(Circulation. 1995;91:2435-2444.)
© 1995 American Heart Association, Inc.
Articles |
Fundamental Limitations of [18F]2-Deoxy-2-Fluoro-D-Glucose for Assessing Myocardial Glucose Uptake
From the University of Texas Houston Medical School, Department of Internal Medicine, Division of Cardiology.
Correspondence to Dr Heinrich Taegtmeyer, MD, DPhil, Division of Cardiology, Department of Medicine, University of Texas Houston Medical School, 6431 Fannin, MSB, Houston, TX 77030. E-mail ht@heart.med.uth.tmc.edu.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Background The glucose tracer analog [18F]2-deoxy-2-fluoro-D-glucose (FDG) is widely used for assessing regional myocardial glucose metabolism in vivo. The reproducibility of this method has recently been questioned because of a discordant affinity of hexokinase for its substrates glucose and 2-deoxyglucose. We therefore compared rates of glucose utilization simultaneously with tissue time-activity curves of FDG uptake before and after changes in the physiological environment of the heart.
Methods and Results Isolated working rat hearts were perfused for 60 minutes with recirculating Krebs buffer containing glucose (10 mmol/L), FDG (1 µCi/mL), [2-3H]glucose (0.05 µCi/mL), and [U-14C]2-deoxyglucose (2-DG; 0.025 µCi/mL). Myocardial glucose uptake was measured by tracer ([2-3H]glucose) and tracer analog methods (FDG and 2-DG) before and after the addition of either insulin (1 mU/mL), epinephrine (1 µmol/L), lactate (40 mmol/L), or D,L-ß-hydroxybutyrate (40 mmol/L) at 30 minutes of perfusion and after acute changes in cardiac workload. Under steady-state conditions, myocardial rates of glucose utilization as measured by tritiated water (3H2O) production from metabolism of [2-3H]glucose, FDG uptake, and 2-DG retention were linearly related. The addition of competing substrates decreased glucose utilization immediately. The addition of insulin increased the rate of glucose utilization as measured by the glucose tracer but not as measured by the tracer analogs. The ratio of 3H2O release/myocardial FDG uptake increased by 111% after the addition of insulin, by 428% after the addition of lactate, and by 232% after the addition of ß-hydroxybutyrate. Epinephrine increased rates of glucose utilization and contractile performance, whereas there was no increase in glucose uptake with a comparable increase in workload alone. There was no change in the relation between the glucose tracer and the tracer analog either with epinephrine or with acute changes in workload.
Conclusions The uptake and retention of FDG in heart muscle is linearly related to glucose utilization only under steady-state conditions. Addition of insulin or of competing substrates changes the relation between uptake of the glucose tracer and FDG. These observations preclude the determination of absolute rates of myocardial glucose uptake by the tracer analog method under non–steady-state conditions.
Key Words: insulin • glucose
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
During the past two decades [18F]2-deoxy-2-fluoro-D-glucose (FDG) has been widely used to assess glucose uptake in normal and diseased heart muscle.1 2 3 4 5 The rationale is relatively simple: like glucose and its analog 2-deoxyglucose, FDG is transported into the cell by specific glucose transporters and phosphorylated by the enzyme hexokinase. Once inside the cardiac myocyte, the phosphorylated tracer analog is not metabolized any further. Hence, the accumulation of FDG has the potential of tracing glucose uptake, although it cannot trace the metabolic fate of glucose inside the cell.
After the usefulness of FDG for metabolic imaging of the heart had been demonstrated,1 investigators applied the tracer kinetic model of Sokoloff et al6 to quantify the regional "myocardial rate of glucose metabolism in vivo."7 8 A correction factor that equates 2-DG uptake to glucose uptake was experimentally derived and called the "lumped constant." However, since the lumped constant used to determine myocardial rates of glucose metabolism was derived as a codependent variable, we have argued that the quantitative analysis of regional rates of myocardial glucose metabolism may be of limited value.9
Although the uptake of FDG is linear and constant10 and traces glucose uptake under steady-state conditions, the relation between tracer analog and a true glucose tracer is not always the same.11 At least two reports have shown that the lumped constant changes with insulin,11 12 and this change has been attributed to compartmentation of hexokinase II (EC 2.7.1.1) as well as to a differential affinity of hexokinase for glucose and 2-DG.12 These findings raise the question of whether other physiological perturbations change the relation between a glucose analog and glucose in a setting akin to the normal metabolic milieu of the heart.
To validate the tracer analog method, uptake of FDG must be measured simultaneously with a true glucose tracer under conditions similar to those in vivo in which FDG is used to assess myocardial glucose metabolism. We therefore examined the effects of a variety of experimental interventions, such as catecholamine stimulation, acute changes in workload, and the addition of competing substrates, on myocardial uptake of the glucose analogs FDG and 2-DG and a true glucose tracer, [2-3H]glucose. The isolated working rat heart model was used to measure substrate utilization, cardiac work, and uptake of glucose, FDG, and 2-DG precisely and under defined experimental conditions. We found that the addition of insulin or of a second substrate (particularly lactate) changed the relation between the glucose tracer and FDG. We believe that the disproportionate change in FDG uptake relative to glucose is important to the use of FDG in positron emission tomography (PET) of the heart.
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Animals
Male Sprague-Dawley rats (weight, 275 to 300 g) obtained from Harlan were fed ad libitum on Purina laboratory chow or were fasted overnight (16 hours) with free access to water.
Materials
All chemicals were obtained from Fisher Scientific
or Sigma
Chemical Co. All enzymes and cofactors were obtained from Boehringer
Mannheim or Sigma. Regular human insulin (Novolin R) was obtained from
Novo-Nordisk.
Radioisotopes
The positron-emitting glucose analog FDG
(specific activity
>5000 Ci/mmol, 
200 µCi per perfusion) was prepared at the
University of Texas cyclotron facility at Houston by the method of
Hamacher et al as described in detail previously
(Nguyêñ et al10 ). High-performance liquid
chromatography–purified [2-3H]glucose (10 µCi
per
perfusion) and [U-14C]2-deoxyglucose (5 µCi per
perfusion) were obtained from Amersham Corp. The purity of
[2-3H]glucose was ascertained by measuring the intrinsic
3H2O content of the tracer.
Working Heart Preparation
The preparation has been described
in detail
earlier.10 13 Briefly, rats were anesthetized by
injection
of sodium pentobarbital (100 mg/kg body wt IP). After injection of
heparin (200 IU) into the inferior vena cava, the heart was rapidly
removed and placed in ice-cold Krebs-Henseleit bicarbonate buffer. A
brief period of retrograde perfusion (<5 minutes) with oxygenated
buffer containing glucose (10 mmol/L) was necessary to wash out any
blood from the heart and to perform the left atrial cannulation. Hearts
were then switched to the working preparation. The perfusate (37°C)
consisted of Krebs-Henseleit bicarbonate saline14 (200 mL)
equilibrated with 95% O2/5% CO2 and
contained glucose (10 mmol/L) as substrate, as well as other additions
according to the individual protocols. Bovine serum albumin free of
fatty acid (BSA; Cohn fraction V, fatty acid free, 1% wt/vol) was
added to the perfusate, to which insulin or epinephrine was added. The
perfusate was recirculated for the duration of the experiment. Aortic
flow and coronary flow were measured every 5 minutes. Cardiac output
was calculated as the sum of aortic and coronary flow. Heart rate and
aortic pressures were continuously measured with a Hewlett-Packard
transducer and recording system. The perfusion chamber was placed
between a pair of coincidence detectors to monitor the tissue uptake of
FDG. In addition, radioactivity in the perfusate (input
function)10 was measured.
