Quantification of myocardial glucose utilization by PET and 1-carbon-11-glucose

5

Alterations in myocardial glucose metabolism play akey role in normal cardiac development and physiology,as well as in a variety of myocardial pathologic condi-tions. Noninvasive measurements of the rate of myocar-dial glucose utilization (rMGU) are performed routinelywith positron emission tomography (PET) and fluorine18 fluorodeoxyglucose (FDG).1-4 Because the net uptakeand phosphorylation of glucose and FDG differ substan-tially, a correction factor known a priori, termed the

lumped constant, must be included in the calculation ofrMGU. However, results of several studies have shownthat the value for the lumped constant may be altered bychanges in the levels of competing plasma substrates orinsulin, thus decreasing the accuracy of the FDG methodfor quantifying glucose utilization.5,6 Although a strategyhas been devised in isolated heart preparations to accountfor the variable lumped constant, its accuracy is unclearin animals and human beings where the integrativeeffects of the plasma substrate and hormonal environ-ment on myocardial glucose metabolism are present.7

Furthermore, the stability of the lumped constant and theapplicability of potential solutions to account for its vari-ability under conditions that alter myocardial glucose uti-lization, such as coronary artery disease, diabetic melli-tus, or hypertension, are unknown.

These problems can potentially be avoided by the useof radiolabeled glucose as a radiopharmaceutical. Glucoselabeled with carbon 11 has been produced in sufficientquantities by the photosynthetic method for PET studies inhuman beings. Unfortunately, this method results in the C-11 label being distributed among the 6 carbons, limiting the

ORIGINAL ARTICLES

Quantification of myocardial glucose utilization by PET and 1–carbon-11–glucose

Pilar Herrero, MS,a Carla J. Weinheimer, MS,b Carmen Dence, MS,c

William F. Oellerich, MD, PhD,b and Robert J. Gropler, MDa,b

Background. Measurements of the rate of myocardial glucose utilization (rMGU) play a keyrole in the assessment of alterations in myocardial substrate metabolism in normal and abnor-mal cardiac states. In this study we determined whether rMGU could be quantified by positronemission tomography (PET) and 1–carbon-11–glucose.

Methods and Results. Twenty dogs were studied with a variety of interventions includingfasting (n = 5), hyperinsulinemic-euglycemic clamp at rest (n = 6), clamp and phenylephrine (n= 5), and clamp and dobutamine (n = 4). Measurements of myocardial blood flow and rMGUwere made by PET with oxygen-15–water and 1–C-11–glucose, respectively. Arterial-coronarysinus sampling was performed to measure rMGU by the Fick method. Values for rMGU rangedfrom 50 to 2436 nmol/g/min. Myocardial 1–C-11–glucose images of high quality were obtained.There was a close and direct correlation between values for rMGU measured by PET and thosemeasured directly (y = 0.86x + 112, r = 0.98, P < .0001). The coefficient of variation for theregional estimates of rMGU ranged from 11.3% ± 7.4% during clamp at rest to 16.3% ± 8.4%during clamp with phenylephrine.

Conclusions. It now appears possible to quantify myocardial glucose utilization by PET with1–C-11–glucose. This method should become a valuable tool in the assessment of alterations inmyocardial glucose metabolism in both normal and abnormal myocardium. (J Nucl Cardiol2002;9:5-14.)

Key Words: Glucose • metabolism • myocardium • tomography

From Cardiovascular Imaging Laboratory, Edward MallinckrodtInstitute of Radiologya; the Cardiovascular Division, Department ofInternal Medicineb; and Division of Radiological Sciences, EdwardMallinckrodt Institute of Radiologyc; Washington University Schoolof Medicine, St Louis, Mo.

Received for publication Aug 16, 2001; final revision accepted Sept 25,2001. Published online Nov 7, 2001.

This work was supported by NIH grant HL13581.Reprint requests: Pilar Herrero, MS, Cardiovascular Imaging

Laboratory, Mallinckrodt Institute of Radiology, 510 S Kings-highway Blvd, St Louis, MO 63110; [email protected].

