a1369380ba4e32715acc.png"},{"id":97138996,"identity":"14ce07ad-aa40-4c0f-9884-c56cf5b51aee","added_by":"auto","created_at":"2025-12-01 09:59:30","extension":"png","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":38586,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFig3.png","url":"https://assets-eu.researchsquare.com/files/rs-7739411/v1/7bb46e8493e203f01c12875f.png"},{"id":97136671,"identity":"e5016949-4eb3-4e9b-93ed-76492827c169","added_by":"auto","created_at":"2025-12-01 09:56:51","extension":"png","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":43467,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7739411/v1/bec73a53469818ee00e5a3ef.png"},{"id":96977884,"identity":"6d2b94d7-2e33-4a3d-827c-7ed6472222a0","added_by":"auto","created_at":"2025-11-28 08:49:18","extension":"xml","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":126188,"visible":true,"origin":"","legend":"","description":"","filename":"EJRED25004190structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7739411/v1/5fe47ccedcfe145ee75838dc.xml"},{"id":97137677,"identity":"cc54fd36-5d9d-499b-96dd-e6de36e37cd4","added_by":"auto","created_at":"2025-12-01 09:58:04","extension":"html","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":136580,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7739411/v1/6e2f9b99f7a14e31f45b3262.html"},{"id":96977863,"identity":"668a1b58-cf47-470e-963e-cb7deeadbb21","added_by":"auto","created_at":"2025-11-28 08:49:18","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":492268,"visible":true,"origin":"","legend":"\u003cp\u003eComparison between the transversal slice with the highest myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG of the routine PET/CT (upper row) with the corresponding slice of the study PET/CT (lower row) shows that a remarkable decrease of myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake and number of inadequate suppressed segments can be seen in the majority of patients after caffeine anhydrous\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-7739411/v1/59756bef0ef647d24b9aeb61.png"},{"id":96977871,"identity":"7f03613e-8cc8-44d2-8639-d59e022cd8b9","added_by":"auto","created_at":"2025-11-28 08:49:18","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":149640,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of segments with inadequate myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG suppression demonstrates that the study protocol (B) resulted in a significant (p\u0026lt;0.001) lower total number of segments with inadequate suppression (median = 1) than the routine protocol (A) (median = 4)\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-7739411/v1/873c18e5910f3de2960fd6b3.png"},{"id":97137693,"identity":"bc9cff2f-4304-4245-bea7-dc5269a99223","added_by":"auto","created_at":"2025-12-01 09:58:04","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":221082,"visible":true,"origin":"","legend":"\u003cp\u003eIndividual parallel line plots of all patients representing FFA (mmol/L) values before caffeine and [18F]FDG show a large intraindividual variability in the changes of FFA levels following caffeine intake.\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-7739411/v1/1a8fab1a61a856aa14b35e3c.png"},{"id":101942995,"identity":"d7ec1e94-e9a3-408e-9d60-5c84a26e0615","added_by":"auto","created_at":"2026-02-05 09:39:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2693332,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7739411/v1/b9668682-7841-4e96-90a3-fd39baf08931.pdf"},{"id":96977879,"identity":"4107919f-e706-4c40-9e2f-b78e5886d02f","added_by":"auto","created_at":"2025-11-28 08:49:18","extension":"pdf","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":155765,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7739411/v1/122e716953fac41cc9ed1ded.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003ePre-administration of caffeine anhydrous food supplement potentially improves suppression of physiologic myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake: a feasibility study.\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003ePositron emission tomography computed tomography (PET/CT) with 18F-2-fluoro-2-deoxyglucose ([\u003csup\u003e18\u003c/sup\u003eF]FDG) has an increasingly important role in diagnosing and managing cardiac inflammation and infection [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Cells involved in the inflammatory process exhibit increased glycolysis and, consequently, enhanced [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake, primarily facilitated by insulin-independent glucose transporters (GLUT)1 and GLUT3 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. A significant challenge in cardiac [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT is the physiological glucose uptake by the myocardium, mainly mediated by insulin-dependent GLUT4, and to a lesser extent by GLUT1 [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. This can complicate the differentiation between normal diffuse physiological uptake and focal or focal on diffuse uptake due to inflammatory tissue [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This issue can be addressed by manipulating insulin-dependent GLUT4 uptake through high-fat and no- (HFNC) or low- (HFLC) carbohydrate diets for 12 to 24 hours, followed by at least 12 hours of fasting, as recommended by the 2025 Society of Nuclear Medicine and Molecular Imaging (SNMMI)/European Association of Nuclear Medicine (EANM) guideline [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Additionally, administering unfractionated heparin (50 IU/kg) 15 minutes before [\u003csup\u003e18\u003c/sup\u003eF]FDG injection may further suppress physiological uptake by stimulating lipolysis in the capillary endothelium, leading to a temporary increase in serum free fatty acid (FFA) levels [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, some studies have questioned the added benefit of heparin [\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Despite these protocols, 5\u0026ndash;20% of patients still exhibit inadequate myocardial uptake suppression, indicating a need for further refinement of the protocol [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Caffeine anhydrous (\u0026le;\u0026thinsp;5 mg/kg) acts as an adenosine receptor antagonist that stimulates lipolysis in adipose tissue and promotes the adrenergic release of epinephrine, a \u003cem\u003eβ-\u003c/em\u003eadrenergic receptor (\u003cem\u003eβ\u003c/em\u003eAR) agonist, which stimulates \u003cem\u003eβ\u003c/em\u003eAR-mediated lipolysis in adipose tissue and reduces glucose uptake by \u003cem\u003eβ\u003c/em\u003eAR-mediated inhibition of GLUT4 expression and translocation to the cell membrane [\u003cspan additionalcitationids=\"CR17 CR18 CR19 CR20\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Therefore, caffeine anhydrous may reduce physiological myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake. This study aims to investigate the feasibility of using a caffeine anhydrous food supplement to suppress myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ePatients\u003c/h2\u003e\u003cp\u003eThe medical ethical committee of our institution allowed for eight adult patients (four females, four males: mean age 50.4\u0026thinsp;\u0026plusmn;\u0026thinsp;13.4 years), who in routine clinical care were deemed to have had inadequate myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG suppression with the standard HFNC diet and \u0026gt;\u0026thinsp;12 hours of fasting on their routine [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT, to be included prospectively between February 2023 and August 2024. Exclusion criteria were pregnancy or breastfeeding; history of heart failure; uncontrolled or untreated hypertension; hypersensitivity to caffeine, use of \u003cem\u003eβ\u003c/em\u003e-blockers, adenosine, stiripentol, or melatonin; started or changed anti-inflammatory therapy between routine and study PET/CT. An exception was made for patient number 5, who was diagnosed with cardiac sarcoidosis. However, high left ventricle (LV) [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake in the routine PET/CT hindered therapy evaluation, suggesting this patient might benefit from the study. The study was approved by the Medical Ethical Committee of the Erasmus Medical Center (MEC-2022-0053), written informed consent was obtained from all the patients, and procedures were in accordance with the Declaration of Helsinki of 1964, as revised in 2013.