Experimental Protocol
Six groups of rats were studied. The
protocols are shown in Fig 1
. Perfusions were carried out at
standard workload
conditions (left atrial pressure, 10 cm H2O; aortic
afterload, 100 cm H2O), with the following exceptions: (1)
Perfusions to which insulin was added were performed at low workload
(left atrial pressure, 7.5 cm H2O; aortic afterload, 70 cm
H2O), since myocardial responsiveness to insulin is
increased at low workload.15 (2) In the work jump
experiments, hearts were initially perfused at low workload before it
was changed to high workload (left atrial pressure, 15 cm
H2O; aortic afterload, 140 cm H2O). In group 1
(control), hearts (n=4) were perfused at standard workload. This group
served as control for hearts to which either lactate,
ß-hydroxybutyrate, or epinephrine was added. In a second control
group, hearts from fasted animals (n=4) were perfused at low workload.
This group served as control for hearts to which insulin was added. In
group 2, insulin (1 mU/mL) was added at 30 minutes (n=8); hearts from
fasted animals were perfused at low workload. In group 3, sodium
L(+)lactate (40 mmol/L) was added at 30 minutes (n=9);
hearts from fed animals were perfused at standard workload. In group 4,
sodium D,L-ß-hydroxybutyrate (40 mmol/L) was added at
30 minutes (n=7); hearts from fed animals were perfused at standard
workload. In group 5, epinephrine (1 µmol/L) was added at 30 minutes
(n=6); hearts from fasted animals were perfused at standard workload.
Solutions of epinephrine were prepared immediately before their
addition, and the perfusions continued in the dark so as to avoid
degradation of epinephrine. In group 6, work jump (n=12), hearts from
fasted animals were perfused at low workload for the first 20 minutes
of perfusion. At 20 minutes, the workload was increased and maintained
at high workload for the next 20 minutes before returning to low
workload for the final 20 minutes of the experiment.
|
Radioactive Tracer Protocols
FDG and
[2-3H]glucose were present in all
experiments throughout. Activity of FDG in the perfusate and myocardial
FDG accumulation were recorded continuously.
3H2O was measured in perfusate samples
withdrawn at 5-minute intervals. [U-14C]2-DG was added at
30 minutes together with other additions made at the same time. In the
work jump experiments, [U-14C]2-DG was added at 40
minutes along with a decrease in the workload on the heart. All hearts
were subjected to a 5-minute "washout" period with nonradioactive
perfusate before being freeze-clamped.
To assess the uptake of 2-DG before any intervention was made, hearts were perfused at low or at standard workload for 30 minutes in a separate series of experiments. 2-DG was added at the beginning of the experiment, and the hearts were subsequently freeze-clamped at 30 minutes of perfusion. In separate experiments, hearts were perfused for 20 minutes (n=4) at low workload and then for 40 minutes, 20 minutes at low workload followed by 20 minutes at high workload (n=4), and subsequently freeze-clamped. 2-DG was added either at the beginning of the perfusion or after 20 minutes of perfusion to measure the uptake of 2-DG at low and at high workloads, respectively. [2-3H]glucose was present throughout the perfusion period in both cases for comparison with the glucose analog 2-DG.
Assessment of Contractile Performance
Contractile
performance, measured at 5-minute intervals, was
assessed as cardiac power (in milliwatts) by the method of
Kannengiesser et al16 : Power=aortic pressure
(mm Hg)xcardiac output
(mL/min)x(2.22x10-3).
Measurement of Radioactivity
FDG
18F
radioactivity in tissue was externally recorded
by a pair of coincidence 
-photon detectors placed on opposite sides
of the heart, as previously described in detail.10 The
processed signals were sent to their respective scalers (models 1774
and 1790C, Canberra) and then passed through a controller interface
(model 188, Canberra). The input function was counted by ß-counting
of a portion of the recirculating perfusate as described
earlier.10 All counts were decay-corrected from the time
at which measured activity of FDG was added. Tissue time-activity of
myocardial FDG uptake and perfusate activity were analyzed as described
by Patlak et al.17 The slope of the Patlak plot
represents the fractional rate of transport and phosphorylation
of [18F]FDG from an extracellular compartment to an
intracellular compartment under steady-state conditions. Tissue
coincidence counts (cps) were not converted into microcuries per gram
because such a conversion requires assumptions about the size and shape
of the heart and incurs substantial potential inaccuracies. A well
counter (Gamma Products) was used to determine the specific activity of
FDG in the perfusate.
3H and 14C
Dual-label counting of these isotopes was performed on a Packard
1500 liquid scintillation counter by the method of spectral index
analysis as described by the manufacturer (Packard Instruments).
Glucose utilization was determined by the rate of
3H2O production from
[2-3H]glucose.18
3H2O was separated from
[2-3H]glucose by anion exchange
chromatography19 on AG-1X8 resin (Bio-rad Laboratories,
Inc). The method for measuring [U-14C]2-deoxyglucose has
been described previously in detail12 and was adapted from
the method of Hom et al.20 In the present work, the
perfusate was changed to a nonrecirculating, tracer-free perfusate for
the last 5 minutes of perfusion. The rationale for this "washout"
technique is based on our earlier observation that the phosphorylation
product of 2-DG is the only form of the tracer analog retained by the
heart,10 which obviates the need for a separate isotopic
extracellular fluid space marker. The efficacy of the washout was
assessed by monitoring the radioactivity of the perfusate during the
washout and by determining the specific activity of a sample of
perfusate withdrawn at 65 minutes, immediately before the heart was
freeze-clamped. The specific activity of the perfusate at the end of
the washout was comparable to background activity, and the error
introduced in assessment of myocardial 2-DG uptake was determined to be
1% to 2%.
Experimental Strategy
Myocardial uptake of the glucose tracer
and tracer analogs were
simultaneously compared, as illustrated in Fig 2. The
rate of 3H2O release, measured at 5-minute
intervals and expressed as the slope of the time-activity graph, was
compared with Patlak graphical analysis of tissue time-activity
curves of myocardial [18F]FDG uptake. Slopes of
time-activity curves were determined by linear regression analysis.
