Suppression of Myocardial 18 F-FDG Uptake by Preparing Patients with a High-Fat, Low-Carbohydrate Diet

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1 Nuclear Medicine Original Research Williams and Kolodny Patient Preparation Protocol to Suppress Myocardial FDG Uptake Nuclear Medicine Original Research Gethin Williams 1 Gerald M. Kolodny Williams G, Kolodny GM Keywords: cardiac imaging, contrast media, coronary artery disease, FDG, myocardium, patient preparation protocol, PET/CT DOI: /AJR Received April 13, 2007; accepted after revision September 21, Both authors: Division of Nuclear Medicine, Department of Radiology, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA Address correspondence to G. M. Kolodny (gkolodny@bidmc. harvard.edu). WEB This is a Web exclusive article. AJR 2008; 190:W151 W X/08/1902 W151 American Roentgen Ray Society Suppression of Myocardial 18 F-FDG Uptake by Preparing Patients with a High-Fat, Low-Carbohydrate Diet OBJECTIVE. Myocardial 18 F-FDG uptake in PET scans in patients prepared by the usual fasting protocol may result in difficulties in interpretation because variable uptake may yield false-positive results regarding mediastinal abnormalities. We aimed to analyze, retrospectively, the effect of diet on myocardial FDG uptake. MATERIALS AND METHODS. The fasting group comprised 101 consecutive patients before a clinical change in the patient preparation protocol. The new diet group comprised 60 consecutive patients after the clinical protocol change who were directed to consume a very high-fat, low-carbohydrate, protein-permitted (VHFLCPP) diet before FDG injection. All patients were given a questionnaire that was used to verify diet adherence. Nonadherers or patients failing to complete questionnaires were excluded from analysis. Myocardial uptake was evaluated by measuring the maximum standardized uptake value (SUV max) in areas defined by CT as being cardiac. RESULTS. The average SUV max for the fasting group (n = 101) was 8.8 ± 5.7, and the average SUV max for the VHFLCPP group (n = 60) was 3.9 ± 3.6. The one-tailed Student s t test yielded a p value of < CONCLUSION. A VHFLCPP meal eaten 3 6 hours before FDG injection suppresses myocardial FDG uptake. This should facilitate definition of mediastinal abnormalities on FDG PET, particularly with stand-alone PET. Furthermore, this patient preparation protocol may permit the detection of biologically active coronary artery disease. T he currently accepted patient preparation protocols for 18 F- FDG PET involve fasting for 4 12 hours. The aim of fasting is to produce low levels of glucose and insulin so that FDG, a glucose analog, shows optimal uptake. Competitive inhibition of uptake by serum glucose and of insulin-dependent uptake by muscle and fat, mediated by glucose transporter (GLUT)-4 receptors, is minimized. However, this also results in variable physiologic myocardial uptake, which has been reported to result in false-positive findings in PET studies [1, 2]. It would therefore be advantageous to have a preparation method that reproducibly decreased myocardial FDG uptake. Minimizing myocardial FDG uptake should decrease false-positive studies because a decrease in the background uptake should facilitate the definition of mediastinal FDG uptake. Factors that might influence myocardial uptake of FDG that have been examined include patient age, fasting time, blood glucose levels, and use of a low-carbohydrate diet. Age and fasting time do not influence FDG physiologic uptake in the myocardium. Changes induced in blood glucose levels may have a nonlinear effect on myocardial uptake [2]. The authors of one report described their finding that a low-carbohydrate diet decreased artifactual myocardial uptake [3]. The Randle cycle (fatty acid glucose cycle) has established that fatty acid loading suppresses glucose metabolism [4] and that glucose loading suppresses fatty acid utilization by the myocardium. Our patient preparation protocol initially involved a fast of at least 4 hours after a low-carbohydrate diet. We elected to further optimize insulin and glucose levels by having patients eat a very high-fat, lowcarbohydrate, protein-permitted (VHFLCPP) meal before fasting. We reasoned that the Randle effect would assist in lowering glucose and insulin levels further. Soon after the protocol change, we noticed that myocardial uptake was apparently decreased using this new protocol; therefore, a retrospective analysis AJR:190, February 2008 W151