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy [F]FDG PET/CT procedure\u003c/h3\u003e\n\u003cp\u003eFor this study, an [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT with additional caffeine anhydrous was performed 27.8\u0026thinsp;\u0026plusmn;\u0026thinsp;16.1 (range 7\u0026ndash;56) days after the routine [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT. Patients were instructed to eat and drink only the HFNC products that were listed in their medical records for the routine scan and to keep track of these items in a food diary. Furthermore, it was agreed that the fasting time should be similar to the one before the previous routine scan. At the study day, patients were asked to drink 1 litre of water for 2.5 hours prior to [\u003csup\u003e18\u003c/sup\u003eF]FDG injection. After placing an intravenous (IV) cannula, patients received an oral food supplement tablet containing 200 mg caffeine anhydrous (Pure caffeine, Myprotein, Manchester, United Kingdom), which is considered safe for adults [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. According to our local protocol, 232\u0026thinsp;\u0026plusmn;\u0026thinsp;87 MBq (routine) and 230\u0026thinsp;\u0026plusmn;\u0026thinsp;84 MBq (study)[\u003csup\u003e18\u003c/sup\u003eF]FDG was injected 59\u0026thinsp;\u0026plusmn;\u0026thinsp;2 minutes after caffeine intake followed by rest in a warm, dimly lit room. After 58\u0026thinsp;\u0026plusmn;\u0026thinsp;3 minutes (routine and study), patients were scanned on a Siemens Biograph mCT PET/CT scanner (Siemens Healthineers, Erlangen, Germany). First, a low-dose CT was acquired for attenuation correction and localization purposes with 120 kV; 40 Quality reference mAs; 0.5 seconds rotation time; pitch of 0.8 mm; slice thickness of 2 mm; Siemens B19f low-dose for emission computed tomography kernel, and a reconstructed slice thickness of 2 mm. Followed by PET acquisition for 3 (\u0026le;\u0026thinsp;100 kg) or 4 (\u0026gt;\u0026thinsp;101 kg) minutes per bedposition, which was reconstructed with ordered subset expectation maximization 3D with all standard corrections; point spread function; time of flight; 3 iterations, 21 subsets on a matrix of 400\u0026times;400 with a voxel size of 2.0\u0026times;2.0\u0026times;2.0 and 3 mm (visual analysis) or 5 mm (semi-quantitative analysis (EANM Research Ltd. 2 (EARL2) compliant) Gaussian post-reconstruction filter.\u003c/p\u003e\n\u003ch3\u003eImage analysis\u003c/h3\u003e\n\u003cp\u003eTwo experienced nuclear medicine physicians (TM and QL), blinded for patient data and preparation method, assessed the scans in two randomly divided groups, in two separate sessions (at least two weeks apart) using Hermia Gold Smart Workstation version 2.17 (Hermes Medical Solutions, Stockholm, Sweden). First, they scored myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake in the entire myocardium using a 5-point scale according to Scholtens et al. [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] ranging from 0 to 4: 0 (Myocardium less than left ventricular blood pool); 1 (Myocardium equal to left ventricular blood pool); 2 (Myocardium greater than left ventricular blood pool but less than liver); 3 (Myocardium focally greater than liver); 4 (Myocardium diffusely greater than liver). These scores were dichotomized into adequate (0, 1, and 2) and inadequate (3 and 4) myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG suppression for the final analysis. Additionally, segments with inadequate (3 or 4) myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG suppression were marked on a 17-segment model. In case of disagreement between the physicians, the scoring and segments were established through a consensus evaluation. Furthermore, the extra-cardiac image quality was scored using a 4-point scale according to Halpern et al.[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] ranging from 1 to 4: 1 (Non-diagnostic); 2 (Poor); 3 (Moderate); 4 (Good). Extra-cardiac semi-quantitative image quality was determined using VUE PACS version 12 (Philips Medical Systems Nederland BV, Best, The Netherlands) by a third experienced nuclear medicine physician (LG). Volume of interest measurements were applied to determine the mean standard uptake value (SUVmean) of right ventricle bloodpool (\u0026Oslash;=1.5cm) and right liver lobe (\u0026Oslash;=3.0cm). The threshold segmentation tool, with a 50% segmentation range of the maximum value point inside the volume boundaries, was used to measure SUVmean and max values in up to 5 lesions per patient.\u003c/p\u003e\n\u003ch3\u003ePatient Monitoring\u003c/h3\u003e\n\u003cp\u003eVenous blood was sampled from the IV-cannula for blood glucose (mmol/L) and FFA (mmol/L) analysis before caffeine intake and before [\u003csup\u003e18\u003c/sup\u003eF]FDG injection. Heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were measured before caffeine intake, before [\u003csup\u003e18\u003c/sup\u003eF]FDG injection, and after PET/CT. A symptom and mood questionnaire (supplementary material) was carried out at three time points: before caffeine intake, before [\u003csup\u003e18\u003c/sup\u003eF]FDG injection, and after PET/CT. The symptom and mood questionnaire was adapted from the Symptom-Q questionnaire, which assesses keto-induction symptoms and incorporates a simplified 5-point scale indicator of mood state, both developed by Harvey et al.[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. All symptom scores were summed to calculate an overall sum of symptoms score (SOSS) between 0 and 48 for subsequent analysis [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eAll statistical analyses were performed using Graphpad PRISM version 9. To compare myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake suppression between the two scans, a McNemar test (α\u0026thinsp;=\u0026thinsp;0.05) was conducted. A Shapiro-Wilk test (α\u0026thinsp;=\u0026thinsp;0.05) was used to assess normality and select the correct test for the following analyses. A paired t-test (α\u0026thinsp;=\u0026thinsp;0.05) or a Wilcoxon signed-rank test (α\u0026thinsp;=\u0026thinsp;0.05) was performed to compare differences in continuous variables. An analysis of variance (ANOVA) repeated measurement test (α\u0026thinsp;=\u0026thinsp;0.05) (including Mauchly\u0026rsquo;s test of sphericity with a Greenhouse-Geisser correction for nonsphericity) or a Friedman test (α\u0026thinsp;=\u0026thinsp;0.05) followed by Dunnett\u0026rsquo;s or Dunn\u0026rsquo;s multiple comparisons post hoc test was used to identify significant differences across the three time points for HR, SBP, DBP, SOSS scores and mood state scores.