(Circulation. 2000;102:908.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Spatial Heterogeneity in Fasting and Insulin-Stimulated 18F-2-Deoxyglucose Uptake in Pigs With Hibernating Myocardium
From the Department of Veterans Affairs Western New York Health Care System and Department of Medicine at the University at Buffalo, NY.
Correspondence to James A. Fallavollita, MD, Biomedical Research Bldg, Room 347, University at Buffalo, 3435 Main St, Buffalo, NY 14214. E-mail jaf7{at}buffalo.edu
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Abstract |
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Background—Previous studies of hibernating myocardium in the fasting state have shown regionally increased 18F-2-deoxyglucose (FDG) uptake with a marked transmural gradient. We hypothesized that this adaptation to chronic ischemia might be associated with altered maximal FDG uptake.
Methods and Results—Pigs were instrumented with a 1.5-mm proximal left anterior descending artery (LAD) stenosis. Studies were conducted 106±4 days later on anesthetized animals with complete LAD occlusion and anteroapical dysfunction. In fasting animals (n=9), FDG uptake in dysfunctional LAD regions was 2-fold higher than in normally perfused myocardium (7.9±1.2 versus 4.0±0.5µmol · min-1 · 100 g-1, P<0.05), with a pronounced transmural gradient (endocardial/epicardial ratio 2.56±0.19 versus 1.25±0.03, P<0.05). Euglycemic, hyperinsulinemic clamp (insulin clamp, n=8) produced a 5- to 9-fold increase in FDG uptake, but there was no longer a regional difference in accumulation (LAD, 37.8±4.2 versus normal, 36.4±5.1 µmol · min-1 · 100 g-1, P=NS) and the transmural distribution was uniform. FDG uptake in the fasting state varied inversely with coronary flow during vasodilation. In contrast, during insulin clamp there was no relation between FDG uptake and vasodilated flow, resulting in a reduced spatial heterogeneity in individual samples (relative dispersion=SD/mean; fasting, 52±5% versus insulin, 24±2%, P<0.05).
Conclusions—In the fasting state, FDG uptake in pigs with hibernating myocardium was heterogeneous and was increased in dysfunctional regions with a marked transmural gradient and high spatial heterogeneity. In contrast, FDG uptake was more homogeneously distributed during insulin clamp with (1) uptake in dysfunctional myocardium similar to remote normal regions, (2) uniform transmural distribution, and (3) reduced spatial heterogeneity.
Key Words: collateral circulation • hibernation • glucose • insulin
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the fasting state, viable chronically dysfunctional myocardium exhibits enhanced uptake of the positron-emitting glucose analog 18F-2-deoxyglucose (FDG) in comparison to normally perfused myocardium in humans1 and in pigs.2 3 Evaluating transmural FDG uptake in pigs revealed that the greatest increase in deposition was localized to the subendocardium and that local uptake varied inversely with local coronary flow reserve.2 In contrast, clinical studies performed with PET have shown that FDG uptake increases during euglycemic hyperinsulinemic clamp (insulin clamp), but it is unclear if maximal FDG uptake in dysfunctional regions is normal4 or mildly reduced.1 5 While speculative, a small reduction in full-thickness insulin-stimulated FDG uptake could be even more pronounced in the subendocardium and raise the possibility of a negative relation between chronic repetitive ischemia and maximal glucose transport.
Since transmural variations in FDG uptake can only be assessed by ex vivo counting, the present study was performed in pigs with hibernating myocardium. The primary objectives of this study were to (1) determine if FDG uptake during insulin clamp in pigs with chronically dysfunctional myocardium is similar to humans with hibernating myocardium, (2) determine the magnitude of FDG uptake during insulin clamp and to identify whether a transmural gradient favoring the subendocardium exists, (3) determine the relations between flow (both resting and vasodilated) and FDG uptake (both fasted and during insulin clamp) as indexes of flow-metabolism mismatching, and (4) determine the spatial heterogeneity of flow and FDG uptake in normal and hibernating myocardium.
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Methods |
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All experimental procedures and protocols conformed to institutional guidelines for the care and use of animals in research. The initial instrumentation and experimental protocol have been previously published in detail.2 3 6 Briefly, juvenile pigs (n=19) were instrumented with a 1.5-mm Delran stenosis on the proximal left anterior descending artery (LAD). Three to 4 months later, the pigs were fasted overnight. Anesthesia was induced with a Telazol (50 mg/mL tiletamine and 50 mg/mL zolazepam)/100 mg/mL xylazine) mixture (0.022 mL/kg IM) and maintained with isoflurane (1% to 3%) supplemented with additional Telazol/xylazine (0.011 mL/kg IM PRN). Catheters were placed retrograde from the carotid arteries into the left atrium for pressure monitoring and microsphere injection and the left ventricle for contrast ventriculography. Arterial pressure and reference withdrawal samples for microspheres were taken from a femoral artery. Pharmacological agents were administered through a jugular vein. Animals were heparinized (100 U/kg IV), and hemodynamics were allowed to equilibrate for
30 minutes.
