Metabolic Complexities in Cardiac Imaging

Abstract

HomeCirculationVol. 91, No. 9Metabolic Complexities in Cardiac Imaging Free AccessResearch ArticleDownload EPUBAboutView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticleDownload EPUBMetabolic Complexities in Cardiac Imaging Kieran Clarke and Richard L. Veech Kieran ClarkeKieran Clarke From the Department of Biochemistry (K.C.), University of Oxford, Oxford, UK; and LMMB (R.L.V.), NIAAA, Rockville, Md. Search for more papers by this author and Richard L. VeechRichard L. Veech From the Department of Biochemistry (K.C.), University of Oxford, Oxford, UK; and LMMB (R.L.V.), NIAAA, Rockville, Md. Search for more papers by this author Originally published1 May 1995https://doi.org/10.1161/01.CIR.91.9.2299Circulation. 1995;91:2299–2301For patients with advanced ischemic heart disease, positron emission tomography (PET) is a reimbursable method for identifying those suitable for revascularization. This will probably increase the use of PET in deciding whether potentially life-enhancing, but costly, interventions will be performed. In this issue of Circulation, an important article by Taegtmeyer and colleagues1 shows that it may not be possible to use the seductive, computer-derived colored images produced by PET as a quantitative measure of myocardial metabolic rate. These researchers have shown that accumulation of [2-18F]fluoro-2-deoxy-d-glucose (FDG), a widely used PET tracer, does not give an accurate measure of glucose metabolism under many of the physiological, metabolic, and hormonal conditions experienced by the heart. Modeling of FDG as a glucose analogue for glycolysis in the heart comes in large part from work in brain metabolism,2 where glucose is the major metabolic fuel and glycogen synthesis from glucose is essentially nil. In contrast, the heart is omnivorous in its choice of metabolic fuels, with a preference for fatty acids and with considerable glycogen synthesis and degradation.34 Consequently, expressions such as “myocardial glucose metabolism” and “myocardial glucose utilization” were coined in part out of recognition that FDG flux rates are unable to distinguish glycogen synthesis from glycolysis. In the heart, therefore, a measure of the rate of FDG accumulation may be just that—a measure of FDG accumulation and not a measure of metabolic rate.If one is to interpret the meaning of a change in FDG accumulation over time, a number of assumptions governing the rates of the reactions of glucose transport and phosphorylation must be met. The major reactions determining the extent of the intracellular use of glucose and FDG are transport into the cell, phosphorylation in the hexokinase reaction, dephosphorylation of glucose-6-phosphate (G6P) and FDG-6-phosphate (FDG6P), and transport out of the cell. Each of these reactions has finite forward and reverse rates that may change with hormonal conditions and substrate availability,4 not to mention a host of allosteric and covalent modifiers, both known and unknown. Therefore, the use of a constant, the “lumped constant,” to correct for the differences in transport and phosphorylation rates of glucose and FDG is incorrect. Because the extent of FDG accumulation in the heart alters for a great variety of reasons, FDG may never provide a quantitative measure of glucose metabolic rate. Given these limitations, the assumption that FDG accumulation measured by PET detects viable tissue in hypoperfused regions of myocardium due to accelerated glycolysis3 must be viewed as questionable. Increased regional uptake of FDG relative to blood flow, FDG extraction, has been used as a clinical marker for distinguishing viable myocardium from myocardial fibrosis in patients with coronary artery disease and left ventricular dysfunction.567 Thus, on the basis of PET scan evidence, patients may be identified as candidates for coronary artery bypass or angioplasty. Although important qualitative deductions, such as an obviously reduced blood flow to a section of the heart, can be made from visual inspection of the tomographic image, it is the reliability of the numerical representation of the radionuclide distribution that is of critical importance. Measurement of the rate of glucose uptake is often made by Patlak graphic analysis8 of myocardial FDG kinetics with the assumption that dephosphorylation of FDG6P is negligible. This implies that the tracer is trapped irreversibly in the cell and therefore net uptake of FDG is unidirectional. The validity of this assumption in the brain was challenged more than a decade ago,910 and a long controversy followed.111213 More recently, the assumption that FDG6P is not dephosphorylated has been questioned in the rat1415 and human16 heart. Estimates of the rate constant for FDG6P dephosphorylation vary considerably, from 0.016 to 0.039 min−1 in the brain17 and from 0.004 to 0.033 min−1 in the heart.1618 If FDG6P is dephosphorylated, then Patlak analysis of FDG time-activity curves would underestimate glucose use. Using the rate of 3H2O production from [2-3H]glucose to estimate glucose uptake in the working rat heart, Taegtmeyer and colleagues1 have demonstrated that Patlak analysis of FDG time-activity curves underestimates glucose uptake to a variable extent. They report underestimations of as much as 45% in control heart and between 37% and 89% in the presence of insulin, lactate, and d,l-β-hydroxybutyrate, conditions that change in vivo. Their conclusions also apply to the ischemic heart, in which lactate and epinephrine levels increase, glycogen is depleted, and serum insulin levels are low.3 Another study of the working rat heart has shown that the steady-state phosphorylation rate of FDG underestimates glucose uptake by as much as 67%, with increasing glucose concentrations in the presence of insulin.14 Both studies suggest that the greatest underestimation occurs under conditions that favor glycogen synthesis.4 Liedtke et al19 concluded that labeled deoxyglucose is an insensitive marker of exogenous glucose use under conditions of low glucose flux. These differences can be understood in terms of the relative control strengths of glucose and FDG in transport and the phosphorylation reaction.4Variability