\u003c/p\u003e\u003cp\u003eThe sample size calculation was based on [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT in oncology [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] as the only existing test-retest [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT study in cardiac inflammatory [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] provided no useful information for sample size calculation. Therefore, we assumed that the test-retest SUV measurements in inflammatory extra-cardiac lesions are in line with SUV measurements in oncology. The equality formula for a pair of continuous data proposed by Chow et al [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] was used for sample size calculation. A power analysis with a 5% two-sided alpha of type I error (\u003cem\u003eZα/2\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.960) and 90% statistical power (\u003cem\u003eZβ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.28) was performed. For σ, a SUVmean standard deviation (SD) of 12.5% was used. In sample size calculations for oncology, under ideal conditions, this is around 10% [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. However, in the current study, patient preparation between the scans was different, and patient adherence to the diet and fasting may have differed, even with prior agreements on food products and fasting time. For ϵ, a clinically meaningful SUVmean change of 15% will be used based on the recent information statement from the SNMMI, American Society of Nuclear Cardiology (ASNC), and EANM [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The sample size calculation resulted in a sample size of 8 patients for this feasibility study.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003ePatient characteristics \u0026amp; diagnostics\u003c/h2\u003e\u003cp\u003eThe patient characteristics are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. As shown, the mean fasting time was significantly (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.037) longer for the study (14h16m\u0026thinsp;\u0026plusmn;\u0026thinsp;01h07m) PET/CT than for the routine (13h32m\u0026thinsp;\u0026plusmn;\u0026thinsp;00:31m) PET/CT. Six patients were habitual users of caffeine-containing substances and had abstained for at least 13 hours. Six patients had extra-cardiac sarcoidosis, one had sarcoidosis-like disease, and one had clinical suspicion of sarcoidosis. Except for patient 5, no signs of LV cardiac involvement were found in patients with other tests before routine PET/CT. Three patients (1,3, and 6) showed inadequate physiological [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake suppression on previous PET/CT scans.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePatient characteristics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003ePatient\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eSex\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003em/f\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eAge\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003e(years)\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eFasting time\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eRoutine/\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eStudy\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003ePET/CT (hour)\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eHabitual caffeine user (yes/no)/ hours abstained for study PET/CT\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eDiagnosis\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cem\u003eTreatment\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eECG/\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eHolter/\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eUltrasound/\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eMRI/\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003ePET findings before routine PET/CT\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ef\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13:40/\u003c/p\u003e\u003cp\u003e13:40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYes/\u003c/p\u003e\u003cp\u003e13:40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSarcoid-like disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eGolimumab\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eECG/Holter/\u003c/p\u003e\u003cp\u003eUltrasound and PET: all normal\u003c/p\u003e\u003cp\u003ePET/CT uptake LV physiological pattern, despite HFNC\u0026thinsp;+\u0026thinsp;\u0026gt;\u0026thinsp;12h fasting\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ef\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13:10/\u003c/p\u003e\u003cp\u003e13:05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYes/\u003c/p\u003e\u003cp\u003e13:05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eClinical suspicion of sarcoidosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMethotrexate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eECG/Holter/Ultrasound/\u003c/p\u003e\u003cp\u003eMRI: PET: all normal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ef\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13:50/\u003c/p\u003e\u003cp\u003e15:15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYes/\u003c/p\u003e\u003cp\u003e\u0026gt;\u0026thinsp;24:00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSarcoidosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eInfluximab\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eECG/PET: all normal\u003c/p\u003e\u003cp\u003ePET/CT slightly higher uptake LV physiological pattern, despite HFNC\u0026thinsp;+\u0026thinsp;\u0026gt;\u0026thinsp;12-hour fasting\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ef\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14:20/\u003c/p\u003e\u003cp\u003e15:00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYes/\u003c/p\u003e\u003cp\u003e15:00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSarcoidosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eECG: RBTB\u003c/p\u003e\u003cp\u003ePET: normal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003em\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14:10/\u003c/p\u003e\u003cp\u003e16:10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSarcoidosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMethotrexate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eEGC: RBTB\u003c/p\u003e\u003cp\u003eUltrasound: Normal\u003c/p\u003e\u003cp\u003eMRI: focal LGE mid-myocardial basal infero-lateral\u003c/p\u003e\u003cp\u003ePET/CT: Uptake LV basal inferolateral, possibly cardiac sarcoidosis with low-carbohydrate diet and unknown fasting time\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003em\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13:05/\u003c/p\u003e\u003cp\u003e14:40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYes/\u003c/p\u003e\u003cp\u003e\u0026gt;\u0026thinsp;24:00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSarcoidosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePrednisone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eECG: normal\u003c/p\u003e\u003cp\u003ePET: high LV cardiac uptake\u003c/p\u003e\u003cp\u003e-\u0026gt;no diet and prolonged fasting, possibly physiological\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e7\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003em\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12:45/\u003c/p\u003e\u003cp\u003e12:55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSarcoidosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eHydroxy-chloroquine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eECG: normal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003em\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13:20\u003c/p\u003e\u003cp\u003e13:30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYes/\u003c/p\u003e\u003cp\u003e17:30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSarcoidosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eECG/\u003c/p\u003e\u003cp\u003eUltrasound:\u003c/p\u003e\u003cp\u003enormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"8\" nameend=\"c8\" namest=\"c1\"\u003e\u003cp\u003eECG: Electrocardiogram; LV: left ventricle; HFNC: High-fat no-carbohydrate; MRI: Magnetic resonance imaging; RBTB: Right bundle branch block; LGE: Late Gadolinium enhancement\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eMyocardial [F]FDG suppression image analysis\u003c/h3\u003e\n\u003cp\u003eFigure 1 compares the transversal slice with the highest myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG of the routine PET/CT with the corresponding slice of the study PET/CT. A substantial decrease in myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake is observed in the majority of patients after the second PET/CT with