Patlak slopes (FDG uptake) and 3H2O slopes
(glucose uptake) are expressed in units of µL perfusate · g
tissue-1 · min-1. Rates of glucose
uptake
were also measured from an end-point analysis as determined by
retention of [U-14C]2-deoxyglucose and by the release of
3H2O from [2-3H]glucose.
|
Calibration Procedures
The accuracy of the coincidence
counting system over the
experimental range of counts was confirmed from a correlation study of
counts as a function of activity decay with [18F]FDG. The
AG-1X8 resin was checked by passing a known quantity of
[2-3H]glucose and 3H2O through a
column of resin.
Perfusate Assays
Samples (1 mL) of the recirculating
perfusate were withdrawn
every 5 minutes. Glucose and lactate assays were performed immediately
with a glucose/lactate analyzer (2300 STAT, YSI Inc). The glucose
concentration (µmol/mL perfusate) was used to determine the specific
activity of [2-3H]glucose and
[U-14C]2-deoxyglucose. In experiments that included
insulin, the concentration of insulin in perfusate samples determined
by radioimmunoassay (Pharmacia Fine Chemicals) was 250±8 µU/mL and
did not change significantly in the course of the perfusion.
Tissue Extraction and Metabolites
At the end of the
perfusion, hearts were freeze-clamped between
aluminum blocks cooled to the temperature of liquid
nitrogen21 and stored at -70°C. The frozen tissue was
ground under liquid nitrogen. Glycogen content of the tissue powder was
determined as described by Walaas and Walaas.22 Total
lipid extracts were prepared from a portion of the ground myocardial
tissue.23 Triglyceride fractions were isolated by
thin-layer chromatography on Whatman silica gel 60 A, with chloroform
as mobile phase, and extracted from the silica gel.23
Triglycerides were determined from glycerol liberated upon alkaline
hydrolysis.24 A small portion of the pulverized tissue was
oven-dried for determination of the dry weight.
Statistical Analysis
All data are presented as
mean±SD. Statistical analysis
was performed on a Macintosh computer with a STATVIEW SE
statistical package. Single-factor ANOVA and repeated-measures ANOVA
were performed. Post hoc comparisons were performed with Scheffé
F test if significant statistical differences were
demonstrated.25
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Fig 3
shows a representative
experiment with a heart perfused at standard workload. Rates of glucose
uptake were linear under steady-state conditions when measured by
either the rate of 3H2O production from
[2-3H]glucose, slope of FDG accumulation (Patlak slope),
or the retention of 2-DG. The relation between glucose analog and the
glucose tracer did not change when measured by either the
3H2O/Patlak slope ratio or the ratio of uptake
of glucose/2-DG. The first two tables show glucose uptake by hearts
from fed animals perfused at standard workload (Table 1)
and by hearts from fasted animals perfused at low workload (Table
2). Mean cardiac power was 8.56±1.22 mW and
5.78±0.28
mW (P<.05) for control hearts perfused at standard and low
workloads, respectively. Comparison of Tables 1 and
2 shows that the
uptake of glucose was higher in hearts from fed animals perfused at
standard workload than in hearts from fasted animals perfused at low
workload (P<.05). However, neither the nutritional state of
the animal nor the workload affected the relation between glucose
tracer and tracer analog.
|
|
|
The addition of insulin (Fig 4) caused a significant
increase in glucose uptake without a significant increase in the uptake
of FDG. The ratio of 3H2O release to FDG uptake
(3H2O/Patlak) increased by 111%
(P<.004). Although glucose utilization and retention of
2-DG increased (Table 3) after addition of insulin
(255% and 57%, respectively), the ratio of glucose uptake to 2-DG
retention (Glu/2-DG) increased by 63±25% (P<.03). Mean
cardiac power was stable before and after the addition of insulin
(5.63±0.82 versus 5.53±1.12 mW, P=NS).
|
|
The addition of lactate (40 mmol/L) or ß-hydroxybutyrate (40 mmol/L)
significantly decreased the uptake of the glucose tracer and the tracer
analog (Figs 5 and 6). Lactate induced a
decrease of 89% and ß-hydroxybutyrate, a decrease of 82% in the
Patlak slope (Table 4). Glucose uptake decreased by 56%
(6.54±1.85 versus 2.74±1.48
µmol · min-1 · g
dry wt-1, P<.0001) after addition of
lactate. The addition of ß-hydroxybutyrate suppressed glucose uptake
by 45% (6.90±1.52 versus 3.81±1.21
µmol · min-1 · g dry wt-1,
P<.002). The 3H2O/Patlak slope
ratio increased by 428% (P<.004) and by 232%
(P<.02) after the addition of lactate and
ß-hydroxybutyrate, respectively. Cardiac power remained stable both
before and after the addition of lactate (8.24±1.45 versus
8.49±1.12
mW, P=NS) and before and after the addition of
ß-hydroxybutyrate (8.32±1.3 versus 8.19±1.9 mW,
P=NS).
|
|
|
The addition of epinephrine (1 µmol/L) (Fig 7)
caused a significant increase in the Patlak slope (+68%,
P<.05), as well as a significant increase in the slope of
3H2O (+86%, P<.0003). Cardiac
power increased by 25% (P<.05) after epinephrine was added
(Table 5). Glucose uptake increased by 75% and by 88%
when traced by [2-3H]glucose and
[U-14C]2-DG, respectively.
|
|
To test the hypothesis that the increase in glucose uptake observed
with epinephrine was due to the inotropic effect of epinephrine on the
heart, we raised both preload and afterload of hearts perfused with
glucose alone (Table 6). Although the work jump achieved
by changing the workload was greater than that achieved by epinephrine
stimulation, no change in glucose uptake was noted (Fig 8).
Hence, it is unlikely that the increase in cardiac
power accounts for the increase in glucose uptake. The most likely
source of energy was from the breakdown of endogenous substrates (see
below).
|
|
Neither the addition of epinephrine nor acute changes in workload
significantly changed the 3H2O/Patlak slope
ratio or the Glu/2-DG ratio (Tables 5
and 6).
Epinephrine-induced
depletion of myocardial glycogen content was significantly greater than
that induced by an acute increase in afterload (68.1% versus 35.6%,
respectively; P<.0001). Epinephrine also caused a
significant depletion of myocardial triglyceride content (98.3±7.84
versus 40.1±16.1 µmol · g dry wt-1 for
control and
epinephrine-treated hearts, respectively; P<.001). The
results indicate that epinephrine mobilizes endogenous as well as
exogenous fuel sources simultaneously with an increase in contractile
performance.
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
The present study was undertaken to determine whether the glucose tracer analog method using FDG for the assessment of regional myocardial glucose metabolism yields consistent and reproducible results under controlled experimental conditions. We found a significant disparity between glucose and glucose analog methods in the assessment of glucose utilization not only after insulin but also after addition of either lactate or ß-hydroxybutyrate. Comparable results were obtained when glucose utilization was traced by either method after stimulation with epinephrine or with acute changes in workload. The differential uptake of FDG relative to glucose in the presence of insulin or lactate may be clinically significant to the use of FDG in PET studies.