2 Williams and Kolodny was undertaken of the studies performed before and after the change in patient preparation to determine whether this impression was correct. Materials and Methods The study was a HIPAA-compliant retrospective study and was approved by the Beth Israel Deaconess Medical Center s institutional review board. The fasting group comprised patients who presented to our institution for PET/CT before September 2005, when the patient preparation protocol was fasting overnight or for 4 hours before scanning with instructions to cease sugar intake the evening before scanning. The VHFLCPP group comprised patients who presented after September 2005, when the protocol was changed to a VHFLCPP meal before fasting prior to scanning. The indications for scanning in both groups were primarily lymphoma. However, patients also included those with lung cancer, breast cancer, melanoma, and other cancers. In the VHFLCPP group, 35 patients (58%) had lymphoma, 13 (22%) had lung cancer, four (7%) had breast cancer, three (5%) had melanoma, and five (8%) had other cancers. In the fasting group, 50 (50%) had lymphoma, 25 (25%) had lung cancer, six (6%) had breast cancer, four (4%) had melanoma, and 16 (16%) had other cancers. After IV injection of 740 MBq (20 mci) of FDG, patients stayed in a semidarkened quiet room for minutes. Plasma glucose measurements before injection were less than 200 mg/ dl in all patients. The patients were then scanned using a 4-MDCT scanner (Discovery/LightSpeed PET/CT, GE Healthcare). An initial CT scout image (30 ma, 120 kvp) was obtained. The body was then scanned from the base of the skull to the mid thighs using helical CT at 0.8 second per rotation at 100 ma and 149 kvp with a section thickness of 5 mm and a 4.25-mm interval. Thin oral, but no IV, barium contrast material was used in all studies. Patients were instructed to breathe normally during the acquisition. Images were then obtained with 5 minutes per bed position and were iteratively reconstructed using CT-based attenuation correction. Quantitation of FDG Uptake Visual uptake categoric scale To estimate the effect of meal timing on FDG uptake, we used a visual scale. FDG PET/CT scans from 101 patients prepared by fasting were divided into four groups on the basis of a qualitative visual estimation of FDG myocardial uptake: 0, homogeneously minimal; 1, mostly minimal or mild uptake; 2, mostly intense or moderate uptake; and 3, homogeneously intense. This scale is a Likert scale that is often used as a psychometric response scale in survey research and was found useful here. Standardized uptake value (SUV) measurements (continuous scale) The minimum SUV (SUV min ) and maximum SUV (SUV max ) were measured in each subject s myocardium using PET/ CT images. CT defined the anatomic boundaries, and a region-of-interest tool was used to trace around the ventricles to determine SUV min and SUV max. VHFLCPP Diet and Questionnaire The change in protocol resulted in patients being given written instructions to eat a VHFLCPP meal before scanning. Because this study was not a prospective experimental trial, amounts were not specified. A menu of permitted and banned foods was given to patients. Telephone instructions were also given at the time of a confirmation telephone interaction. Appendix 1 outlines the diet instructions for dinner the evening before scanning and breakfast on the day of scanning. This diet includes high fats and low carbohydrates. Patients with insulin-dependent diabetes were advised to eat high-fat, low-carbohydrate meals and to take their insulin. To verify adherence to the diet, patients were given a questionnaire at the time of PET inquiring about their complete diet during the previous 24 hours, the