additional caffeine anhydrous one hour before [\u003csup\u003e18\u003c/sup\u003eF]FDG injection. The number of patients with adequate myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake suppression increased from one patient (see discussion) in the routine PET/CT group to five patients in the study PET/CT group. Figure\u0026nbsp;2 illustrates that the study protocol led to a significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) reduction in the total number of segments with inadequate suppression (median\u0026thinsp;=\u0026thinsp;1) compared to the routine protocol (median\u0026thinsp;=\u0026thinsp;4). The number of inadequately suppressed segments decreased from 9 to 2 segments in patient 2, who showed focal uptake, and from 13 to 4 segments in patient 8, who exhibited diffuse uptake. These inadequate suppressed segments were located in the basal and mid postero-antero-lateral areas (segments 5,6,11, and 12). In patient 6, all segments presented diffuse uptake in both scans, although it was markedly less intense on the study PET/CT. Furthermore, both scans of patient 3 scored adequate myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake suppression in the blinded review.\u003c/p\u003e\u003cp\u003e\u003cb\u003eFigure\u0026nbsp;1\u003c/b\u003e Comparison between the transversal slice with the highest myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG of the routine PET/CT (upper row) with the corresponding slice of the study PET/CT (lower row) shows that a remarkable decrease of myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake and number of inadequate suppressed segments can be seen in the majority of patients after caffeine anhydrous\u003c/p\u003e\u003cp\u003e\u003cb\u003eFigure\u0026nbsp;2\u003c/b\u003e Comparison of segments with inadequate myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG suppression demonstrates that the study protocol (B) resulted in a significant (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) lower total number of segments with inadequate suppression (median\u0026thinsp;=\u0026thinsp;1) than the routine protocol (A) (median\u0026thinsp;=\u0026thinsp;4)\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eExtra-cardiac image quality analysis\u003c/h2\u003e\u003cp\u003eThe results of the extra-cardiac image quality analysis are presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The visual and semi-quantitative extra-cardiac image quality did not show significant differences between the two groups. However, SUVmax and SUVmean values of 20 lesions were significantly (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026le;\u0026thinsp;0.02) lower in the study PET/CT. The mean change of SUVmean change of -9% between the scans is below the clinically meaningful SUVmean change threshold of 15%.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD values of visual and semi-quantitative extra-cardiac image quality analysis\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eRoutine PET/CT\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eStudy PET/CT\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eVisual extra-cardiac image quality score\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSUVmean bloodpool\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSUVmean liver\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSUVmax lesions\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSUVmean lesions\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e\u003cp\u003eSignificant differences (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) are indicated with an asterisk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003ePatient monitoring\u003c/h2\u003e\u003cp\u003eThe results of the blood glucose and FFA measurements before caffeine and [\u003csup\u003e18\u003c/sup\u003eF]FDG are displayed in Table\u0026nbsp;3. As can be seen, mean blood glucose and FFA levels were not significantly (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.191) different between the measurements. However, a large intraindividual variability in the changes of FFA levels following caffeine intake can be seen in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 100%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 3: Mean \u0026plusmn; SD values of blood glucose and FFA measurements\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 29.8851%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.9885%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eRoutine PET/CT before [18F]-FDG\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.9885%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eStudy PET/CT\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ebefore caffeine\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24.1379%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eRoutine PET/CT before [\u003csup\u003e18\u003c/sup\u003eF]-FDG\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 29.8851%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eBlood glucose (mmol/L)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.9885%;\"\u003e\n \u003cp\u003e5.9\u0026plusmn;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.9885%;\"\u003e\n \u003cp\u003e5.6\u0026plusmn;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24.1379%;\"\u003e\n \u003cp\u003e5.6\u0026plusmn;0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 29.8851%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eFFA (mmol/L)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.9885%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.9885%;\"\u003e\n \u003cp\u003e0.67\u0026plusmn;0.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24.1379%;\"\u003e\n \u003cp\u003e0.67\u0026plusmn;0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 100%;\"\u003e\n \u003cp\u003eSignificant differences (p\u0026le;0.05) are indicated with an asterisk\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e4\u003c/span\u003e reports the hemodynamic monitoring parameters. During the hour after caffeine intake, mean HR decreased significantly, and mean SBP and mean DBP increased slightly. After PET/CT, the mean HR returned to before caffeine values, while the mean DBP remained slightly higher (+\u0026thinsp;4.1 mmHg) and mean SBP was significantly higher (+\u0026thinsp;8.8 mmHg). As shown in the lower part of the table, the SOSS and mood state scores remained stable following caffeine anhydrous intake.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD values of patient monitoring parameters for before caffeine intake versus before [18F]FDG and after PET/CT\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003ePatient monitoring parameter\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eBefore caffeine\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eBefore [\u003c/em\u003e\u003csup\u003e\u003cem\u003e18\u003c/em\u003e\u003c/sup\u003e\u003cem\u003eF]FDG\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eAfter PET/CT\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHeart rate (HR)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e73.6\u0026thinsp;\u0026plusmn;\u0026thinsp;13.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e65.6\u0026thinsp;\u0026plusmn;\u0026thinsp;11.6**\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e70.4\u0026thinsp;\u0026plusmn;\u0026thinsp;12.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSystolic blood pressure (SBP)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e127.6\u0026thinsp;\u0026plusmn;\u0026thinsp;10.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e134.6\u0026thinsp;\u0026plusmn;\u0026thinsp;14.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e136.4\u0026thinsp;\u0026plusmn;\u0026thinsp;12.8*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDiastolic blood pressure (DBP)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e81.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e83.1\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e85.6\u0026thinsp;\u0026plusmn;\u0026thinsp;6.