Model
The results must be viewed in the context of the
experimental
preparation and the tissue under examination. Myocardial glucose
metabolism has been studied in monkey,26
dog,1 rabbit,8 rat,10 and human
heart.27 In the working rat heart preparation, workload
and substrate concentration can be controlled precisely, and stable
concentrations of glucose and insulin make it possible to apply a
euglycemic hyperinsulinemic clamp. A new steady-state condition was
reached in all groups in the present study either immediately
(after addition of lactate or ß-hydroxybutyrate) or after a delay of
several minutes (with insulin or epinephrine). Since the uptake of
tracer by the myocardium is dependent on the extracellular
concentration (input function) of the tracer in the
perfusate,10 it is essential to document that the input
function is constant throughout the experiment (±1.5% in the
present series). In most in vivo studies, FDG is presented as a
bolus, and the rate of disappearance of the tracer from the blood pool
is calculated with reference to activity measured in the blood pool of
the left ventricle soon after injection.27 Clinically,
after oral glucose loading, glucose levels are not constant over the
observation period, insulin and lactate levels vary, and frequently the
arterial input function is not measured, all of which are confounding
variables in the interpretation or quantification of FDG uptake. In
clinical PET, increased uptake of FDG is observed with an increase in
insulin levels in response to oral glucose. Inconsistencies in FDG
uptake have also been overcome by coadministration of glucose and
insulin,28 by oral glucose loading after
fasting,29 or by the euglycemic clamp
technique.30 The clinical observations are consistent with
our earlier findings that isolated hearts from fasted animals show
greater insulin responsiveness when presented with glucose,
lactate, and insulin.12 It is likely that the effect of an
oral glucose load in clinical studies with FDG is related to an
increased myocardial sensitivity to insulin in the presence of a
variety of additional exogenous substrates. However, the present
study failed to show a significant increase in the uptake of FDG after
insulin when glucose was the only substrate. We chose not to include an
additional substrate to avoid the confounding effect of competing
substrates on the uptake of glucose. This experimental design most
likely explains the lack of a significant effect of insulin on the
uptake of FDG.
Triple Tracer Technique
FDG has the advantage of a high time
resolution (500 milliseconds)
for the assessment of glucose uptake. Patlak transformation of
decay-corrected tissue time-activity curves normalizes the slope of FDG
uptake for the measured input function. A disadvantage is that
quantification of FDG uptake from Patlak slopes involves assumptions
regarding the shape and size of the heart. The release of
3H2O from the detritiation of
[2-3H]glucose occurs in a reversible reaction catalyzed
by glucose 6-phosphate isomerase (EC 5.3.1.9) and can be used to
measure glucose transport and phosphorylation. Although the question
could be raised of whether insulin or competing substrates affect
glucose 6-phosphate isomerase activity, this is unlikely, for two
reasons. First, the turnover rate of the cycle between glucose
6-phosphate and fructose 6-phosphate is significantly greater than flux
through the glycolytic pathway,18 and second, we have
already shown that insulin changes the kinetic properties of hexokinase
II.12 The validity of this method in skeletal muscle
tissue has been established by Katz and Dunn,18 and the
method has subsequently been used in heart muscle by Ng et
al11 and Russell et al.12 Although the time
resolution with 3H2O production is not as good
as it is with FDG, it is possible to obtain slopes (rates) of glucose
utilization over defined periods of time and compare those with Patlak
slopes of FDG. We used the rate of 3H2O
production from [2-3H]glucose as our gold standard
because it is a direct measure of glucose utilization. The
[U-14C]2-deoxyglucose method was used to provide an
independent control glucose analog for the uptake of FDG. A
disadvantage is that determination of the uptake and retention of
[U-14C]2-deoxyglucose requires freeze-clamping of the
heart. Since 2-DG provides a single end-point measurement, the uptake
of 2-DG must be extrapolated from multiple experiments with different
hearts. Hence, although comparisons can be made between hearts perfused
under experimental conditions and control hearts, it is not possible to
compare the rates of uptake of 2-DG under baseline and new steady-state
conditions in the same heart.
Lumped Constant
The present results have direct bearing on
the correction
factor used to convert rates of tracer uptake to uptake of tracee
(lumped constant, LC). Phelps et al31 reported a value of
0.38 for the LC in intact canine myocardium. Subsequently, the same
investigators reported an experimentally derived value of 0.67 for the
LC3 that has since been widely used. It is possible that
the different values reported by the same laboratory are due to the
acquisition of data under different steady-state conditions. Although
it has previously been stressed that the lumped constant does not
change in heart muscle,32 33 it must be noted that
these
results were obtained in an isolated interventricular septum
preparation that was externally paced and perfused at a low coronary
flow (1 mL saline perfusate · min-1 · g wet
wt-1). The isolated working rat heart used in our
study is of comparable mass, but it beats spontaneously and exhibits
coronary flow rates in excess of 20 mL
perfusate · min-1 · g wet
wt-1. Ng et
al11 34 used the same preparation and demonstrated a
greater utilization of glucose relative to FDG after insulin at high
workload. These investigators suggested that the LC is not constant but
is independently sensitive to the concentration of glucose in the
perfusate and that the LC rises as glycolysis becomes rate
limiting.11
We have previously shown that insulin increases hexokinase activity associated with the mitochondrial fraction of tissue extracts.12 Although the redistribution of hexokinase to the mitochondria did not affect the apparent affinity constant for glucose, hexokinase bound to mitochondria exhibited an 8.5-fold increase in the Km for 2-DG compared with hexokinase in the cytosol. Our findings support and extend the observations of Ng et al and Russell et al.12 The difference in values for the LC in the report by Russell et al and in the present study is most likely due to the different experimental design. Whereas Russell et al used an extracellular fluid space marker12 20 to correct for the uptake of 2-DG, we used a washout technique but came to the same conclusions. The washout technique allows accurate determination of the error introduced from the radioactivity of the perfusate in each experiment. We determined that the optimal duration of the washout period causing the least error was 5 minutes; however, the error with even a 60-second washout was less than 5%. It is also likely that a 5-minute washout period will decrease the error from an intracellular accumulation of nonphosphorylated 2-DG. This experimental detail appears to account for the higher rate of uptake of 2-DG in the study by Russell et al compared with that in the present study.
Physiological Implications
Glucose is an essential fuel for
energy production in the
heart.35 36 Control of the metabolic flux of glucose
metabolism in the heart is not exerted by a single enzyme but rather is
variably distributed among enzymes depending on substrate availability,
hormonal stimulation, and other conditions such as the dietary state of
the animal, coronary flow, cardiac output, and the workload on the
heart.37 In heart muscle and in other tissues able to meet
energy needs through oxidation of a variety of substrates besides
glucose, it is therefore reasonable to assume that regulatory
mechanisms affect glucose transport and phosphorylation differently
from transport and phosphorylation of the glucose tracer analog. In
contrast, tissues such as the brain or tumor cells normally meet their
energy requirements exclusively through glucose. The uptake and
retention of the glucose tracer analog in these
"glucose-dependent" tissues is a function of the metabolic
activity of the tissue and of the input function of FDG. Hence, the
quantitative relation between glucose and the glucose analog is
unlikely to be affected, and FDG would provide a more accurate
assessment of glucose utilization in those tissues than in heart
muscle.
