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Featured researchAbstracts and commentaries Short-term treatment with ranolazine improves mechanical
efficiency in dogs with chronic heart failure The present study assesses whether ranolazine increases left ventricular (LV) function without an increase in myocardial oxygen consumption (MVO2) and thus improves LV mechanical efficiency in dogs with heart failure. Ranolazine did not change MVO2, and LV mechanical efficiency increased (22.4% ± 2.8% to 30.9% ± 3.4%, P < 0.05). In contrast, dobutamine significantly increased MVO2 and did not improve mechanical efficiency. Thus, short-term treatment with ranolazine improved LV function without an increase in MVO2, resulting in an increased myocardial mechanical efficiency in dogs with heart failure. Commentary Quantification of myocardial glucose utilization by PET and 1-carbon-11-glucose Measurements of the rate of myocardial glucose utilization (rMGU)
play a key role in the assessment of alterations in myocardial
substrate metabolism in normal and abnormal cardiac states. In
this study we determined whether rMGU could be quantified by positron
emission tomography (PET) and
1-carbon-11-glucose. Twenty dogs were studied with a variety of
interventions including fasting (n =5), hyperinsulinemic-euglycemic
clamp at rest (n =6), clamp and phenylephrine (n =5), and clamp
and dobutamine
(n =4). Commentary
Image-derived input functions for determination of MRGlu in cardiac (18)F-FDG PET scans. van der Weerdt AP, Klein LJ, Boellaard R, Visser CA, Visser FC, Lammertsma AA. Department of Cardiology and PET Center, Institute for Cardiovascular Research-VU, VU Medical Center, Amsterdam, The Netherlands. Image-derived input functions (IDIF) are frequently used in cardiac (18)F-FDG PET studies for determination of the myocardial metabolic rate of glucose (MRGlu). The purpose of this study was to assess which vascular structure is most suited for defining the IDIF, using online arterial blood sampling (AS) as the gold standard. METHODS: In 18 patients with ischemic heart disease, 370 MBq FDG were injected during a hyperinsulinemic euglycemic clamp. Studies were performed with a Siemens/CTI HR+ PET scanner using a dynamic scanning protocol. A fully automated blood-sampling device was used for continuous AS. IDIF were obtained using regions of interest (ROIs) of 3 different sizes defined on the left ventricle (LV), left atrium (LA), ascending aorta (AA), and descending aorta (DA). MRGlu was calculated with all input functions. Ratios between MRGlu obtained with IDIF and AS were calculated for each patient. RESULTS: Time-activity curves from smaller ROIs suffered more from statistical noise with only a modest reduction of spillover effects, which led to more variation in calculated MRGlu. Mean ratios of MRGlu obtained with IDIF and AS were close to 1 when AA and DA (0.97 +/- 0.07 and 1.00 +/- 0.11, respectively) were used to define the input function. However, when LA and LV were used, mean ratios were 0.81 +/- 0.06 and 0.79 +/- 0.08, respectively, reflecting a significant underestimation of MRGlu. The use of AA for defining the input function resulted in the best agreement with AS and the smallest interobserver variation. CONCLUSION: The ascending aorta is the structure of choice for defining IDIF and a large ROI (diameter, approximately 15 mm) should be used to minimize the effects of statistical noise. Publication Types:
Measurement of glucose consumption using [(18)F]fluorodeoxyglucose. Wienhard K. Max-Planck-Institut fur Neurologische Forschung, Gleueler Strasse 50, 50931 Koln, Germany. klaus.wienhard@pet.mpin-koeln.mpg.de The [(18)F]fluorodeoxyglucose (FDG) method to measure glucose metabolism quantitatively in humans is reviewed. The assumptions and the mathematical formulation of the underlying autoradiographic Sokoloff model and its adaptation to positron emission tomography (PET) are described. Various implementations to estimate glucose consumption from measured tissue activity with PET are presented. The dependence on the "lumped constant" and on the accuracy of the input function is discussed. Recommendations for the practical application of different procedures for performing FDG studies are given. Publication Types:
Effect of flow and vascular heterogeneity on glucose metabolism in isolated dog hearts. Kuikka JT. Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Finland. jkuikka@uku.fi In non-ischaemic myocardium glucose uptake is assumed to be proportional to blood flow. We investigated the effect of regional vascular heterogeneity on glucose metabolism at various flow rates in the isolated blood-perfused dog hearts. Aortic bolus injections contained an intravascular reference tracer (albumin) and two of three glucoses: L-glucose (an extracellular tracer), D-glucose and 2-deoxy-D-glucose. Flow ranged from 0.5 to 2 4 ml min(-1) g(-1). Vascular heterogeneity was calculated from the albumin outflow dilution curve. A three-region convection-diffusion from the abumin outflow dilution curve. A three-region, convection-diffusion model was fitted to outflow dilution curves to estimate glucose metabolic rate (consumption). The results of 2-deoxy-D-glucose experiments showed that the lumped constant was dependent on flow, glucose metabolic rate was proportional to flow and dependent on the heterogeneity of the myocardial vasculature. The results support the views that without accounting the regional flow heterogeneity, glucose metabolic rate will be underestimated. PMID: 12005155 [PubMed - indexed for MEDLINE]
Glucose uptake and lumped constant variability in normal human hearts determined with [18F]fluorodeoxyglucose. Botker HE, Bottcher M, Schmitz O, Gee A, Hansen SB, Cold GE, Nielsen TT, Gjedde A. Department of Cardiology, Skejby Hospital, Aarhus, Denmark. BACKGROUND: Myocardial glucose uptake can be measured with [18F]fluoro-2-deoxyglucose (FDG) and positron emission tomography (PET). However, changes of myocardial metabolism may alter the ratio between the net rates of FDG and glucose uptake, known as the lumped constant. We tested the hypothesis that the variability of the lumped constant determined in animals explains the disagreement between human net myocardial glucose uptake calculated from aortocoronary sinus deficits and measured with PET. METHODS AND RESULTS: In the three-compartment model of glucose transfer into cells, the lumped constant is a function of the relationship between the net and the unidirectional rates of uptake of glucose and glucose tracers such as FDG. Using this principle, validated in the human brain and the animal heart under experimental conditions, we estimated the lumped constant of the human heart by PET in 10 healthy men under several metabolic conditions established by altering the circulating insulin level during a euglycemic clamp and with somatostatin and heparin infusions. The lumped constant varied systematically between 0.44 and 1.35. At insulin levels below 100 pmol/L, free fatty acids were inversely related to serum insulin levels and the lumped constant increased linearly with serum insulin concentration. At insulin levels above 100 pmol/L, free fatty acids were suppressed and the lumped constant varied in inverse proportion to the insulin level. When the lumped constant was estimated in this manner, net myocardial glucose uptake agreed with that determined in previous measurements of blood flow and aortocoronary sinus deficit. CONCLUSION: In the intact human organism, the cardiac lumped constant varies with the metabolic condition, as predicted from studies of the brain and animal heart under experimental conditions. PMID: 9115064 [PubMed - indexed for MEDLINE]
Comment in:
Lumped constant for deoxyglucose is decreased when myocardial glucose uptake is enhanced. Hashimoto K, Nishimura T, Imahashi KI, Yamaguchi H, Hori M, Kusuoka H. Division of Tracer Kinetics, Biomedical Research Center, Osaka University Medical School, Suita, Osaka 565-0871, Japan. Quantification of myocardial glucose uptake by positron emission tomography with [18F]fluorodeoxyglucose (FDG) requires the "lumped constant" (LC), which corrects the difference of affinity between glucose and FDG to glucose transporters and phosphorylating system. Since LC was introduced, it has been considered to be constant. However, this has recently been questioned. To elucidate the constancy of LC by other than radioisotope techniques, the accumulation rate of sugar phosphates (d[SP]/dt) was measured in isolated, perfused rat hearts by 31P NMR spectroscopy with 2-deoxyglucose (DG). We postulate alpha as the affinity of DG to transporters and the phosphorylating system relative to that of glucose. Theoretically, alpha is equivalent to LC. We determined alpha by measuring d[SP]/dt at DG concentration ([DG]) = 10, 7, 5, and 3 mmol/l, keeping the total of glucose concentration ([glucose]) and [DG] to 10 mmol/l. When the glucose uptake was enhanced by insulin (10 mU/ml) or stunning, calculated alpha was reduced (insulin stimulated, 0.15; stunning, 0.19) compared with the control (0.59). These results indicate that LC can be evaluated by methods without radiolabeled tracers and is smaller when glucose uptake is augmented. PMID: 9887025 [PubMed - indexed for MEDLINE]