Copyright © 2001 by the American Society of Nuclear Cardiology.1071-3581/2001/$35.00 + 0 43/1/120635doi:10.1067/mnc.2001.120635

accurate characterization of the tracer’s metabolic fate.Recently, synthesis procedures to produce glucose radiola-beled with C-11 specifically at the one-carbon position(1–carbon-11–glucose) have been developed.8,9 This syn-thesis offers the advantage of nearly all of the radiolabelbeing trapped as metabolites of intermediary metabolismwithin the first 5 or 10 minutes after tracer administration.10

Numerous investigators have demonstrated that accuratemeasurements of cerebral glucose utilization can be per-formed by PET and 1–C-11–glucose with the use of appro-priate compartmental models.11-13 The purpose of thisstudy was to determine whether rMGU could be quantifiedin dog hearts by compartmental modeling of myocardialkinetics of 1–C-11–glucose as measured by PET.

METHODS

Animal Preparation

All animal experiments were conducted in compliancewith the Guidelines for the Care and Use of Research Animalsestablished by Washington University’s Animal StudiesCommittee. The dogs were fasted for 12 to 18 hours before pre-medication with morphine sulfate (1-2 mg/kg) subcutaneously.Thirty to sixty minutes after premedication with morphine sul-fate, the dogs were anesthetized with sodium thiopental (12.5mg/kg) followed by α-chloralose (72 mg/kg) given intra-venously. They were intubated and ventilated with room air andsupplemental oxygen to maintain arterial blood gases within thephysiological range. After the induction of anesthesia and intu-bation, catheters were placed in the thoracic aorta via thefemoral arteries for monitoring of arterial blood pressure andarterial sampling. One femoral vein was cannulated to obtaininferior vena cava samples and to administer drugs. The rightexternal jugular vein was exposed for placement of a coronarysinus catheter under fluoroscopic guidance. Correct placementof the catheter in the coronary sinus was confirmed first radio-graphically (by means of contrast material) and then by mea-surement of oxygen saturation in both coronary sinus and infe-rior vena cava blood samples.

To attain a wide range in rMGU, 20 dogs were studiedunder the following conditions. Five were studied under fast-ing conditions, and 15 were studied during hyperinsulinemic-euglycemic clamp, which entailed a continuous infusion ofinsulin (70 mU/kg/h) with an adjustable infusion of 20% dex-trose.14 Four of these dogs were studied during coadministra-tion of the clamp and dobutamine (10 µg/kg/min), a predomi-nantly β-adrenergic agonist. It was anticipated that theperipheral lipolytic effects of β-adrenergic stimulation wouldmarkedly increase plasma fatty acid levels and blunt theexpected increase in rMGU as a result of the catecholamineeffect on the myocardium. To produce conditions of preferen-tial or high glucose use, the other 11 dogs were studied eitherat rest (n = 6) or during coadministration of phenylephrine (n= 5, 0.84-1.6 µg/kg/min), a predominantly α-adrenergic ago-nist. These 5 dogs were supplemented with intermittent bolusesof intravenous atropine (0.5 mg) to maintain the heart rate at

preinfusion rates. After completion of the PET study, the ani-mals were euthanized with an overdose of anesthesia and potas-sium chloride.

Production of 1–C-11–glucose

This compound was synthesized according to a publishedprocedure.9 In brief, C-11–NH4CN (ammonium cyanide) wasreacted with D-arabinose in a borate buffer solution. The nitrileadduct obtained was converted by hydrogenolysis with Raneynickel to a mixture of C-11–D-mannose and D-glucose. Afterpurification by high-performance liquid chromatography on anAminex HPX-87P column, 1–C-11–D-glucose was obtained asa sterile and pyrogen-free isotonic solution, with a radiochemi-cal purity of about 99.0%.

Imaging Protocol

All PET studies were performed on standard commercialtomographs available at Washington University. The electrocar-diogram, hemodynamics, and blood gas values were monitoredthroughout the study. A transmission scan was performed to cor-rect for photon attenuation. To measure myocardial perfusion,oxygen-15–water (0.40 mCi/kg) was administered as an intra-venous bolus and dynamic PET data were acquired for 5 minutes(5-second frames). After decay of O-15 radioactivity was allowedfor, 1–C-11–glucose (15-20 mCi) was administered as a bolus,followed by 60 minutes of dynamic data collection. To measureplasma C-11 and carbon-11–carbon dioxide activity, paired arte-rial and coronary sinus blood samples were obtained throughoutthe imaging session (total of 12 paired samples). To measurerMGU on the basis of the myocardial extraction of glucose andto verify the stability of the substrate environment, arterial andcoronary sinus blood samples were obtained at the beginning,middle, and end of the scanning interval for 1–C-11–glucose.