In heart and in skeletal muscle, glucose uptake has been shown to be suppressed with the addition of competing substrates such as lactate, fatty acids, or their breakdown products, ketone bodies. Preliminary studies with FDG from our laboratory have estimated that the uptake of glucose is suppressed by 90% with 40 mmol/L lactate and by 64% with 40 mmol/L ß-hydroxybutyrate.38 In the present study, the uptake of 2-DG and [2-3H]glucose was also suppressed with the addition of either lactate or ß-hydroxybutyrate. However, the addition of competing substrates induced a significantly greater suppression of FDG uptake compared with that of glucose. The mechanism of a disparate suppression of FDG uptake compared with that of glucose is not known. The effect of competing substrates on the affinity of hexokinase for its substrates has not yet been studied. It is also possible that both lactate and ß-hydroxybutyrate effect an increase in the rate of transport of FDG from intracellular back to the extracellular space (k2 in the two-compartment model of Sokoloff et al6 ). This mechanism may also be responsible for the immediate suppression of glucose uptake noted on addition of either substrate.
Schneider et al39 observed that the enhanced lactate extraction in the reperfusion period after ischemia was associated with suppression of glucose utilization. In the present study, a supraphysiological concentration of lactate was used and induced a greater suppression of FDG uptake than the uptake of glucose. This observation may have clinical implications, although the studies were performed in a nonischemic preparation. In clinical PET studies on patients with ischemic heart disease, increased uptake of FDG and decreased coronary flow (flow-metabolism mismatch) are equated with reversibly ischemic ("viable") heart muscle. Conversely, the lack of uptake of FDG is equated with "nonviable" myocardium. It is conceivable that excess lactate in an ischemic territory could disproportionately suppress FDG uptake relative to that of glucose, thereby obscuring true glucose uptake by the myocardium, and render invalid assumptions on the viability of the myocardium in the ischemic territory.
It is of interest that acute changes in workload were not associated with a change in rates of glucose utilization in the present study. Opie40 reported that an acute increase in workload increases myocardial glucose uptake in the isolated retrogradely perfused rat heart. Gertz et al41 reported that in humans, myocardial glucose utilization increases with exercise. Conversely, Nguyêñ et al10 showed that the uptake of FDG decreases with a decrease in the workload. The seemingly conflicting results of the present study point to the important contributions of endogenous substrates to myocardial fuel metabolism. Competition between exogenous and endogenous substrates for the fuel of respiration in the heart in response to changes in the workload has been recognized since the beginning of this century.42 Evans43 already suggested half a century ago that endogenous glycogen stores are used to meet the energy requirements associated with an increase in the workload on the heart.
Catecholamines have also long been known to increase glucose utilization.44 45 This increase is associated with an increase in cardiac performance and thus oxygen demand of the heart. However, increased cardiac work is an unlikely mechanism for an increase in glucose uptake. In the present study, we observed no increase in glucose uptake after an acute increase in the workload was the only intervention made. Furthermore, the increase in glucose utilization after epinephrine stimulation is observed after a delay of 5 to 7 minutes after administration of epinephrine, whereas cardiac performance increases immediately. The dichotomy between glucose uptake and an increase in workload suggests that other mechanisms may be responsible for the increase in glucose uptake noted after epinephrine stimulation. It has been suggested that an increase in glycogen turnover enhances glucose utilization.41 Nolte et al46 recently showed that epinephrine induced glycogen depletion and increased glucose transport in skeletal muscle in the absence of an increase in contractile performance. Like insulin, epinephrine has also been shown to recruit the glucose transporter GLUT4 to the sarcolemma,47 although it is not known whether an increase in glycogen turnover in heart muscle can cause this recruitment.
In contrast to the present in vitro experiments, Merhige et al28 observed a decrease in the uptake of FDG after an infusion of dopamine in an intact dog model. The depression in FDG uptake was attributed to an increase in circulating free fatty acids. The effect was reversed with insulin. Since an increase in fatty acid utilization for energy production results in a decrease in glucose oxidation,48 an increase in myocardial triglyceride breakdown could also have accounted for the decrease in uptake of FDG observed. However, in the present study, epinephrine caused an increase in glucose utilization despite a significant decrease in myocardial triglyceride content. Hence, it is most likely that the suppression of FDG uptake observed in vivo with catecholamine stimulation is not due to myocardial triglyceride breakdown but rather to an associated increase in circulating fatty acids that competes with glucose to mask the "insulin-like" action of epinephrine on myocardial glucose utilization. Thus, in the intact animal model of Merhige et al, catecholamine stimulation caused a decrease in FDG uptake due to an associated increase in fatty acids. However, in the more controlled isolated heart model used in this study, catecholamine stimulation had the direct effect of increased FDG uptake in the absence of changes in fatty acids or other competing substrates. These observations emphasize the importance of competing substrates on the uptake of glucose analogs under various physiological conditions.
Conclusions
The present studies in the isolated working rat
heart
demonstrate the limitations of FDG as an analog for measuring rates of
myocardial glucose metabolism. Although the mechanisms by which
insulin, lactate, or ß-hydroxybutyrate decreases the uptake of FDG
relative to glucose are not completely known, they are likely to
involve the affinity of hexokinase for the tracer analog. The effect of
competing substrates and insulin on changing the relation between the
uptake of glucose and glucose analog must be considered when FDG is
used to assess regional myocardial rates of glucose metabolism. The
change in the relation between glucose tracer and tracer analogs
renders FDG a qualitative, rather than a quantitative, tracer for
myocardial glucose utilization. Although these limitations do not
invalidate FDG as a tracer for the rapid kinetic analysis of
glucose uptake, they call attention to the influence of the metabolic
environment on the uptake of FDG relative to glucose.
|
Acknowledgments |
|---|
This work was supported in part by the National Heart, Lung, and Blood Institute (RO1 HL-43133) and a Grant-in-Aid from the American Heart Association (National Center). Torsten Doenst was the recipient of a student fellowship from the German Academic Exchange Service (DAAD) and was on leave from the University of Göttingen, Germany. We acknowledge the technical assistance of Patrick Guthrie, Jonathan Lee, Sonya Carmical, and Alexis Woods and thank the cyclotron staff of the Positron Diagnostic and Research Center at the University of Texas Health Science Center, Houston, for preparation of FDG. We are also grateful to Drs K. Lance Gould and James E. Holden for their critical comments on the manuscript.
|
Footnotes |
|---|
Guest editor for this article was Howard E. Morgan, MD, Sigfried and Janet Weis Center, Danville, Pennsylvania.
Received October 27, 1994; revision received December 28, 1994; accepted January 10, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Phelps ME, Hoffman EJ, Selin C, Huang SC, Robinson G, Macdonald N, Schelbert H, Kuhl DE. Investigation of [18F] 2-fluoro-2-deoxyglucose for the measure of myocardial glucose metabolism. J Nucl Med. 1978;19:1311-1319.