time of their last meal or snack, and any exercise during the 24 hours before scanning. Investigating the Timing of the VHFLCPP Meal Not all patients adhered to the instructions to eat a VHFLCPP meal 4 hours before scanning. Because these patients were given questionnaires, the time of the VHFLCPP meal before FDG injection was self-reported. Myocardial uptake was scored using the qualitative scale (Likert scale) described earlier to correlate the intensity of myocardial uptake with the time interval between the meal and scanning. Comparison of Fasting Protocol with the VHFLCPP Preparation Protocol The myocardial SUV max (a continuous variable) was measured in studies using the fasting protocol and in studies in which patients adhered to the VHFLCPP meal instructions. Means and SDs of the control group and test group were determined, and the one-tailed Student s t test was used to assess p values. Intrapatient Comparison of Chronic Inflammatory Sites: Fasting Versus VHFLCPP Diet To evaluate the effect of dietary manipulation on FDG uptake in noncardiac sites, sites of chronic TABLE 1: Characteristics of Control Group and Test Group Characteristic Patient Preparation Protocol Fasting Group (n = 101) VHFLCPP Diet Group (n = 60) Mean age ± SD (y) 57 ± ± a Mean blood glucose level ± SD (mg/dl) 96 ± ± a Sex (no. [%] of patients) M 62 (61) 40 (67) F 39 (39) 20 (33) Indication for 18 F-FDG PET (no. [%] of patients) Lymphoma 50 (50) 35 (58) Nonlymphoma c 51 (50) 25 (42) Diabetes (no. [%] of patients) Yes 7 (7) 4 (7) No 84 (83) 47 (78) Unknown 10 (10) 9 (15) Renal disease (no. [%] of patients) Yes 8 (8) 1 (2) No 83 (82) 50 (83) Unknown 10 (10) 9 (15) p 0.46 b 0.26 b 0.94 b Note VHFLCPP = very high-fat, low-carbohydrate, protein-permitted. a Student s t test. b Fisher s exact test p value from chi-square test. c Nonlymphoma in the VHFLCPP group comprised lung cancer in 13 (22%), breast cancer in four (7%), melanoma in three (5%), and other cancers in five (8%) versus 25 (25%), six (6%), four (4%), and 16 (16%), respectively, in the fasting group b W152 AJR:190, February 2008

3 Patient Preparation Protocol to Suppress Myocardial FDG Uptake inflammation in patients undergoing FDG PET/CT within 8 weeks of each other that is, before and after the clinical preparation protocol was changed were retrospectively analyzed. Sites of inflammation (osteoarthritis, tendinitis, dental) were identified and classified as chronic if they were seen on both scans. The SUVsmax were measured, and a site-to-site comparison was performed using the paired Student s t test. Patients were excluded if major changes in biodistribution due to chemotherapy (i.e., stimulated bone marrow uptake) had occurred or if scans showed abnormal findings (e.g., high blood glucose, diffuse skeletal muscle uptake). Results Table 1 shows patient age, blood glucose level, sex, diagnosis, and prevalence of diabetes and renal disease in the control and test groups. There was no statistically significant difference in any of these measures between the two groups. Figure 1 shows the myocardial SUV min and SUV max for the fasting protocol patients whose myocardial FDG uptake was qualitatively (i.e., visually) graded as 0 (homogeneously minimal), 1 (mostly minimal or mild uptake), 2 (mostly intense or moderate uptake), or 3 (homogeneously intense). Qualitatively, visual grading (a categoric value) correlated with FDG uptake as determined by SUV max measurements (a continuous variable). Figure 2 shows the qualitative FDG uptake for nonadherent patients who ate a VHFLCPP meal at different times before FDG injection. Figure 3 compares the SUVs max for the 60 test patients who completed questionnaires indicating adherence to the VHFLCPP diet (from 83 total) with those for the 101 fasting protocol patients. The mean and SD for the SUV max was 3.9 ± 3.6 and 8.8 ± 5.7, respectively, with a one-tail Student s t test indicating significance (p < ). No effect was observed with SUV min. Figure 4 shows lateral and frontal views of a maximum-intensity-projection scan from a PET study in a patient with several metastases close to the