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eOverall sum of symptoms scores (SOSS)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMood state score\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eSignificant differences compared to pre-caffeine values are indicated with * p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 or ** p\u0026thinsp;\u0026lt;\u0026thinsp;0.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this feasibility study is the first to demonstrate that administering additional caffeine anhydrous food supplement safely significantly (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) improves myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake suppression in patients who experience inadequate myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake suppression following a standard HFNC diet and more than 12 hours of fasting. The feasibility of administering additional caffeine anhydrous is further supported by the maintenance of visual and semi-quantitative image quality, as well as good tolerability among the participants.\u003c/p\u003e\u003cp\u003eDespite the good results in most patients, a certain degree of inadequate suppression was still observed in a fairly distinctive pattern, located exclusively in the basal and mid postero-antero-lateral areas, which are known to commonly exhibit physiological diffuse or focal uptake [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Follow-up diagnostic exams after the study PET/CT (such as ECG, Holter, ultrasound, and MRI), under the same treatment conditions, confirmed the absence of myocardial inflammation or ischemia in all but one patient. The one patient (patient 6) who exhibited inadequate suppression on both PET/CT scans, albeit still a reduced intensity of diffuse uptake on the study PET/CT with additional caffeine anhydrous administration, was ultimately diagnosed with extensive cardiac sarcoidosis after being referred for a new ECG and MRI. Additionally, this one patient with less intense yet persistent myocardial uptake also had extensive pulmonary disease, which may have resulted in increased myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake due to upregulated GLUT1 and downregulated fatty acid transporters in the myocardium [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. That one patient (patient 3) was included based on the original medical report stating insufficient myocardial suppression, but scored as adequate suppression on both scans upon blinded review in this study is regarded inherent to differences in an individual case in a clinical setting versus scoring a series of studies in a research setting. Previous studies [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] have noted that subjective scoring in patients with myocardial uptake similar to liver uptake can lead to interobserver disagreement. While semi-quantitative measurements are more objective, cardiac segmentation can be challenging for patients with focal or no uptake [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], making such assessments unfeasible for the current study.\u003c/p\u003e\u003cp\u003eCaffeine anhydrous did not impact the extra-cardiac visual image quality and lesion SUV measurements, as it specifically affects GLUT4 [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] and not GLUT1 and 3, which are involved in inflammation. The mean change in SUVmean between routine and study PET/CT was \u0026minus;\u0026thinsp;9%, which is below the clinically meaningful SUVmean change of 15% [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. However, this significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026le;\u0026thinsp;0.02) decrease was primarily due to nonspecific lesions in patient 1. After exclusion of this patient, the mean change in SUVmean dropped to -1.8%, with no significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.289) differences between the scans.\u003c/p\u003e\u003cp\u003eThe hemodynamic trends showed an increase in SBP and DBP due to vasoconstriction due to adenosine receptor blockage, along with a baroreceptor-mediated decrease HR during the first hour. These findings are consistent with previous studies involving similar caffeine intake levels [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. After the PET/CT, SBP was significantly higher, largely due to patient 2, whose SBP increased by approximately 12 mmHg following the [\u003csup\u003e18\u003c/sup\u003eF]FDG injection. This observation supports findings of previous studies in older patients [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], and after excluding patient 2, there was no significant difference (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.174) in SBP. Further monitoring of the patients revealed no negative symptoms or mood effects, which is consistent with findings of the European Food Safety Authority [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn contrast to previous studies with comparable caffeine dosage [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], current study showed both increased and decreased FFA levels after caffeine ingestion. A possible explanation might be that persons with a high baseline FFA level due to the HFNC diet might reached their maximum FFA level within the hour after caffeine ingestion in combination with a higher energy expenditure [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. However, no other study investigated the FFA response to caffeine after a HFNC diet and this requires further investigation.\u003c/p\u003e\u003cp\u003eA strength of this study is its design, where each patient serves as their own control. Notably, there is only one other extensive controlled study that compares the standard preparation with the addition of heparin within the same patient, conducted by Gormsen et al. [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Unfortunately, studies of this design are limited in the number of participants due to ethical regulations. However, our appropriately calculated sample size provides generalizable results. In contrast to these two smaller studies, several larger studies [\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] that focus on strategies to suppress myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake are primarily case-control or retrospective studies. These studies are influenced by individual differences in myocardial substrate metabolism. Additionally, they did not confirm adherence to diet and/or report precise fasting times, which may have introduced bias.\u003c/p\u003e\u003cp\u003eA limitation of the current study is the absence of measurements for ketosis with beta-hydroxybutyrate (BHB). Previous studies [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan additionalcitationids=\"CR42\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e] have shown a relationship between BHB levels and the suppression of myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake. However, some patients with low BHB still demonstrated adequate myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake suppression and vice versa [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. This suggests that myocardial substrate metabolism is quite complex, with significant interindividual variations, indicating that further research is needed. A weakness of the current study it that, despite providing comprehensive instructions and emphasizing the importance of using the same food products and adhering to the specific time for the pre-fast meal through both email and telephone communication with all patients, there was some slight variability in food products and fasting times. This inconsistency may have introduced bias in the amount of myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake suppression. However, this occurrence of bias varies among patients. For instance, in patient 3, the PET/CT scan conducted using the standard preparation before the