Regional perfusion was assessed with colored
microspheres.2 In 1 animal, high baseline
absorbance (caused by foreign matter contamination) precluded
assessment of regional flow. After a resting flow measurement,
myocardial function was assessed with contrast
ventriculography.2 3 Anteroapical wall motion was
quantified by wall motion score (3, normal; 2, mild hypokinesis; 1,
severe hypokinesis; and 0, akinesis) and the centerline
method.3 7 Flow and function were then quantified during
inotropic stimulation with a submaximal epinephrine infusion
(0.12±0.01 µg ·
kg-1 ·
min-1 IV for 20
minutes). Approximately 30 minutes later, adenosine
vasodilation was produced (0.9 mg ·
kg-1 ·
min-1 IV for 15
minutes) with phenylephrine (8.29±0.56 µg ·
kg-1 ·
min-1 IV) infused to
maintain arterial pressure. Complete occlusion of the LAD
was documented in each animal by coronary
angiography.2
FDG Quantification by Ex Vivo Tissue Counting
One hour after the last pharmacological intervention, blood was
obtained for metabolic substrate levels. Glucose and
lactate were quantified by an automated oxidation analysis (all
animals, ABL System 605, Radiometer Medical A/S). An enzymatic
colorimetric assay was used to quantify nonesterified
fatty acids (fasting, n=8; insulin, n=5; NEFA C, Wako Chemicals USA,
Inc), and a radioimmunoassay was used to quantify insulin (fasting,
n=8; insulin, n=5; Biotrak, Amersham International). Ten animals
received FDG in the fasting state, and in 9 animals glucose (and FDG)
uptake was stimulated with a euglycemic
hyperinsulinemic clamp.1 Insulin (regular
purified pork insulin, 100 U/mL, Novo Nordisk) was infused at 1 mU
· kg-1 ·
min-1 with a 20% dextrose
infusion adjusted to maintain glucose at preinsulin
levels.1 Insulin and glucose infusions were continued
until the heart was removed for sampling.
FDG (1 to 2 mCi, Department of Nuclear Medicine, University at Buffalo;
Buffalo, NY)8 was injected as a bolus, and an
arterial sample was withdrawn (1 mL/min) for 45 minutes to
determine the integrated FDG time-activity curve. After FDG
accumulation, the heart was arrested with intravenous KCl
and rapidly excised. A mid-ventricular ring was divided
into 12 full-thickness wedges, which were subdivided into
subendocardial, mid-myocardial, and subepicardial layers. Samples were
placed into tared vials, weighed, and annihilation 
-radiation at 511
keV measured in a -counter (model 1470, EG&G Wallac
Inc).2 3 The same samples were used for
microsphere flow determinations. The average sample weight
(n=491) was 0.89±0.01 g.
FDG deposition was determined by dividing FDG activity in individual samples by the integrated arterial input curve.2 9 The rate of FDG uptake (RFDGU in µmol · min-1 · 100 g-1) was estimated as the product of FDG deposition · glucose · 1004.
Histology
Myocardial rings apical and basal to the ring used for
microsphere and FDG analyses were incubated in
triphenyl tetrazolium chloride to exclude myocardial necrosis.
Additional samples were trichrome stained to quantify connective tissue
by standard point-counting techniques.2 Two animals had
gross evidence of myocardial infarction (1 fasting and 1
insulin-stimulated) that encompassed >1% of the left
ventricular mass. They were excluded from further
analysis; therefore, the final results compare 9 animals
receiving FDG in the fasting state and 8 animals that were injected
during insulin clamp.