Analysis of PET Data

Myocardial O-15–water and 1–C-11–glucose images werereoriented to generate standard short-axis and long-axis views.On the composite O-15–water images (corrected for O-15activity emanating from the intravascular compartment) and the1–C-11–glucose images, regions of interest encompassing theseptal, anterior, lateral, and inferior walls (3-5 cm3) were placedon 3 to 4 midventricular short-axis slices to generate myocar-dial time-activity curves. To obtain the input function, a smallregion of interest (1 cm3) was placed within the left atrial cav-ity on an O-15–water and 1–C-11–glucose midventricular slicein the vertical long-axis orientation. Within these regions ofinterest, myocardial and blood time-activity curves were gener-ated for O-15–water and 1–C-11–glucose. Subsequently, valuesfor myocardial blood flow (MBF) and rMGU were calculatedand averaged to obtain one value for MBF and rMGU per dog.

Measurement of MBF. By application of the image-analysis routine to the time-segmented data, myocardial time-activity curves for each segment were generated. From thesedata, MBF (in milliliters per gram per minute) was quantified

6 Herrero et alQuantification of myocardial glucose utilization

Journal of Nuclear CardiologyJanuary/February 2002

through use of a compartmental modeling approach developedand validated previously at Washington University.15-17

Measurement of rMGU. The kinetics of glucose metab-olism are defined in this study by a 4-compartment model thatrepresents a simplification of myocardial glucose metabolism(Figure 1). In this model, vascular 1–C-11–glucose enters theinterstitial/cytosolic component of myocardium (compartment1) proportional to K1. Once the tracer is in compartment 1, iteither diffuses back into the vasculature at a rate of k2 or it isphosphorylated and metabolized to pyruvate (compartment 2)at a rate of k3. The label can then either form glycogen (com-partment 3) at a rate of k4 or be metabolized via anaerobic oroxidative pathways (compartment 4) at a rate of k5. Metabolitesfrom aerobic and anaerobic metabolism washout into the vas-culature at a rate proportional to flow.

This model is based on the following key assumptions: (1)Arterial and capillary glucose concentrations are the same. (2)Transfer of glucose from interstitium to cytosol is very rapidrelative to hexokinase-mediated phosphorylation,18 thus K1represents the overall rate of glucose delivery into the myocyte,including perfusion as well as transport rates. (3) In the well-oxygenated heart, both the pentophosphate shunt and transami-nation between pyruvate and alanine are negligible. (4) Themodel does not differentiate between aerobic and anaerobicmetabolism. (5) The vascular volume is assumed to be 0.1mL/g. (6) During the study period the amount of glycogen con-verted back to glucose-6-phosphate is negligible.

The differential equations defining the model are as fol-lows:

dq1(t)/dt = K1 Ca(t) – (k2 + k3 + k5) q2(t) (1)

dq2(t)/dt = k3 q1(t) – (k4 + k5) q2(t) (2)

dq3(t)/dt = k4 q1(t) (3)

dq4(t)/dt = k5 q2(t) – (F/V) q4(t) (4)

Total tracer concentration in myocardium as a function of timecan be defined as the sum of the tracer in each compartment:

qt(t) = q1(t) + q2(t) + q3(t) + q4(t) (5)

in which Ca(t) is arterial 1–C-11–glucose concentration (incounts per minute per milliliter) (input function); K1 and k2-k5are turnover rate constants describing the transfer of tracer

between compartments (K1, in milliliters per gram per minute,and k2-k5 in min–1); qn is concentration of tracer in compart-ment n (in counts per minute per milliliter); qt is total concen-tration of tracer in myocardium (in counts per minute per milli-liter); F is MBF (in milliliters per gram per minute); and V isfractional vascular volume (assumed to be 10% of total volume[in milliliters per gram]).