Glucose metabolism in reperfused myocardium measured by [2-18F] 2-fluorodeoxyglucose and PET. Kofoed KF, Schoder H, Knight RJ, Buxton DB. Department of Molecular Pharmacology, UCLA School of Medicine, USA. OBJECTIVE: [2-18F] 2-fluorodeoxyglucose (FDG) is widely used to trace glucose metabolism for cardiac imaging with positron emission tomography. Because the transport and phosphorylation rates differ for glucose and FDG, a lumped constant (LC) is used to correct for these differences. The effects of ischemia and reperfusion on the LC in vivo are unknown. To determine the validity of FDG as a tracer of glucose metabolism in post-ischemic myocardium in vivo, the relationship between glucose uptake (GU) and FDG metabolic rate (FDG-MR) was assessed early post-reperfusion following a transient ischemic event. METHODS: FDG metabolic rate, measured with FDG and PET, was compared to invasive measurements of substrate metabolism in reperfused and global myocardium of dogs subjected to 25 min ischemia and 2 h reperfusion. RESULTS: The FDG metabolic rate was decreased 20 +/- 4% in reperfused relative to remote myocardium. Glucose oxidation and lactate uptake were also decreased in reperfused relative to global myocardium, by 26 +/- 6% and 60 +/- 8% respectively. Glucose uptake did not differ significantly between reperfused and global myocardium. A linear correlation between FDG metabolic rate and glucose uptake was found in both reperfused and remote myocardium. Estimates of the LC from the slopes of the regression lines were similar in reperfused and remote myocardium, 1.25 and 1.44 respectively, and did not differ significantly from the LC determined in control dogs, 1.1. CONCLUSIONS: We conclude that the FDG metabolic rate continues to correlate well with glucose metabolism in reperfused myocardium. While FDG metabolic rate was modestly decreased in the absence of a significant change in glucose uptake, large alterations in the LC are not found 2 h post-reperfusion in vivo. PMID: 10728352 [PubMed - indexed for MEDLINE]
Sensitivity of myocardial fluorodeoxyglucose lumped constant to glucose and insulin. Ng CK, Holden JE, DeGrado TR, Raffel DM, Kornguth ML, Gatley SJ. Department of Medical Physics, University of Wisconsin, Madison 53706. The lumped constant (LC) that relates the steady-state phosphorylation rate of 2-[18F]-fluoro-2-deoxy-D-glucose (2-FDG) to that of glucose was determined in an isolated working rat heart model by direct assay of phosphorylation product formation. Five conditions were tested: 5 and 30 mM glucose without insulin, and 2, 3.5, and 5 mM glucose + 10 mU/ml insulin, all at high external work load. Hearts were continuously perfused with 2-FDG and tritiated glucose without recirculation. The steady-state production of tritiated water was used to monitor the glucose phosphorylation rate. Perfused hearts were freeze-clamped and extracted in perchloric acid, and 2-FDG-6-phosphate was separated from 2-FDG with a formate column. The accumulation of 2-FDG phosphorylation products in tissue was also determined from the slopes of the total tissue radioactivity time courses measured by external gamma-ray detection. Without insulin, the LC value decreased 18% as perfusate glucose concentration was increased sixfold (0.94 +/- 0.06 at 5 mM vs. 0.77 +/- 0.17 at 30 mM). With insulin, the LC rose from 0.33 +/- 0.03 at 5 mM to 1.19 +/- 0.05 at 2 mM glucose concentration. The trends can be interpreted in terms of the concept of control strength; the LC value rises as glycolysis becomes rate limited by transport into cells. This potential variability of the LC must be addressed in the quantitative interpretation of myocardial deoxyglucose studies. PMID: 1996702 [PubMed - indexed for MEDLINE] Frans C. Visser |
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