Data Analysis
Data are presented as mean±SEM. Flow and FDG in the LAD
and normal regions represent weighted means for all samples
within a given region after the perfusion boundaries were determined
from the distribution of flow during vasodilation.2
Relative dispersion (RD; SD/mean) was determined on a regional basis
per pig. Measurements in the LAD and normal regions were compared by
means of paired t tests. Differences between pharmacological
interventions were assessed by means of ANOVA and t tests
with the Bonferroni correction for multiple comparisons. Fasting and
insulin-stimulated groups were compared by means of unpaired
t tests. A value of P<0.05 was considered
significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Flow and Function in Pigs With Hibernating Myocardium
Animals were studied 106±4 days after instrumentation, at which time they were in good health and weighed 85±5 kg. Blood gases and hematocrits were no different between the groups and averaged: pH, 7.41±0.00; PCO2, 46±1 mm Hg, PO2, 511±21 mm Hg; Hct, 33±1%. Baseline hemodynamics (Table 1
) were slightly lower in the
fasting group; however, resting microsphere flow measurements
were not different. Figure 1 illustrates
the transmural distribution of flow in the dysfunctional LAD region
versus the normally perfused region at rest, during submaximal
epinephrine infusion, and during adenosine
vasodilation. Subendocardial flow and the endocardial/epicardial
(endo/epi) ratio were regionally reduced at rest (Table 2). In contrast to the increases in flow
to remote normal regions during inotropic (epinephrine) and
vasodilatory stimuli (adenosine), flow was significantly lower
than baseline in the LAD subendocardium during these interventions and
accompanied by a fall in the endo/epi ratio.
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) and adenosine
vasodilation (
) in each layer of myocardial wall. In contrast,
subendocardium (Endo) of LAD region actually showed reduced perfusion
during each intervention, demonstrating critical reduction in flow
reserve. Although flow to subepicardium significantly increased with
metabolic and pharmacological stimuli, mid-myocardial (Mid)
and full-thickness weighted averages (FT) did not change in comparison
to resting values. Epi indicates epicardium.
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Anteroapical wall motion was reduced in all animals, with an average wall motion score of 0.9±0.2 (normal=3) and a corresponding centerline score of -1.85±0.14 (normal=0). Both scores improved during epinephrine infusion (wall motion score 0.9±0.2 to 1.2±0.2, P=0.10; centerline score -1.85±0.14 to -1.52±0.19, P<0.05). Connective tissue staining by point counting was slightly increased in the dysfunctional LAD region in comparison to normally perfused myocardium (8.0±0.8% versus 3.8±0.2%, P<0.05).
FDG Uptake: Fasting Versus Euglycemic
Hyperinsulinemic Clamp
Hemodynamics, substrate, and insulin levels
obtained immediately before FDG administration are presented in
Table 3. Hemodynamics had
returned to baseline in each group. Insulin clamp resulted in a 20-fold
increase in serum insulin, a slight increase in glucose, and reduced
free fatty acids.1 5 Figure 2 illustrates the RFDGU in viable,
dysfunctional myocardium versus normally perfused regions
under fasting conditions (left graph) and during insulin clamp (right
graph). Subendocardial and full-thickness RFDGU as well as the endo/epi
ratios are presented in Table 4.
Under fasting conditions, the RFDGU was significantly higher in all
layers of the dysfunctional region as compared with normal
myocardium. In addition, there was a pronounced transmural
gradient such that the RFDGU in the subendocardium was 2.6-fold higher
than in the subepicardium (Table 4 and Figure 2, left
graph). Insulin clamp (Figure 2, right graph) resulted in
significant increases in the RFDGU in each layer of each region.
However, with insulin, FDG accumulation was homogeneous,
with no spatial differences across the myocardial wall or in
circumferential distribution (Figure 3).
Thus, the marked transmural gradient in FDG accumulation under fasting
conditions was completely abolished during insulin clamp.
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Correlation of Flow and FDG Uptake: Fasting Versus
Euglycemic Hyperinsulinemic Clamp
As a method of assessing the flow-metabolism mismatch
in hibernating myocardium, flow and FDG uptake were
correlated in individual myocardial samples (Figures 4 and 5).
Under resting conditions in the fasting state (Figure 4, upper
graph), there was no correlation between flow and FDG uptake. However,
during insulin clamp (Figure 4, lower graph), weak inverse
correlations were present between resting flow and FDG uptake in
both hibernating and normally perfused regions
(r2=0.04 to 0.07).
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) or samples from normally perfused remote region (
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Better correlations were found for fasting FDG uptake with the use of
maximal flow during pharmacological vasodilation as an index of the
susceptibility to develop myocardial ischemia (Figure 5
, upper graph). In contrast to a weak relation in the normally perfused
remote region (r2=0.03), the
hibernating region demonstrated a steep inverse relation with dramatic
increases in FDG uptake at reduced levels of vasodilated flow
(r2=0.50). During insulin clamp
(Figure 5, lower graph), similar FDG uptake in hibernating and
normal myocardium resulted in no correlation between FDG
uptake and local coronary flow reserve. Thus, the strongest
correlation was between vasodilated flow and FDG uptake under fasting
conditions, suggesting that the propensity of a region to develop
ischemia is associated with increased FDG uptake in the fasting
state.