To define the true input function, arterial blood C-11 activ-ity obtained from the PET images was corrected for C-11–carbon dioxide activity measured from direct blood sampling.For this model the partial volume correction was fixed to valuesobtained from O-15–water studies.15-17 Spillover from blood tomyocardium (Fbm) was estimated, along with model turnoverrates. Solution of the differential equations describing the masstransfer of the tracer from blood to the different compartmentsand estimation of the model rate constants (K1 and k2-k5) andFbm were performed with the use of well-established numericalmethods.19,20

Total regional myocardial glucose utilization (rMGU) (innanomoles per gram per minute) was then calculated from esti-mated turnover rates and glucose plasma levels as follows:

rMGU = GLUb · GLUuptake (6)

in which GLUb is plasma glucose concentration (in nanomolesper milliliter) and GLUuptake is the rate at which glucose is takenup by myocardium (in milliliters per gram per minute).

The plasma glucose concentration (GLUb) was determinedfrom arterial blood samples taken during the PET studies.Under the assumption that true steady-state conditions are pre-sent, myocardial glucose uptake can be calculated from the esti-mated turnover rate constants (ie, differential equations were setto zero) as follows:

GLUuptake (in milliliters per gram per minute) = (7)(K1 · k3)/(k2 + k3)

Thus,

rMGU (nanomoles per gram per minute) = (8)GLUb · [(K1 · k3)/(k2 + k3)]

Measurement of Radioactive Plasma Metabolites

The percentage of arterial and coronary sinus C-11–carbondioxide in the plasma was measured through use of the follow-

Journal of Nuclear CardiologyVolume 9, Number 1;5-14

Herrero et alQuantification of myocardial glucose utilization

7

Figure 1. Configuration of the compartmental model of myocardial 1–C-11–glucose kinetics.


ing procedure. A plasma sample was deposited in a test tube,acidified with 6N hydrogen chloride, sparred with nitrogenfor 10 minutes to eliminate the C-11–carbon dioxide, andcounted for radioactivity. Another plasma sample was keptunder basic conditions, and radioactivity was measured. Thecount difference between the test tubes was used to calculatethe percent C-11–carbon dioxide present in the plasma. Inaddition, total C-11–carbon dioxide production (counts) wasmeasured by integration of the differences in coronary sinus

and arterial C-11–carbon dioxide counts over the 60-minutestudy period.

Measurements of Nonradioactive Plasma Substrates

Glucose and lactate plasma levels were assayed enzymati-cally with a commercially available 2300 STAT Plus Analyzer(YSI Life Sciences). Plasma fatty acid levels were measured


Figure 2. Myocardial 1–C-11–glucose images obtained 40 to 60 minutes after tracer injection in dogs studied duringeither fasting (Fasted), hyperinsulinemic-euglycemic clamp at rest (Clamp/Rest), or hyperinsulinemic-euglycemicclamp with phenylephrine (Clamp/Phenylephrine). Images are displayed in the short-axis view. S, Septum; A, anterior;L, lateral; I, inferior. Color scale: white, highest counts; blue, lowest counts.

Figure 3. Time-activity curves from the dog studies shown in Figure 2: Fasted (A), clamp/rest (B), andclamp/phenylephrine (C).

A B C

A

B C

with capillary gas chromatography and high-performance liq-uid chromatography.

Statistical Analysis

All data are presented as mean ± SD. Correlations werecalculated by linear regression. The differences betweengrouped data were compared by means of analysis of variancewith differences localized by the post hoc Scheffé test. A Pvalue < .05 was considered statistically significant.

RESULTS

Hemodynamics, Myocardial Perfusion, andMyocardial Oxygen Consumption

Measurements of hemodynamics, MBF, andmyocardial oxygen consumption (MVO2) for the 4groups of dogs are shown in Table 1. Consistent with theα-agonist effect of phenylephrine, systolic and diastolicblood pressures were highest in the clamp/phenylephrinegroup. The reason for the increase in systolic blood pres-sure in the fasted group is unclear. The heart rate washighest in the clamp/dobutamine group, consistent withthe β1 effects of this drug. As a result of all of thesechanges, the rate-pressure product tended to be higher inthese 3 groups when compared with the clamp/restgroup. As a result of technical difficulties with the oxime-ter, values for MVO2 could not be obtained in 2 dogsstudied during clamp with dobutamine. Commensuratewith a low rate-pressure product, both MVO2 and MBFwere lowest in dogs studied during clamp at rest. Of note,MVO2 and MBF were highest in the clamp/dobutaminegroup, consistent with the combined effects of an ele-vated rate-pressure product and oxygen wastage inducedby β-adrenergic stimulation.