heart that are clearly delineated as a result of suppression of myocardial FDG uptake. To test the hypothesis that the VHFLCPP diet has no effect on other sites of FDG uptake, we determined FDG uptake in sites of chronic inflammation. We retrospectively analyzed FDG uptake data, as determined by SUVs, in extracardiac sites of chronic inflammation in patients who had been scanned within 8 weeks, first prepared by the fasting method then by the new protocol. No PET studies were excluded. In eight patients and 16 sites of extracardiac inflammation (osteoarthritis, n = 10; tendinitis, n = 5; dental, n = 1), there was no statistical difference between pairs using the paired Student s t test (p = 0.30; SUV max range, ). Discussion Our results show that a VHFLCPP meal 3 6 hours before FDG injection suppresses myocardial FDG uptake. The mechanism is likely the result of the Randle cycle, which has established that fatty acid loading suppresses glucose metabolism [4]. Fig. 1 Quantitation of minimum standardized uptake value (SUV min ) and maximum standardized uptake value (SUV max ) in patients prepared by fasting of qualitative (visually assessed) 18 F-FDG uptake using a Likert scale: 0 = minimal uptake, 1 = mostly minimal or mild uptake, 2 = mostly intense or moderate uptake, and 3 = homogeneously intense. AJR:190, February 2008 W153

4 Williams and Kolodny Qualitative FDG Uptake Time from Meal to FDG Injection (h) Fig. 2 Qualitative (visually assessed) 18 F-FDG and glucose uptake at time from ingestion of very highfat, low-carbohydrate, protein-permitted meal to FDG injection. Further, myocardial tissue prefers free fatty acids (FFAs). Therefore, it appears flooding the myocardium with its preferred substrate and waiting until after the peak of postprandial hyperinsulinemia suppresses myocardial FDG uptake. During postprandial hyperinsulinemia, GLUT-4 mediated myocardial FDG uptake is high. After 6 8 hours, myocardial FDG uptake becomes variable, emulating studies with the fasting preparation. A basis for our observations is suggested by a report that elevated blood FFAs decreased myocardial glucose uptake. This change was effected by infusing heparin and triglycerides [5]. Heparin displaces lipoprotein lipase in capillaries so triglycerides are cleaved to yield FFAs, which are the myocardium s preferred substrate. There is also a report that FFAs inhibit GLUT-4 expression in cardiac muscle [6]. Although sucralose (Splenda, Johnson & Johnson) is not known to have carbohydrate properties, whether it would affect myocardial FDG uptake was unknown because VHFLCPP Fasting SUV max its chemical structure, unlike the chemical structure of other artificial sweeteners, is similar to that of glucose. We therefore instructed patients not to eat or drink foods containing Splenda before scanning. There are two potential uses of a VHFLCPP preparation protocol. First, regarding more accurate definition of mediastinal pathology, the variable myocardial uptake due to the usual fasting patient protocols can give rise to falsepositive studies, especially in PET-only studies [1]. This new method should facilitate increased accuracy, particularly in the definition of mediastinal pathology (Fig. 4). Empirically, tumor FDG uptake did not appear to be affected. Selected patients with prior FDG-avid scans showed essentially unchanged uptake when other measures of tumor change were absent when prepared with the VHFLCPP diet. However, a prospective study, now in preparation, rather than this retrospective study, is necessary to confirm this finding. Uptake in sites of chronic inflammation, such as arthritic joints, in the same patient was compared before and after the change in the patient preparation protocol. Sixteen sites in eight patients analyzed showed no significant change in patients prepared by either method (p = 0.30). Second, this method of patient preparation may permit the detection of biologically active coronary artery disease (CAD) [7]. Intravascular inflammation can be detected in extracardiac areas where background FDG uptake is minimal. Vasculitides not only canbe detected by FDG