routine PET/CT scan showed inadequate suppression, despite a longer fasting period (15.40 hours) compared to both the routine and study PET/CT scans. Another weakness of this study is that patients were allowed to consume caffeine-containing drinks until 11 hours before taking the caffeine anhydrous food supplement, as per the routine study diet. This might have led to some tolerance in habitual heavy users, like patient 8. Unlike the other patients, this patient exhibited minimal changes in HR and BP, suggesting the presence of caffeine tolerance [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. It is recommended that patients abstain from caffeine for at least 24 hours to improve their response to acute caffeine intake [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Additionally, it\u0026rsquo;s important to note that coffee cannot replace caffeine anhydrous, as other organic compounds like chlorogenic acids in coffee can interfere with caffeine's binding to adenosine receptors. This can reduce its effectiveness in promoting lipolysis and inhibiting GLUT4 [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake [\u003cspan additionalcitationids=\"CR46\" citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDespite the small number of patients in this study, the findings support the hypothesis that an additional food supplement of caffeine anhydrous improves [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake suppression in patients who do not achieve adequate [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake suppression following standard preparation. To validate these results, further research is needed with larger patient groups, and at least 24 hours of caffeine abstinence. Alternatively, there is an ongoing search for PET tracers that are more specific than [\u003csup\u003e18\u003c/sup\u003eF]FDG for myocardial inflammation. Currently, data is available on [\u003csup\u003e68\u003c/sup\u003eGa]Ga-Somatostatin analogues [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e], [\u003csup\u003e68\u003c/sup\u003eGa]Ga-Pentixafor [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e], and [\u003csup\u003e68\u003c/sup\u003eGa]Ga-fibroblast activation protein inhibitors [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. To date, however, only small studies have been conducted, and larger, prospective studies are necessary to evaluate their potential effectiveness, along with addressing issues related to availability and reimbursement.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAdditional caffeine anhydrous food supplement one hour before [\u003csup\u003e18\u003c/sup\u003eF]FDG administration has the potency to safely improve myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake suppression, while maintaining extra-cardiac visual and semi-quantitative image quality in patients with inadequate suppression after standard preparation.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eGLUT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eglucose transporter\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePET/CT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003epositron emission tomography/computed tomography\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e[\u003csup\u003e18\u003c/sup\u003eF]FDG\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003e18F-2-fluoro-2-deoxyglucose\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHFNC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ehigh-fat, no-carbohydrate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHFLC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ehigh-fat, low-carbohydrate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSNMMI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSociety of Nuclear Medicine and Molecular Imaging\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eEANM\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eEuropean Association of Nuclear Medicine\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eFFA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003efree fatty acids\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cem\u003eβ\u003c/em\u003eAR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003e\u003cem\u003eβ-\u003c/em\u003eadrenergic receptor\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eLV\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eleft ventricle\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIV\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eintravenously\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eEARL2\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eEANM Research Ltd. 2\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSUVmean\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003emean standard uptake value\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eheart rate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSBP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003esystolic blood pressure\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDBP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ediastolic blood pressure\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSOSS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003esum of symptoms score\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eASNC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAmerican Society of Nuclear Cardiology\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eECG\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eElectrocardiogram\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMRI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMagnetic resonance imaging\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRBTB\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRight bundle branch block\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eLGE\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eLate Gadolinium enhancement\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eBHB\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ebeta-hydroxybutyrate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cp\u003e The study was approved by the Medical Ethical Committee of the Erasmus Medical Centre (reference number: MEC-2022-0053).\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cp\u003e Patients signed informed consent regarding publishing their data and images.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eCompeting interests\u003c/h2\u003e\u003cp\u003eThe authors have no competing interests to declare that are relevant to the content of this article.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThe authors did not receive support from any organization for the submitted work. This project was funded by the department of Radiology \u0026amp; Nuclear medicine, Erasmus MC, Rotterdam, The Netherlands\u003c/p\u003e\u003ch2\u003eAuthors' contributions\u003c/h2\u003e\u003cp\u003eCC, TB, and FV contributed to the study concepts and to the study design. CC contributed to the data collection. QL and TM contributed to the visual analysis. LG contributed to the semi-quantitative analysis. CC contributed to the data analysis and statistical analysis. CC, TB, TM, FV, QL, and LG contributed to the data interpretation, to the manuscript preparation, to the manuscript editing, and reviewing. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eJamar 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(4):647\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang ZG, Yu MM, Han Y, Wu FY, Yang GJ, Li DC, Liu SM. Correlation of Glut-1 and Glut-3 expression with F-18 FDG uptake in pulmonary inflammatory lesions. Med (Baltim). 2016;95(48):e5462.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOlson AL, Pessin JE. Structure, function, and regulation of the mammalian facilitative glucose transporter gene family. Annu Rev Nutr. 1996;16:235\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDepre C, Vanoverschelde JL, Taegtmeyer H. Glucose for the heart. Circulation. 