2. Schelbert HR, Phelps ME, Hoffman E, Huang SC, Kuhl DE. Regional myocardial blood flow, metabolism, and function assessed noninvasively with positron emission tomography. Am J Cardiol. 1980;46:1269-1277. [Medline] [Order article via Infotrieve]
3. Schelbert HR, Schwaiger M. Positron emission tomography studies of the heart. In: Positron Emission Tomography and Autoradiography: Principles and Applications for the Brain and the Heart. Phelps ME, Mazziota JC, Schelbert HR, eds. New York, NY: Raven Press; 1986:581-661.
4.
Schwaiger M, Hicks R. The clinical role of metabolic imaging
of the heart by positron emission tomography. J Nucl Med. 1991;32:565-578.
5. Camici P, Ferrannini E, Opie LH. Myocardial metabolism in ischemic heart disease: basic principles and application to imaging by positron emission tomography. Prog Cardiovasc Dis. 1989;32:217-238. [Medline] [Order article via Infotrieve]
6. Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakurada O, Shinohara M. The [14C] deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem. 1977;28:897-916. [Medline] [Order article via Infotrieve]
7.
Ratib O, Phelps ME, Huang SC, Henze E, Selin CE, Schelbert
HR. Positron tomography with deoxyglucose for estimating local
myocardial glucose metabolism. J Nucl Med. 1982;23:577-586.
8. Krivokapich J, Huang S-C, Phelps ME, Barrio JR, Watanabe CR, Selin CE, Shine KI. Estimation of rabbit myocardial metabolic rate for glucose using fluoro-deoxyglucose. Am J Physiol. 1982;243:H884-H895.
9. Taegtmeyer H. Utility and limitations of [18F]2-deoxy-2-fluoro-D-glucose for the assessment of flux through metabolic pathways in heart muscle: a critical appraisal. In: Schwaiger M, ed. Cardiac Positron Emission Tomography. Norwell, Mass: Kluwer Academic Publishers; 1995.
10.
Nguyêñ VTB, Mossberg KA, Tewson T, Wong WH, Rowe
RW, Coleman GC, Taegtmeyer H. Temporal analysis of myocardial
glucose metabolism by 18F-2-deoxy-2-fluoro-D-glucose.
Am J Physiol. 1990;259:H1022-H1031.
11.
Ng CK, Holden JE, DeGrado TR, Raffel DM, Kornguth ML, Gatley
SJ. Sensitivity of myocardial fluorodeoxyglucose lumped constant to
glucose and insulin. Am J Physiol. 1991;260:H593-H603.
12. Russell RR, Mrus JM, Mommesin JI, Taegtmeyer H. Compartmentation of hexokinase in rat heart: a critical factor for tracer kinetic analysis of myocardial glucose metabolism. J Clin Invest. 1992;90:1972-1977.
13. Taegtmeyer H, Hems R, Krebs HA. Utilization of energy providing substrates in the isolated working rat heart. Biochem J. 1980;186:701-711. [Medline] [Order article via Infotrieve]
14. Krebs HA, Henseleit K. Untersuchungen über die Harnstoffbildung im Tierkörper. Hoppe-Seylers Z Physiol Chem. 1932;210:33-66.
15.
Russell RR, Nguyêñ VTB, Mrus JM, Taegtmeyer H.
Fasting and lactate unmask insulin responsiveness in the isolated
working rat heart. Am J Physiol. 1992;263:E556-E561.
16. Kannengiesser GJ, Opie LH, Van der Werff TJ. Impaired cardiac work and oxygen uptake after reperfusion of regionally ischaemic myocardium. J Mol Cell Cardiol. 1979;11:197-207. [Medline] [Order article via Infotrieve]
17. Patlak CS, Blasberg RG, Fenstermacher JD. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab. 1983;3:1-7. [Medline] [Order article via Infotrieve]
18. Katz J, Dunn A. Glucose-2-t as a tracer for glucose metabolism. Biochemistry. 1967;6:1-5. [Medline] [Order article via Infotrieve]
19.
Marshall RC, Nash WW, Shine KI, Phelps ME, Ricchiuti N.
Glucose metabolism during ischemia due to excessive oxygen demand or
altered coronary flow in the isolated arterially perfused rabbit
septum. Circ Res. 1981;49:640-648.
20. Hom FG, Goodner CJ, Berrie MA. A (3H) 2-deoxyglucose method for comparing rates of glucose metabolism and insulin responses among rat tissues in vivo. Diabetes. 1984;33:141-152. [Abstract]
21. Wollenberger A, Ristau O, Schoffa G. Eine einfache Technik der extrem schnellen Abkühlung größerer Gewebsstücke. Pflugers Arch. 1960;270:399-412. [Medline] [Order article via Infotrieve]
22.
Walaas O, Walaas E. Effect of epinephrine on rat diaphragm.
J Biol Chem. 1950;187:769-776.
23. Bligh EG, Dyer WJ. A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959;378:911-917.
24. Eggstein M, Kuhlmann E. Triglycerides and glycerol: determination after alkaline hydrolysis. Methods Enzymat Anal. 1974;4:1825-1831.
25. Zar JH. Biostatistical Analysis. 2nd ed. Englewood Cliffs, NJ: Prentice-Hall Inc; 1984.
26.
Gallagher BM, Ansari A, Atkins H, Casella V, Christman DE,
Fowler JS, Ido T, MacGregor RR, Sam P, Wan C-N, Wolf AP, Kuhl DE,
Reivich M. Radiopharmaceuticals, XXVII: 18-F labelled
2-deoxy-2-fluoro-D-glucose as a radiopharmaceutical for measuring
regional myocardial glucose metabolism in vivo: tissue
distribution and imaging studies in animals. J Nucl Med. 1977;18:990-996.
27.
Gambhir SS, Schwaiger M, Huang SC, Krivokapich J, Schelbert
HR, Nienaber CA, Phelps ME. Simple noninvasive quantification method
for measuring myocardial glucose utilization in humans employing
positron emission tomography and fluorine-18 deoxyglucose. J Nucl
Med. 1989;30:359-366.
28. Merhige ME, Ekas R, Mossberg K, Taegtmeyer H, Gould KL. Catecholamine stimulation, substrate competition, and myocardial glucose uptake in conscious dogs assessed with positron emission tomography. Circ Res. 1987;61(suppl II):II-124-II-129.
29. Tillisch J, Brunken R, Marshall R, Schwaiger M, Mandelkern M, Phelps M, Schelbert H. Prediction of reversibility of cardiac wall motion abnormalities predicted by positron tomography, 18fluoro-deoxyglucose, and 13NH3. N Engl J Med. 1986;314:884-888. [Abstract]
30.
Knuuti MJ, Nuutila P, Ruotsalainen U, Saraste M, Harkonen R,
Ahonen A, Teras M, Haaparant M, Wegelius U, Haapanen A, Hartiala J,
Voipio-Pulkki LM. Euglycemic hyperinsulinemic clamp and oral glucose
load in stimulating myocardial glucose utilization during
positron-emission tomography. J Nucl Med. 1992;33:1255-1262.