Plasma Substrate Levels and MyocardialSubstrate Utilization

Shown in Table 2 are the arterial plasma levels forfree fatty acids, glucose, and lactate, as well as the extrac-tion fractions and utilization rates for these substrates,obtained in the 4 groups of dogs. Plasma fatty acid levelswere highest in the fasted group and tended to be higherin the clamp/dobutamine group, consistent with theperipheral lipolytic effects of β-adrenergic stimulation.Plasma glucose and lactate levels did not differ signifi-cantly among the groups. Myocardial extraction of fattyacids tended to be lowest in the clamp/rest group.Myocardial extraction of glucose and lactate were high-est in the clamp/phenylephrine group. Myocardial fattyacid utilization was highest in the clamp/dobutaminegroup, reflecting the increase in plasma fatty acids,myocardial extraction of fatty acids, and MBF.Myocardial glucose utilization was highest in theclamp/phenylephrine group, reflecting the combinedeffects of an increased extraction of glucose and anincrease in MBF. There were no significant differences inmyocardial lactate utilization rates among the groups.

PET Data Analysis

Representative myocardial images of 1–C-11–glucoseare shown in Figure 2. As expected, differential myocar-dial uptake of tracer increased with increasing levels ofrMGU. Whereas myocardium could not be differentiatedfrom blood in the fasted state, it could readily be differ-entiated during clamp at rest and even more so duringphenylephrine. The arterial and myocardial time-activitycurves for these images are shown in Figure 3. In allcases, the blood cleared rapidly, with less than 10% ofactivity present by 10 minutes after tracer injection. Incontrast, the myocardial time-activity curves differedmarkedly in both their height relative to the blood curve



9

Figure 4. A, Correlation between PET-derived measurements of myocardial glucose extraction fraction and directly mea-sured values. B, Correlation between PET-derived measurements of myocardial glucose utilization rates and directlymeasured values. Open circles represent mean regional values, and error bars represent SD of the mean.

A B

and shape. Consistent with the image obtained under fast-ing conditions, the myocardial time-activity curve between40 and 60 minutes was at a height similar to that of bloodand was flat in shape. In contrast, during hyperinsuline-mic-euglycemic clamp, the myocardial time-activity curvewas higher than that of blood and had a shape consistentwith initial uptake and subsequent slow clearance. Thesefindings became more pronounced during coadministra-tion of the clamp and phenylephrine, consistent with theexpected increase in both glucose uptake and metabolismthat should occur with this intervention.

Mean turnover rate constant estimates are shown inTable 3. Values reflecting glucose transport (K1), hexo-kinase-mediated phosphorylation (k3), and glycolysis(k5) were highest in the clamp/phenylephrine group. Thispattern is consistent with the effects of insulin andincreased cardiac work on these processes.

Figure 4 demonstrates a close correlation betweenPET-derived values for myocardial extraction of glucoseand values for myocardial extraction of glucose mea-

sured directly over a wide range of substrate and insulinavailability and levels of cardiac work. A similar closecorrelation was observed between PET-derived values forrMGU and directly measured values for rMGU.However, in both cases there was slight underestimation(about 15%) of glucose extraction and rMGU by PET.Directly measured as well as PET-derived rMGU valuescorrelated significantly with total C-11–carbon dioxideproduction (r = 0.84, P < .0001, and r = 0.78, P < .0001,respectively). Furthermore, k3 and k5 correlated withtotal C-11–carbon dioxide production (r = 0.77, P < .001,and r = 0.58, P < .01).

Regional analysis of PET-derived rMGU estimatesshowed no significant differences except in the inferiorwall, where values were approximately 8% lower than inthe interventricular septum. The regional variation for theindividual estimates of rMGU during each of the inter-ventions is shown in Table 4. Intra-regional variation wasless than 20% for all interventions. Inter-regional varia-tion was less than 17% for all interventions.