1999;99(4):578\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003evan den Brom C, Bulte C, Loer S, Bouwman RA, Boer C. Diabetes, perioperative ischaemia and volatile anaesthetics: Consequences of derangements in myocardial substrate metabolism. Cardiovasc Diabetol. 2013;12:42.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGlaudemans AW, Israel O, Slart RH. Pitfalls and Limitations of Radionuclide and Hybrid Imaging in Infection and Inflammation. Semin Nucl Med. 2015;45(6):500\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOsborne MT, Hulten EA, Murthy VL, Skali H, Taqueti VR, Dorbala S, et al. Patient preparation for cardiac fluorine-18 fluorodeoxyglucose positron emission tomography imaging of inflammation. J Nucl Cardiol. 2017;24(1):86\u0026ndash;99.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAbikhzer G, Treglia G, Pelletier-Galarneau M, Buscombe J, Chiti A, Dibble EH, et al. EANM/SNMMI guideline/procedure standard for [18F]FDG hybrid PET use in infection and inflammation in adults v2.0. Eur J Nucl Med Mol Imaging. 2025;52(2):510\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eScholtens AM, Verberne HJ, Budde RP, Lam MG. Additional Heparin Preadministration Improves Cardiac Glucose Metabolism Suppression over Low-Carbohydrate Diet Alone in \u0026sup1;⁸F-FDG PET Imaging. J Nucl Med. 2016;57(4):568\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eScholtens AM, van den Berk AM, van der Sluis NL, Esser JP, Lammers GK, de Klerk JMH, et al. Suppression of myocardial glucose metabolism in FDG PET/CT: impact of dose variation in heparin bolus pre-administration. Eur J Nucl Med Mol Imaging. 2020;47(11):2698\u0026ndash;702.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMasuda A, Naya M, Manabe O, Magota K, Yoshinaga K, Tsutsui H, Tamaki N. Administration of unfractionated heparin with prolonged fasting could reduce physiological 18F-fluorodeoxyglucose uptake in the heart. Acta Radiol. 2016;57(6):661\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMorooka M, Moroi M, Uno K, Ito K, Wu J, Nakagawa T, et al. Long fasting is effective in inhibiting physiological myocardial 18F-FDG uptake and for evaluating active lesions of cardiac sarcoidosis. EJNMMI Res. 2014;4(1):1.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGormsen LC, Christensen NL, Bendstrup E, Tolbod LP, Nielsen SS. Complete somatostatin-induced insulin suppression combined with heparin loading does not significantly suppress myocardial 18F-FDG uptake in patients with suspected cardiac sarcoidosis. J Nucl Cardiol. 2013;20(6):1108\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHartikainen S, Veps\u0026auml;l\u0026auml;inen V, Lyyra-Laitinen T, Hedman M, Laitinen T, Tompuri T. Heparin does not improve myocardial glucose metabolism suppression in [18 F]FDG PET/CT in patients with low β-hydroxybutyrate level. EJNMMI Res. 2024;14.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eManabe O, Yoshinaga K, Ohira H, Masuda A, Sato T, Tsujino I, et al. The effects of 18-h fasting with low-carbohydrate diet preparation on suppressed physiological myocardial (18)F-fluorodeoxyglucose (FDG) uptake and possible minimal effects of unfractionated heparin use in patients with suspected cardiac involvement sarcoidosis. J Nucl Cardiol. 2016;23(2):244\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eThong FS, Graham TE. Caffeine-induced impairment of glucose tolerance is abolished by beta-adrenergic receptor blockade in humans. J Appl Physiol (1985). 2002;92(6):2347\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMulder AH, Tack CJ, Olthaar AJ, Smits P, Sweep FC, Bosch RR. Adrenergic receptor stimulation attenuates insulin-stimulated glucose uptake in 3T3-L1 adipocytes by inhibiting GLUT4 translocation. Am J Physiol Endocrinol Metab. 2005;289(4):E627\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDeibert Dc Fau - DeFronzo RA, DeFronzo RA. Epinephrine-induced insulin resistance in man. (0021-9738 (Print)).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBattram DS, Graham TE, Dela F. Caffeine's impairment of insulin-mediated glucose disposal cannot be solely attributed to adrenaline in humans. J Physiol. 2007;583(Pt 3):1069\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMangmool S, Denkaew T, Parichatikanond W, Kurose H. β-Adrenergic Receptor and Insulin Resistance in the Heart. Biomol Ther (Seoul). 2017;25(1):44\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMangmool S, Denkaew T, Phosri S, Pinthong D, Parichatikanond W, Shimauchi T, Nishida M. Sustained βAR Stimulation Mediates Cardiac Insulin Resistance in a PKA-Dependent Manner. Mol Endocrinol. 2016;30(1):118\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePanel EN. Scientific Opinion on the safety of caffeine. EFSA J. 2015;13(5).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHalpern BS, Dahlbom M, Auerbach MA, Schiepers C, Fueger BJ, Weber WA, et al. Optimizing imaging protocols for overweight and obese patients: a lutetium orthosilicate PET/CT study. J Nucl Med. 2005;46(4):603\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHarvey C, Schofield G, Zinn C, Thornley S. Can a 'carbohydrate tolerance questionnaire' predict outcomes from diets differing in carbohydrate content? A pilot study. J Holist Perform. 2019.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDoot RK, Kurland BF, Kinahan PE, Mankoff DA. Design considerations for using PET as a response measure in single site and multicenter clinical trials. Acad Radiol. 2012;19(2):184\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlvi RM, Young BD, Shahab Z, Pan H, Winkler J, Herzog E, Miller EJ. Repeatability and Optimization of FDG Positron Emission Tomography for Evaluation of Cardiac Sarcoidosis. JACC Cardiovasc Imaging. 2019;12(7 Pt 1):1284\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChow SC, Shao J, Wang H, Lokhnygina Y. Sample Size Calculations in Clinical Research. CRC; 2017.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSperry BW, Bateman TM, Akin EA, Bravo PE, Chen W, Dilsizian V et al. Hot spot imaging in cardiovascular diseases: an information statement from SNMMI, ASNC, and EANM. J Nucl Cardiol. 2022;30(2).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNorikane T, Yamamoto Y, Takami Y, Mitamura K, Kobata T, Maeda Y, et al. Physiological myocardial 18F-FDG uptake pattern in oncologic PET/CT: comparison with findings in cardiac sarcoidosis. Asia Ocean J nuclear Med biology. 2024;12:1\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGropler RJ, Siegel BA, Lee KJ, Moerlein SM, Perry DJ, Bergmann SR, Geltman EM. Nonuniformity in myocardial accumulation of fluorine-18-fluorodeoxyglucose in normal fasted humans. J Nucl Med. 1990;31(11):1749\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMaurer AH, Burshteyn M, Adler LP, Gaughan JP, Steiner RM. Variable cardiac 18FDG patterns seen in oncologic positron emission tomography computed tomography: importance for differentiating normal physiology from cardiac and paracardiac disease. J Thorac Imaging. 2012;27(4):263\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOhira H, Ardle BM, deKemp RA, Nery P, Juneau D, Renaud JM, et al. Inter- and Intraobserver Agreement of \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT Image Interpretation in Patients Referred for Assessment of Cardiac Sarcoidosis. Journal of Nuclear Medicine. 2017;58(8):1324.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJosselyn N, MacLean MT, Jean C, Fuchs B, Moon BF, Hwuang E, et al. Classification of Myocardial (18)F-FDG PET Uptake Patterns Using Deep Learning. Radiol Artif Intell. 2021;3(4):e200148.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWhitsett TL, Manion CV, Christensen HD. Cardiovascular effects of coffee and caffeine. Am J Cardiol. 1984;53(7):918\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCasiglia E, Paleari CD, Petucco S, Bongiov\u0026igrave; S, Colangeli G, Baccilieri MS, et al. Haemodynamic effects of coffee and purified caffeine in normal volunteers: a placebo-controlled clinical study. J Hum Hypertens. 