31. Phelps ME, Schelbert HR, Hoffman EJ, Huang SC, Kuhl DE. Positron emission tomography of the heart. Prog Nucl Med. 1980;6:183-209. [Medline] [Order article via Infotrieve]
32.
Krivokapich J, Huang S-C, Selin CE, Phelps ME.
Fluorodeoxyglucose rate constants, lumped constant, and glucose
metabolic rate in rabbit heart. Am J Physiol. 1987;252:H777-H787.
33. Huang SC, Williams BA, Barrio JR, Krivokapich J, Nissenson C, Hoffman EJ, Phelps ME. Measurement of glucose and 2-deoxy-2-[18F]-fluoro-D-glucose transport and phosphorylation rates in myocardium using dual-tracer kinetic experiments. FEBS Lett. 1987;216:128-132. [Medline] [Order article via Infotrieve]
34. Ng CK, Holden JE, DeGrado TR, Kornguth ML, Raffel DM, Gatley SJ. Variation of 2-FDG/glucose lumped constant with substrate and hormone concentration in isolated rat heart. J Nucl Med. 1986;27:966. Abstract.
35. Taegtmeyer H. Energy metabolism of the heart: from basic concepts to clinical applications. Curr Probl Cardiol. 1994;19:57-116.
36. Randle PJ, Priestman DA, Mistry SC, Halsall A. Glucose fatty acid interactions and the regulation of glucose disposal. J Cell Biochem. 1994;55S:1-11.
37.
Kashiwaya Y, Sato K, Tsuchiya N, Thomas S, Fell DA, Veech RL,
Passonneau JV. Control of glucose utilization in working perfused rat
heart. J Biol Chem. 1994;269:25502-25514.
38. Taegtmeyer H, Doenst T, Mommessin JI, Guthrie PH, Williams CM. Further evidence for the importance of anaplerosis in the isolated working rat heart: a tracer kinetic study with [18F] fluoro-2-deoxyglucose (FDG). Circulation. 1993;88(suppl I):I-284. Abstract.
39.
Schneider CA, Nguyêñ VTB, Taegtmeyer H. Feeding
and fasting determine postischemic glucose utilization in isolated
working rat hearts. Am J Physiol. 1991;260:H542-H548.
40. Opie LH. Substrate utilization and glycolysis in the heart. Cardiology. 1971;56:2-21. [Medline] [Order article via Infotrieve]
41. Gertz EW, Wisneski JA, Stanley WC, Neese RA. Myocardial substrate utilization during exercise in humans. J Clin Invest. 1988;82:2017-2025.
42. Rohde E. Stoffwechseluntersuchungen am ueberlebenden Warmblüterherzen, I. Mitteilung zur Physiologie des Herzstoffwechsels. Z Physiol Chem. 1910;68:181-235.
43. Evans G. The glycogen content of the rat heart. J Physiol (Lond). 1934;82:468-480.
44. Evans CL. The effect of glucose on the gaseous metabolism of the isolated mammalian heart. J Physiol (Lond). 1914;47:407-418.
45. Evans CL. The metabolism of cardiac muscle. In: Evans' Recent Advances in Physiology. 6th ed. Newton WH, ed. Philadelphia, Pa: Blakiston's Sons & Co; 1939;7:157-182.
46. Nolte LA, Gulve EA, Holloszy JO. Epinephrine induced in vivo muscle glycogen depletion enhances insulin sensitivity of glucose transport. J Appl Physiol. 1994;765:2054-2058.
47. Rattigan S, Appleby GJ, Clark MG. Insulin like action of catecholamines and Ca2+ to stimulate glucose transport and GLUT4 translocation in perfused rat heart. Biochim Biophys Acta. 1991;1094:217-223. [Medline] [Order article via Infotrieve]
48. Randle PJ, Tubbs PK. Carbohydrate and fatty acid metabolism. In: Handbook of Physiology: The Cardiovascular System. Berne RE, Sperelakis V, Geiger SR, eds. Bethesda, Md: American Physiological Society; 1979:805-844.
This article has been cited by other articles:
 |
|
 |
|
  E. J. Miller, J. Li, K. M. Sinusas, G. D. Holman, and L. H. Young Infusion of a biotinylated bis-glucose photolabel: a new method to quantify cell surface GLUT4 in the intact mouse heart Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1922 - E1928. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L.J. Dearling, A. A. Flynn, J. Sutcliffe-Goulden, I. A. Petrie, R. Boden, A. J. Green, G. M. Boxer, R. H.J. Begent, and R. B. Pedley Analysis of the Regional Uptake of Radiolabeled Deoxyglucose Analogs in Human Tumor Xenografts J. Nucl. Med., January 1, 2004; 45(1): 101 - 107. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. O. McFalls, B. Murad, D. Her, J.-S. Liow, R. Kelly, D. Marx, J. Sikora, and H. B. Ward Repetitive Supply-Demand Ischemia with Dobutamine Increases Glucose Uptake in Postischemic and Remote Myocardium J. Nucl. Med., January 1, 2003; 44(1): 85 - 91. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Herrero, T. L. Sharp, C. Dence, B. M. Haraden, and R. J. Gropler Comparison of 1-11C-Glucose and 18F-FDG for Quantifying Myocardial Glucose Use with PET J. Nucl. Med., November 1, 2002; 43(11): 1530 - 1541. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. L. Bacharach and S. K. Sundaram 18F-FDG in Cardiology and Oncology: The Bitter with the Sweet J. Nucl. Med., November 1, 2002; 43(11): 1542 - 1544. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Kemppainen, T. Fujimoto, K. K Kalliokoski, T. Viljanen, P. Nuutila, and J. Knuuti Myocardial and skeletal muscle glucose uptake during exercise in humans J. Physiol., July 15, 2002; 542(2): 403 - 412. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. O. McFalls, B. Murad, J.-S. Liow, M. C. Gannon, H. C. Haspel, A. Lange, D. Marx, J. Sikora, and H. B. Ward Glucose uptake and glycogen levels are increased in pig heart after repetitive ischemia Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H205 - H211. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. D. Vitale, R. A. deKemp, T. D. Ruddy, K. Williams, and R. S.B. Beanlands Myocardial Glucose Utilization and Optimization of 18F-FDG PET Imaging in Patients with Non-Insulin-Dependent Diabetes Mellitus, Coronary Artery Disease, and Left Ventricular Dysfunction J. Nucl. Med., December 1, 2001; 42(12): 1730 - 1736. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B.L Gerber, F.F Ordoubadi, W Wijns, J.-L.J Vanoverschelde, M.J Knuuti, M Janier, P Melon, P.K Blanksma, A Bol, J.J Bax, et al. Positron emission tomography using18F-fluoro-deoxyglucose and euglycaemic hyperinsulinaemic glucose clamp: optimal criteria for the prediction of recovery of post-ischaemic left ventricular dysfunction. Results from the European Community Concerted Action Multicenter study on use of18F-fluoro-deoxyglucose Positron Emission Tomography for the Detection of Myocardial Viability Eur. Heart J., September 2, 2001; 22(18): 1691 - 1701. [Abstract] [PDF]