Table 2. Substrate arterial concentration, myocardial extraction fraction, and utilization

Arterial concentration Myocardial EF

FFA Glucose LactateIntervention (nmol/mL) (µmol/mL) (µmol/mL) FFA Glucose Lactate

Fasted (n = 5) 3506 ± 2896* 6.38 ± 0.49 1.05 ± 0.30 0.17 ± 0.13 0.04 ± 0.07 0.17 ± 0.20Clamp/rest (n = 6) 164 ± 132 4.69 ± 1.34 0.98 ± 0.28 0.11 ± 0.10 0.13 ± 0.04 0.33 ± 0.09Clamp/PHEN (n = 5) 118 ± 64 5.47 ± 1.11 0.81 ± 0.24 0.27 ± 0.12 0.20 ± 0.09† 0.48 ± 0.06†

Clamp/DOB (n = 4) 1089 ± 607 6.36 ± 1.30 1.37 ± 0.77 0.31 ± 0.11 0.03 ± 0.01 0.22 ± 0.10

Values represent mean ± SD. Myocardial EF calculation = [(arterial – coronary sinus concentration)/arterial concentration]. Myocardial utilization calculation = (arterial – coronary sinus concentration) × MBF.FFA, Free fatty acids; EF, extraction fraction; Clamp, hyperinsulinemic-euglycemic clamp; PHE, phenylephrine; DOB, dobutamine.*P < .05 vs clamp/rest and clamp/PHE.†P < .05 vs fasted and clamp/DOB.‡P < .05 vs all groups.

Table 1. Hemodynamics, MBF, and MVO2

SBP DBP HR RPPIntervention (mm Hg) (mm Hg) (beats/min) (mm Hg · beats/min)

Fasted (n = 5) 152 ± 38 104 ± 30 102 ± 58 12251 ± 8347Clamp/rest (n = 6) 96 ± 24 66 ± 19 91 ± 27 6760 ± 2280Clamp/PHE (n = 5) 169 ± 24* 123 ± 28† 109 ± 26 15603 ± 5918Clamp/DOB (n = 4) 132 ± 32 64 ± 4 173 ± 36* 15060 ± 3372

Values represent mean ± SD.SBP, Systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; RPP, rate-pressure product [(SBP + 2 · DBP)/3) · HR]; Clamp, hyperinsulinemic-euglycemic clamp; PHE, phenylephrine; DOB, dobutamine.*P < .05 vs clamp/rest.†P < .05 vs clamp/rest and clamp/DOB.‡P < .05 vs all groups.

DISCUSSION

Assessment of rMGU plays a key role in furtheringour understanding of the relationship between alterationsin myocardial substrate utilization and mechanical func-tion in both normal and abnormal cardiac states. To date,noninvasive measurements of rMGU have been per-formed routinely by PET with FDG. The results of thisstudy demonstrate that accurate values for rMGU canalso be obtained by PET with 1–C-11–glucose.

PET Imaging of Myocardial Glucose Metabolism

As mentioned previously, measurements of rMGUcan be obtained by PET with FDG on the basis of eithercompartmental modeling or Patlak graphical analysis ofmyocardial FDG kinetics.1-4 However, this approach hasseveral disadvantages. To measure rMGU, the lumpedconstant is needed to account for the differences betweenglucose and deoxyglucose with respect to transmembra-

nous transport and hexokinase-mediated phosphoryla-tion. However, the sensitivity of the lumped constant tothe level of plasma fatty acids and insulin limits its sta-bility.5,6 Recently, an approach has been devised in iso-lated perfused rat hearts to account for this variability. Inbrief, the method combines the ratios between the ratesof net transport and unidirectional transport for FDG andglucose (determined a priori) and the ratio of the unidi-rectional transport and steady-state clearance of FDG(determined by Patlak plots) to calculate the lumped con-stant.7 Although accurate measurements of rMGU wereobtained with this method, its accuracy in vivo and in dis-eased myocardium is unknown. Because of the limitedmetabolic fate of FDG, only values for rMGU can beassessed. The metabolic fate of extracted glucose such asglycogen formation or glycolysis cannot be delineated.Finally, serial imaging with FDG is limited because ofthe 110-minute physical half-life of F-18.