PET but also have begun to be used to monitor treatment [8]. CAD is proposed to progress from active inflammation to chronic calcification. The detection of inflamed, soft, vulnerable plaque could be clinically advantageous. Because noncoronary artery atherosclerosis is detectable in humans with FDG PET [9 11], it is reasonable to Fig. 3 Comparison of maximum standardized uptake value (SUV max ) between patients prepared by fasting (n = 101; mean SUV max ± SD, 8.8 ± 5.7) and by very high-fat, lowcarbohydrate, proteinpermitted (VHFLCPP) diet (n = 60; SUV max, 3.9 ± 3.6). P(T t) one-tail < suggest that the inflammation accompanying biologically active CAD might also be detected by FDG PET. Preliminary data suggest that using this new method to suppress myocardial FDG and glucose uptake, biologically active CAD can be detected [7]. Glycolysis is outside normal physiologic control in cancer cells (the Warburg effect). Macrophages associated with inflammation in arthritis, tendinitis, infection, and coronary artery plaque use GLUT-1 and highaffinity GLUT-3 receptors that are insulin-independent [12] and are not expected to show decreased FDG uptake in patients prepared with a high-fat, low-carbohydrate diet. The patient preparation protocol used here mainly affects insulin-dependent GLUT-4 receptors that are induced in muscle (including cardiac muscle) and adipose tissue [13]. Although theoretically and by empiric observation tumor uptake appears unaffected, matched studies of the same patients prepared by each of the two protocols and scanned 24 hours apart have not been performed. Preparations are now under way to perform such a prospective study to complement this retrospective study. Theoretically, the decrease in myocardial FDG uptake could result in higher uptake in tumors. A prospective study, now in preparation, comparing uptake in tumors in patients prepared by fasting and uptake in the same sites in patients prepared by a high-fat diet in scans obtained 24 hours later will be necessary to determine whether tumor SUVs are indeed higher in patients prepared by this method. However, inflammatory FDG uptake does not appear to be affected by the new patient preparation protocol, as illustrated by the matched studies presented here. Despite the decrease in myocardial FDG uptake, minimal uptake may be seen in some regions. Although improvement in definition of mediastinal pathology is evident, further prospective studies are necessary to document this improvement. The optimal composition of the preparatory diet has not been defined. In this study, the diet was high in protein and fat and very low in carbohydrate, with the assumption that the high fat and very low carbohydrate, via the Randle cycle, minimized myocardial FDG uptake. Studies are being planned to evaluate the optimal composition and a more standardized delivery system, so compliance is increased and exact intake is known. In this study, the time of the last meal and meal description were reported by patients and were not independently verified. This reliance on W154 AJR:190, February 2008

5 Patient Preparation Protocol to Suppress Myocardial FDG Uptake Fig. 4 Example of minimal myocardial uptake facilitating definition of mediastinal abnormality in 58-year-old woman with metastatic breast cancer. A and B, Lateral (A) and frontal (B) views of maximum-intensity-projection scan from PET study show several metastases close to heart that are clearly delineated as result of suppression of myocardial 18 F-FDG uptake. self-reporting may explain the outliers seen in Figure 3 using the VHFLCPP protocol. In addition, because this study was retrospective, we do not know fatty acid or insulin levels. However, we do know that analysis of blood glucose levels in a large number of fasting versus VHFLCPP diet patients showed that the VHFLCPP diet patients had lower blood glucose levels than the fasting group, which is suggestive of the Randle cycle effect. A prospective study analyzing insulin, glucose, and FFA levels would be useful and is planned. Other limitations of this study include the definition of sites of