|
|
|
|
 |
|
 H. Wiggers, M. Noreng, P. K. Paulsen, M. Bottcher, H. Egeblad, T. T. Nielsen, and H. E. Botker Energy stores and metabolites in chronic reversibly and irreversibly dysfunctional myocardium in humans J. Am. Coll. Cardiol., January 1, 2001; 37(1): 100 - 108. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Utriainen, S. Lovisatti, S. Makimattila, A. Bertoldo, S. Weintraub, R. DeFronzo, C. Cobelli, and H. Yki-Jarvinen Direct measurement of the lumped constant for 2-deoxy-[1-14C]glucose in vivo in human skeletal muscle Am J Physiol Endocrinol Metab, July 1, 2000; 279(1): E228 - E233. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. E. Botker, H. Wiggers, M. Bottcher, J. S. Christiansen, T. T. Nielsen, A. Gjedde, and O. Schmitz Short-term effects of growth hormone on myocardial glucose uptake in healthy humans Am J Physiol Endocrinol Metab, June 1, 2000; 278(6): E1053 - E1059. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Otani, Y. Kagaya, Y. Yamane, M. Chida, K. Ito, S. Namiuchi, N. Shiba, Y. Koseki, M. Ninomiya, J. Ikeda, et al. Long-Term Right Ventricular Volume Overload Increases Myocardial Fluorodeoxyglucose Uptake in the Interventricular Septum in Patients With Atrial Septal Defect Circulation, April 11, 2000; 101(14): 1686 - 1692. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. H. McNulty, D. Jagasia, G. W. Cline, C. K. Ng, J. M. Whiting, P. Garg, G. I. Shulman, and R. Soufer Persistent Changes in Myocardial Glucose Metabolism In Vivo During Reperfusion of a Limited-Duration Coronary Occlusion Circulation, February 29, 2000; 101(8): 917 - 922. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. F. Kofoed, H. Schoder, R. J. Knight, and D. B. Buxton Glucose metabolism in reperfused myocardium measured by [2-18F] 2-fluorodeoxyglucose and PET Cardiovasc Res, January 14, 2000; 45(2): 321 - 329. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. O. McFalls, D. Baldwin, D. Marx, P. Fashingbauer, and H. B. Ward Effect of regional hyperemia on myocardial uptake of 2-deoxy-2-[18F]fluoro-D-glucose Am J Physiol Endocrinol Metab, January 1, 2000; 278(1): E96 - E102. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Fallavollita and J. M. Canty Jr Differential 18F-2-Deoxyglucose Uptake in Viable Dysfunctional Myocardium With Normal Resting Perfusion : Evidence for Chronic Stunning in Pigs Circulation, June 1, 1999; 99(21): 2798 - 2805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Paternostro, D. Pagano, T. Gnecchi-Ruscone, R. S Bonser, and P. G Camici Insulin resistance in patients with cardiac hypertrophy Cardiovasc Res, April 1, 1999; 42(1): 246 - 253. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. N. Kitsiou, S. L. Bacharach, M. L. Bartlett, G. Srinivasan, R. M. Summers, A. A. Quyyumi, and V. Dilsizian 13N-ammonia myocardial blood flow and uptake: Relation to functional outcome of asynergic regions after revascularization J. Am. Coll. Cardiol., March 1, 1999; 33(3): 678 - 686. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Depre, J.-L. J. Vanoverschelde, and H. Taegtmeyer Glucose for the Heart Circulation, February 2, 1999; 99(4): 578 - 588. [Full Text] [PDF]
|
|
|
|
|
|
K. Hashimoto, T. Nishimura, K.-I. Imahashi, H. Yamaguchi, M. Hori, and H. Kusuoka Lumped constant for deoxyglucose is decreased when myocardial glucose uptake is enhanced Am J Physiol Heart Circ Physiol, January 1, 1999; 276(1): H129 - H133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Xu, L. Lu, P. Zhu, and G. G. Schwartz beta -Adrenergic stimulation induces transient imbalance between myocardial substrate uptake and metabolism in vivo Am J Physiol Heart Circ Physiol, December 1, 1998; 275(6): H2181 - H2190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Doenst, Q. Han, G. W. Goodwin, P. H. Guthrie, and H. Taegtmeyer Insulin does not change the intracellular distribution of hexokinase in rat heart Am J Physiol Endocrinol Metab, October 1, 1998; 275(4): E558 - E567. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Marshall, P. Powers-Risius, R. H. Huesman, B. W. Reutter, S. E. Taylor, H. E. Maurer, M. K. Huesman, and T. F. Budinger Estimating glucose metabolism using glucose analogs and two tracer kinetic models in isolated rabbit heart Am J Physiol Heart Circ Physiol, August 1, 1998; 275(2): H668 - H679. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Doenst and H. Taegtmeyer Profound Underestimation of Glucose Uptake by [18F]2-Deoxy-2-fluoroglucose in Reperfused Rat Heart Muscle Circulation, June 23, 1998; 97(24): 2454 - 2462. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Fallavollita, B. J. Perry, and J. M. Canty Jr 18F-2-Deoxyglucose Deposition and Regional Flow in Pigs With Chronically Dysfunctional Myocardium : Evidence for Transmural Variations in Chronic Hibernating Myocardium Circulation, April 1, 1997; 95(7): 1900 - 1909. [Abstract] [Full Text]
|
|
|
|
|
|
H. G. Wolpers, W. Burchert, J. van den Hoff, R. Weinhardt, G.-J. Meyer, and P. R. Lichtlen Assessment of Myocardial Viability by Use of 11C-Acetate and Positron Emission Tomography : Threshold Criteria of Reversible Dysfunction Circulation, March 18, 1997; 95(6): 1417 - 1424. [Abstract] [Full Text]
|
|
|
|
|
|
B. L. Gerber, J.-L. J. Vanoverschelde, A. Bol, C. Michel, D. Labar, W. Wijns, and J. A. Melin Myocardial Blood Flow, Glucose Uptake, and Recruitment of Inotropic Reserve in Chronic Left Ventricular Ischemic Dysfunction: Implications for the Pathophysiology of Chronic Myocardial Hibernation Circulation, August 15, 1996; 94(4): 651 - 659. [Abstract] [Full Text]
|
|
|
|
|
|
M. Maki, M. Luotolahti, P. Nuutila, H. Iida, L.-M. Voipio-Pulkki, U. Ruotsalainen, M. Haaparanta, O. Solin, J. Hartiala, R. Harkonen, et al. Glucose Uptake in the Chronically Dysfunctional but Viable Myocardium Circulation, May 1, 1996; 93(9): 1658 - 1666. [Abstract] [Full Text]
|
|
|
|
|
|
K. Clarke and R. L. Veech Metabolic Complexities in Cardiac Imaging Circulation, May 1, 1995; 91(9): 2299 - 2301. [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||