Many of these problems can be obviated by the useof radiolabeled glucose. With the use of the photosyn-thetic method, C-11–glucose has been produced in suffi-cient amounts to permit PET imaging in humanbeings.21-23 However, this method results in the C-11label being distributed among the 6 carbons, making itdifficult to adequately account for the efflux of C-11–carbon dioxide and other metabolites from tissue.22,23

More recently, radiochemical procedures were developedto specifically label glucose in the one-carbon position.8,9

The advantage of this approach is that much of theradioactive label from 1–C-11–glucose is trapped asmetabolites of intermediary metabolism, resulting in aslower turnover in tissue and more accurate assessmentsof the tissue kinetic of the tracer.24 With the use of PETand 1–C-11–glucose, accurate measurements of cerebralglucose metabolic rates under a variety of conditionshave been obtained.11-13 The results of this study suggestthat similar accurate measurements of rMGU can beobtained with this approach.

Overall, the tracer performed as expected with thedifferent interventions designed to alter myocardial glu-cose utilization. Myocardial glucose extraction as mea-sured by the Fick method was lowest in the fasted andclamp/dobutamine groups, consistent with the combinedeffects of low plasma insulin and high plasma fatty acids(in the former case) and high plasma fatty acids alone (inthe latter case). Myocardial glucose extraction increasedprogressively as insulin became available, plasma fattyacids decreased, and cardiac work increased (Table 2).These changes in myocardial extraction were closelyparalleled by PET-derived measurements of myocardialglucose extraction (Figure 4). As a consequence, mea-surements of rMGU measured by PET with 1–C-11–glucose correlated with directly measured values (Figure 4).



11

Myocardial utilization

FFA Glucose Lactate(nmol/g/min) (nmol/g/min) (nmol/g/min)

352 ± 364 123 ± 246 192 ± 2415 ± 16 354 ± 118 199 ± 8949 ± 26 1489 ± 683‡ 597 ± 388

662 ± 365* 439 ± 295 978 ± 972

MBF MVO2(mL/g/min) (µmol/g/min)

0.78 ± 0.29 11.7 ± 0.1*0.64 ± 0.13 6.9 ± 1.91.42 ± 0.60* 19.0 ± 6.3*2.13 ± 0.09‡ 32.5 ± 7.2‡

Moreover, the regional variability of the measurementswas fairly low (Table 4) and was comparable to theregional variability reported for Patlak graphical analysisof myocardial FDG kinetics.3 Finally, no significant dif-ferences in the regional values for rMGU were observedexcept in the inferior wall, where, because of spillover ofC-11 counts from the liver into this wall, values wereapproximately 8% lower than in the interventricular sep-tum. Taken together, the data suggest that accurate mea-surements of rMGU can be obtained on a regional basisas well as for the entire left ventricle.

The model used to estimate rMGU based on themyocardial kinetics of 1–C-11–glucose is a highly sim-plified description of myocardial glucose metabolism.For example, in the current model it is assumed thatmovement of glucose-6-phosphate into the glycogen poolis unidirectional. Clearly, this is not the case under a vari-ety of conditions.25-27 Moreover, there is no accountingfor the production of lactate and its re-uptake inmyocardium (ie, lactate shuttle).28 However, it should beexpected that the amount of lactate produced frommyocardial glycolysis that re-enters the myocardiumshould be low, relative to the amount of lactate producedfrom peripheral sites that is ultimately extracted by theheart. In addition, over the wide range of physiological

substrate and cardiac work environments attained in thisstudy, the impact of C-11–lactate produced by peripheralsites on the accuracy of the PET estimates of rMGUappears to be small. This is because the PET estimates ofrMGU were not overestimated in these studies as wouldbe expected if significant amounts of C-11–lactate wereextracted and metabolized relative to 1–C-11–glucose. Itis also assumed that the contributions of transaminationof pyruvate to alanine and the pentophosphate pathway tooverall glucose utilization are small. Both assumptionsappear reasonable in the well-oxygenated heart, althoughthey may not be under conditions such as myocardialhypertrophy or ischemia and reperfusion.29-32 Despitethese assumptions, accurate estimates of rMGU with thisapproach were obtained under the conditions studied.Further studies will be required to determine whether asimilar level of accuracy will be achieved under morepathological conditions (such as myocardial ischemiaand reperfusion) that alter myocardial glucose metabo-lism.