1992;6(2):95\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eArciero PJ, Ormsbee MJ. Relationship of blood pressure, behavioral mood state, and physical activity following caffeine ingestion in younger and older women. Appl Physiol Nutr Metab. 2009;34(4):754\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eArciero PJ, Gardner AW, Benowitz NL, Poehlman ET. Relationship of blood pressure, heart rate and behavioral mood state to norepinephrine kinetics in younger and older men following caffeine ingestion. Eur J Clin Nutr. 1998;52(11):805\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePatwardhan RV, Desmond PV, Johnson RF, Dunn GD, Robertson DH, Hoyumpa AM Jr., Schenker S. Effects of caffeine on plasma free fatty acids, urinary catecholamines, and drug binding. Clin Pharmacol Ther. 1980;28(3):398\u0026ndash;403.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBenowitz NL, Jacob P 3rd, Mayan H, Denaro C. Sympathomimetic effects of paraxanthine and caffeine in humans. Clin Pharmacol Ther. 1995;58(6):684\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eArciero PJ, Gardner AW, Calles-Escandon J, Benowitz NL, Poehlman ET. Effects of caffeine ingestion on NE kinetics, fat oxidation, and energy expenditure in younger and older men. Am J Physiol. 1995;268(6 Pt 1):E1192\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlfawara MS, Ahmed AI, Saad JM, Han Y, Alahdab F, Al Rifai M, et al. The utility of beta-hydroxybutyrate in detecting myocardial glucose uptake suppression in patients undergoing inflammatory [18F]-FDG PET studies. Eur J Nucl Med Mol Imaging. 2023;50(4):1103\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHartikainen S, Tompuri T, Laitinen T, Laitinen T. Point-of-care β-hydroxybutyrate measurement predicts adequate glucose metabolism suppression in cardiac FDG-PET/CT. Clin Physiol Funct Imaging. 2024;44(5):349\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMadamanchi C, Weinberg RL, Murthy VL. Utility of serum ketone levels for assessment of myocardial glucose suppression for (18)F-fluorodeoxyglucose PET in patients referred for evaluation of endocarditis. J Nucl Cardiol. 2023;30(3):928\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRobertson D, Wade D, Workman R, Woosley RL, Oates JA. Tolerance to the humoral and hemodynamic effects of caffeine in man. J Clin Invest. 1981;67(4):1111\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBattram DS, Arthur R, Weekes A, Graham TE. The glucose intolerance induced by caffeinated coffee ingestion is less pronounced than that due to alkaloid caffeine in men. J Nutr. 2006;136(5):1276\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHodgson AB, Randell RK, Jeukendrup AE. The metabolic and performance effects of caffeine compared to coffee during endurance exercise. PLoS ONE. 2013;8(4):e59561.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGraham TE, Hibbert E, Sathasivam P. Metabolic and exercise endurance effects of coffee and caffeine ingestion. J Appl Physiol (1985). 1998;85(3):883\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLucinian YA, Martineau P, Abikhzer G, Harel F, Pelletier-Galarneau M. Novel tracers to assess myocardial inflammation with radionuclide imaging. J Nuclear Cardiol. 2024:102012.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTreglia G, Albano D. FAPI PET/CT in infectious, inflammatory, and rheumatological diseases: watch it like a hawk or one swallow does not make a summer? Eur J Nucl Med Mol Imaging. 2023;50(7):1848\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"18F-FDG, Positron emission tomography computed tomography, GLUT4, myocardial metabolism, inflammation, caffeine, sarcoidosis","lastPublishedDoi":"10.21203/rs.3.rs-7739411/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7739411/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003ePositron emission tomography/Computed tomography (PET/CT) with [\u003csup\u003e18\u003c/sup\u003eF]FDG has an increasingly relevant role in diagnosing and treatment management of myocardial inflammation and infection. A major confounding factor in cardiac [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT is physiological myocardial glucose uptake, which could obscure pathologic myocardial uptake in disease affected myocardium (e.g., inflammatory conditions). Despite generally accepted conventional measures such as dietary manipulation, extended fasting, and possibly additional intravenous heparin, confounding physiological myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake still occurs in 5\u0026ndash;20% of the patients, and further improvement of the protocol is needed. It is proposed that these patients may benefit from additional pre-administration of caffeine anhydrous as a food supplement. Caffeine acts as an adenosine receptor antagonist, stimulating lipolysis in adipose tissue and promoting adrenergic release of epinephrine. This stimulates \u003cem\u003eβ\u003c/em\u003eAR-mediated lipolysis in adipose tissue and \u003cem\u003eβ\u003c/em\u003eAR-mediated inhibition of insulin-independent glucose transporter (GLUT) 4 expression and translocation, which reduces insulin-dependent GLUT4 myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake. This study aims to investigate the feasibility of using additional caffeine anhydrous pre-administration on myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake suppression.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eAdditional administration of caffeine anhydrous before [\u003csup\u003e18\u003c/sup\u003eF]FDG injection resulted in complete myocardial suppression in five out of eight patients (63%), and a near-complete suppression in two patients (25%). In all patients, there was a significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) reduction in the overall number of segments with inadequate suppression. No significant differences (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05) were observed in visual and semi-quantitative measurements of extra-cardiac image quality and extra-cardiac sarcoid lesions. All monitored patient parameters remained stable, except for an expected significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) decrease in mean heart rate before [\u003csup\u003e18\u003c/sup\u003eF]FDG injection.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003ePre-administration of additional caffeine anhydrous food supplement has the potency to safely improve myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake suppression in patients who experience inadequate myocardial [\u003csup\u003e18\u003c/sup\u003eF]FDG uptake suppression following a standard HFNC diet and more than 12 hours of fasting. This potential improvement could contribute to better diagnosis and consequent treatment management of cardiac inflammation and infection in these patients. The feasibility of administering additional caffeine anhydrous is further supported by the maintenance of visual and semi-quantitative image quality, as well as good tolerability among the participants.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e\u003cp\u003eISCTRP, NLOMON51725. Registered 22 December 2022, https//trialsearch.who.int/Trial2.aspx?TrialID=NLOMON51725\u003c/p\u003e","manuscriptTitle":"Pre-administration of caffeine anhydrous food supplement potentially improves suppression of physiologic myocardial [18F]FDG uptake: a feasibility study.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-28 08:49:13","doi":"10.21203/rs.3.rs-7739411/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b0bb3402-9d67-4dd2-bb7e-0fab4ad63fc4","owner":[],"postedDate":"November 28th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-04T15:36:15+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-28 08:49:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7739411","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7739411","identity":"rs-7739411","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}