under different physiological conditions would explain some of the rather baffling findings in studies in which FDG uptake has been used to quantify metabolic rate, such as increased glucose metabolism in healthy sections of the heart after coronary occlusion, with normal glucose use in the postischemic regions.62021 Similarly, patients with effort angina show greater glucose use in nonischemic areas than in ischemic regions during exercise.3 Several studies of the nonischemic human heart2223242526 have quantified FDG uptake using Patlak graphic analysis, assuming no dephosphorylation of FDG6P and a “lumped constant” of 0.67. These studies show approximately 30% variability in control glucose metabolic rates, despite the use of the same rigorous euglycemic, hyperinsulinemic conditions (see the Table). The variability in the control glucose uptake rates makes it difficult to determine significant changes under different physiological conditions and suggests that the relationship between FDG and glucose transport and phosphorylation may be hard to measure or modify. Because of the complexity of the control of the rates of glucose transport into and out of the cell and because of the multiple controls on the phosphorylation and dephosphorylation of glucose,4 FDG PET will be difficult to use as a quantitative measure of metabolic rate. This has led to new approaches in brain studies, of which the latest is magnetic resonance imaging (MRI) of regional blood flow and oxygen levels termed functional MRI.27 A number of assumptions must hold for this technique to accurately reflect tissue metabolic rates. These assumptions are that cerebral blood flow and volume increase in response to local increased metabolic activity with a concomitant increase in oxygen delivery that exceeds oxygen use. This causes a net decrease in deoxyhemoglobin that increases the relaxation time of protons in the MR signal, leading to brightening of the image in the active regions. In the unlikely event that all of these assumptions hold true, the quantification of functional MR images will not be easy. This method and other MR-based measurements of brain function are in a rapid phase of development and have yet to be applied to the heart. A variety of other radionuclides have been proposed as tracers of metabolic rate, and all are subject, to greater or lesser extents, to variations that govern the reactions of metabolism. For example, the use of [1-11C]acetate to determine oxygen consumption20 may well be an estimate of the size of the glutamate pool, which varies fivefold with changes in insulin and substrates.28 Unfortunately, textbooks portray metabolic regulation as simple and straightforward, when in fact, for metabolic processes to meet the almost infinite changes imposed on them by variable life situations, regulation must be that of a complex system.29 It is a hapless result of the anatomy of the heart that measurements of the rate of H215O formation in the terminal oxidase of the electron transport system have not been possible because of the large amount of 15O2 present in the ventricular blood. This reaction accounts for more than 85% of the oxygen consumed in most tissues and, if it could be used in the heart, would be a relatively precise measure of the overall rate of oxidative metabolism.30The work of the Taegtmeyer group1 seriously questions whether FDG is a valid marker of glucose metabolism and therefore whether absolute quantification of myocardial FDG PET images is at all possible. The current use of FDG as a quantitative marker of glucose uptake reflects a failure to recognize the complexity of metabolic control.429 Of course, one may question the extent to which quantitative measures of glucose metabolism are required in patient diagnosis, given the success of FDG and PET, relative to other methods, in distinguishing viable but dysfunctional myocardium from irreversible ischemic injury and scar tissue. Having shown the deficiencies of FDG, it must be hoped that artifactual results will be avoided in the use of other metabolic tracers by developing a thorough understanding of the intimate biochemical details of all of the reactions involved in their metabolism. We hope this will be done sooner rather than later, if for no other reason than to prevent use of expensive and inaccurate hardware as well as the harm that may be done to patients if misleading conclusions are drawn from inaccurate methods. To deny treatment to patients on the assumption that FDG provides a quantitative measure of glucose metabolism would be a tragedy. Table 1. Human Myocardial Glucose Uptake RatesConditionHeart Glucose Uptake, μmol · kg muscle−1 · min−1ControlPatient/TreatmentDecrease, %StudySedentary/athlete843±91 (7)562 ±65 (7)33Nuutila et al22Type 1 diabetes763±58 (8)789 ±80 (8)NSNuutila et al23Type 2 diabetes971±128 (13)603±82 (9)39Voipio-Pulkki et al24Increased serum FFA839±94 (6)617 ±122 (6)26Nuutila et al25Glucose load737±29 (8)686±31 (8)NSKnuuti et al26FFA indicates free fatty acids. All studies started at 8:00 to 9:00 am after a 10- to 12-h overnight fast and used euglycemic insulin clamp conditions, except after the glucose load. Data are mean±SEM. The number of controls or patients is given in parentheses.FootnotesCorrespondence to Dr Richard L. Veech, LMMB, NIAAA, 12501 Washington Ave, Rockville, MD 20852. References 1 Hariharan R, Bray M, Ganim R, Goodwin GW, Taegtmeyer H. Fundamental limitations of [18F]2-deoxy-2-fluoro-d-glucose for assessing myocardial glucose uptake. Circulation.1995; 91:2435-2444. 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Baltimore, Md: Williams & Wilkins; 1980:388-397.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Hopkins J, Radda G, Veech R and Clarke K (2004) Accumulation of 2-deoxy-d-glucose-6-phosphate as a measure of glucose uptake in the isolated perfused heart: a 31P NMR study, Metabolic Engineering, 10.1016/j.ymben.2003.10.002, 6:1, (36-43), Online publication date: 1-Jan-2004. May 1, 1995Vol 91, Issue 9 Advertisement Article InformationMetrics Copyright © 1995 by American Heart Associationhttps://doi.org/10.1161/01.CIR.91.9.2299 Originally publishedMay 1, 1995 Keywordseditorialsimagingmetabolism Advertisement