On the basis of Figure 4, it appears that PET with1–C-11–glucose underestimates rMGU as measured byabout 15%. One possible reason is the underestimation ofthe height of the tissue curve due to partial volumeeffects. However, the final fitted curve was corrected for



Table 3. Turnover rate constants obtained from kinetic model (Figure 1)

Intervention K1 (mL/g/min) k2 (min–1) k3 (min–1) k4 (min–1) k5 (min–1)

Fasted (n = 5) 0.62 ± 0.17 1.86 ± 0.34 0.06 ± 0.02 0.000 ± 0.000 0.033 ± 0.017Clamp/rest (n = 6) 0.69 ± 0.12 2.00 ± 0.56 0.30 ± 0.10 0.002 ± 0.003 0.038 ± 0.008Clamp/PHE (n = 5) 1.41 ± 0.47* 3.32 ± 1.51 0.75 ± 0.25† 0.004 ± 0.004 0.107 ± 0.058*Clamp/DOB (n = 4) 1.14 ± 0.17 2.46 ± 0.97 0.17 ± 0.07 0.001 ± 0.001 0.074 ± 0.045

Values represent mean ± SD.Clamp, Hyperinsulinemic-euglycemic clamp; PHE, phenylephrine; DOB, dobutamine.*P < .05 vs fast and clamp/rest.†P < .05 vs all groups.

Table 4. Variability in regional rMGU estimates

COV (%)

Intervention ROI (N) Septum Anterior Lateral Inferior All ROIs

Fasted (n = 5 dogs) 20 12.8 ± 5.9 10.5 ± 3.6 13.0 ± 7.9 20.5 ± 15.8 14.3 ± 9.5 (N = 80)Clamp/rest (n = 6 dogs) 24 12.8 ± 9.7 11.9 ± 7.9 9.4 ± 6.7 11.2 ± 6.6 11.3 ± 7.4 (N = 96)Clamp/PHE (n = 5 dogs) 20 17.2 ± 8.2 14.0 ± 10.5 19.4 ± 8.3 14.4 ± 7.9 16.3 ± 8.4 (N = 80)Clamp/DOB (n = 4 dogs) 16 10.9 ± 5.3 15.2 ± 14.1 10.6 ± 5.5 15.9 ± 8.4 13.1 ± 8.5 (N = 64)

Values represent mean ± SD.ROI, Region of interest; COV, coefficient of regional variation; N, number of ROIs.

this effect through use of the correction factor estimatedfrom the O-15–water model, a previously validatedapproach.14 A more likely reason for the underestimationof rMGU is the lack of correction of the arterial inputfunction for C-11–lactate metabolites. If C-11–lactatecontributes significantly to total C-11 activity in theblood, the magnitude of the tissue response relative to thearterial input function will be underestimated, leading toan underestimation of rMGU. We have recently devel-oped a method to rapidly measure C-11–lactate in bloodand will be correcting for this metabolite in future stud-ies. Finally, the underestimation may be related to thefact that 1–C-11–glucose only accounts for the myocar-dial uptake of D-glucose. However, because the uptake ofD-glucose far surpasses that of L-glucose in muscle, theuptake of 1–C-11–glucose should be nearly identical tothat of glucose.33

Another limitation of our current modeling approachis that it does not permit the differentiation of the per-centage of extracted glucose that enters a slow turnoverpool and likely reflects glycogen storage from tracer thatrapidly egresses from myocardium, as well as the com-bined effects of glucose oxidation and lactate production.The shape of myocardial tissue curves, particularly thoseobtained during clamp at rest and during coadministra-tion of phenylephrine, suggests that the label is enteringat least 2 pools with different turnover rates (Figure 2).Moreover, values for k5 correlated myocardial C-11–carbondioxide production measured directly. Although theyrequire further study, these data taken in sum suggest thatthe model can be further optimized to potentially assessthe metabolic fate of extracted 1–C-11–glucose.

Conclusion

It now appears possible to quantify myocardial glu-cose utilization by PET with 1–C-11–glucose. The accu-racy of the approach has been demonstrated over a widerange of substrate availability, insulin levels, and work-load conditions. Further studies will be necessary todetermine the accuracy of the method for quantifyingrMGU in diseased myocardium, as well as the accuracyof the measurements compared with FDG. That beingsaid, PET with 1–C-11–glucose should become a valu-able tool in the assessment of the relationship betweenalterations in myocardial glucose metabolism in bothnormal and abnormal cardiac states.

Acknowledgment

We thank Mary Russo for administrative assistance.The authors have indicated they have no financial conflicts

of interest.

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Quantification of myocardial glucose utilization by PET and 1-carbon-11-glucose