chronic inflammation (osteoarthritis, tendinitis, and dental) that, although empirically reasonable, lack a clear pathologic gold standard. Also, medication profiles were not compared, and theoretically some medications may alter FDG uptake, although the specific effect of most medications on myocardial FDG uptake is not known. A VHFLCPP meal eaten 3 6 hours before FDG injection suppresses myocardial FDG uptake. This should facilitate definition of mediastinal pathology by FDG PET, particularly with stand-alone PET, and may permit the detection of biologically active CAD [7]. References 1. Shreve PD, Anzai Y, Wahl RL. Pitfalls in onco- A logic diagnosis with FDG PET imaging: physiologic and benign variants. RadioGraphics 1999; 19: de Groot M, Meeuwis AP, Kok PJ, Corstens FH, Oyen WJ. Influence of blood glucose level, age and fasting period on non-pathological FDG uptake in heart and gut. Eur J Nucl Med Mol Imaging 2005; 32: Lum D, Wandell S, Ko J, Coel M. Positron emission tomography of thoracic malignancies: reduction of myocardial fluorodeoxyglucose uptake artifacts with a carbohydrate restricted diet. Clin Positron Imaging 2000; 3: Frayn KN. The glucose-fatty acid cycle: a physiological perspective. Biochem Soc Trans 2003; 31: Boden G, Chen X, Ruiz J, White JV, Rossetti L. Mechanisms of fatty acid induced inhibition of glucose uptake. J Clin Invest 1994; 93: Armoni M, Harel C, Bar-Yoseph F, Milo S, Karnieli E. Free fatty acids repress the GLUT4 gene expression in cardiac muscle via novel response elements. J Biol Chem 2005; 280:34, , Williams G, Kolodny GM. A method for detecting biological active coronary artery disease by F18-fluorodeoxyglucose-positron emission tomography/computed tomography. In: Radiological Society of North America scientific assembly and annual meeting program [book online]. Oak Brook, IL: Radiological Society of North Ameri- ca, rsna2006.rsna.org/rsna2006/v2006/ conference/event_display.cfm?em_id= Accessed December 4, Andrews J, Al-Nahhas A, Pennell DJ, et al. Noninvasive imaging in the diagnosis and management of Takayasu s arteritis. Ann Rheum Dis 2004; 63: Tatsumi M, Cohade C, Nakamoto Y, Wahl RL. Fluorodeoxyglucose uptake in the aortic wall at PET/CT: possible finding for active atherosclerosis. Radiology 2003; 229: Rudd JH, Warburton EA, Fryer TD, et al. Imaging atherosclerotic plaque inflammation with [18F]- fluorodeoxyglucose positron emission tomography. Circulation 2002; 105: Ben-Haim S, Kupzov E, Tamir A, Israel O. Evaluation of 18 F-FDG uptake and arterial wall calcifications using 18 F-FDG PET/CT. J Nucl Med 2004; 45: Fu Y, Maianu L, Melbert BR, Garvey WT. Facilitative glucose transporter gene expression in human lymphocytes, monocytes, and macrophages: a role for GLUT isoforms 1, 3, and 5 in the immune response and foam cell formation. Blood Cells Mol Dis 2004; 32: Boden G, Shulman GI. Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. Eur J Clin Invest 2002; 32[suppl 3]:14 23 B AJR:190, February 2008 W155

6 Williams and Kolodny APPENDIX 1: Foods Permitted and Not Permitted the Evening Before and Morning of 18 F-FDG PET Scanning for Patients Prepared with a Very High-Fat, Low-Carbohydrate, Protein-Permitted Diet Permitted Foods Fatty unsweetened (fried or broiled, but not grilled) chicken, turkey, fish, meats (steak, ham, and so on), meat-only sausages, fried eggs, bacon, scrambled eggs prepared without milk, omelet prepared without milk or vegetables, fried eggs and sausages, fried eggs and bacon, hotdogs (plain, without the bun), hamburgers (plain, without the bun or vegetables) Clear liquids without milk or sugars Coffee without milk or sugar Tea without milk or sugar Water Sugar substitutes: Sweet N Low (Cumberland Packing Corp.), NutraSweet (NutraSweet Property Holdings, Inc.), or Equal (Merisant Co.) Not-Permitted Foods Foods containing carbohydrates, sugars, and Splenda (McNeil Nutritionals) Milk, cheese, bread, bagels, cereal, cookies, toast, pasta, crackers, muffins, peanut butter, nuts, fruit juice, potatoes, candy, fruit, rice, chewing gum, mints, cough drops, vegetables, beans, alcohol W156 AJR:190, February 2008