Spatial Heterogeneity of FDG Accumulation
The spatial heterogeneity of FDG uptake and flow
was determined in dysfunctional and normal regions from both fasting
and insulin-stimulated animals. RD are shown in Table 5. Under fasting conditions, the
heterogeneity of FDG uptake in the LAD region
(RD=0.45±0.03) was 3-fold higher than in normal myocardium
(0.15±0.02, P<0.05), reflecting both the marked transmural
variation in FDG uptake and the variability among samples within a
given region. In contrast, during insulin stimulation, not only was FDG
uptake similar in dysfunctional and normal regions, but uptake among
individual samples was also more homogeneously distributed.
The RD of FDG uptake during insulin stimulation was similar in
dysfunctional (0.21±0.03) and normal regions (0.17±0.03) and not
significantly different from the RD of resting flow (0.15±0.01). To
directly compare the spatial heterogeneity of resting
flow, adenosine flow, and FDG uptake, all samples from the
normal regions of both groups of animals were combined (Figure 6). The RD of resting flow (0.15±0.01),
adenosine flow (0.15±0.01), and FDG uptake (0.16±0.02) were
very similar.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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There are several important new findings from this investigation. First, like humans, pigs with hibernating myocardium had a 2-fold regional increase in the FDG uptake in the fasting state but normal FDG uptake when assessed during euglycemic hyperinsulinemic clamp. Second, stimulation of glucose uptake by insulin clamp abolished the marked transmural gradient in FDG uptake present in viable, dysfunctional myocardium under fasting conditions and abolished the inverse relation between FDG uptake and local coronary flow reserve.2 Finally, the strongest correlation between perfusion and FDG uptake was evident between vasodilated flow and FDG uptake under fasting conditions. This suggests that the most important determinant of regional alterations in FDG uptake in hibernating myocardium is the propensity of a region to develop ischemia.
Insulin-Stimulated FDG Accumulation in Hibernating
Myocardium
In the fasting state, the finding of regionally increased FDG
uptake in pigs with hibernating myocardium is in agreement
with patients with coronary artery disease.1
However, previous studies with insulin clamp have shown FDG uptake to
be reduced1 5 or unchanged4 in hibernating as
compared with normal remote regions. Using segmental analysis,
Mäki et al1 found a small but significant reduction
in FDG uptake in dysfunctional regions of 7 patients with
collateral-dependent myocardium and no history of prior
myocardial infarction (72±22 versus 79±21 µmol ·
min-1 · 100
g-1 in normal remote
regions, P<0.05). Gerber et al5 reported
similar results in viable segments of patients with and those without
prior infarction. FDG uptake in dysfunctional regions was 20% lower
as compared with remote regions (38±20 versus 47±18 µmol
· min-1 · 100
g-1, P<0.05).
In contrast, when Marinho et al4 accounted for
potential regional differences in myocardial fibrosis by quantifying
water-perfusable tissue, no regional variations in FDG uptake were
found. FDG uptake in viable segments of patients with prior myocardial
infarction was the same as normally perfused remote regions (44±14
versus 45±19 µmol ·
min-1 · 100
g-1, P=NS).
These results are qualitatively and quantitatively similar to the
results of the present study in which FDG uptake during insulin
clamp was the same in hibernating and normal regions. Thus, the finding
of homogeneous FDG uptake during insulin clamp by Marinho
et al4 and the present study support a role of
regional fibrosis as the explanation for reduced FDG uptake in some
clinical studies, as suggested by Shilvalkar et al.10
Increased FDG uptake in the fasting state has been speculated to reflect alterations in myocardial glucose utilization, resulting in altered glucose transporter expression and increased transport capacity. Quantification of mRNA from biopsies of patients with hibernating myocardium has demonstrated induction of the glucose transporter primarily responsible for basal glucose uptake, GLUT1, with no change in the other major myocardial glucose transporter, GLUT4.11 However, the finding that FDG uptake was similar in hibernating and normal myocardium during insulin clamp argues against altered levels of recruitable glucose transport capacity. Thus, the present study favors a simpler hypothesis for the enhanced basal glucose uptake in hibernating myocardium, that is, a chronic translocation of a portion of intracellular GLUT1 or GLUT4. Further studies will be required to specifically address this issue.
The present data in fasting animals confirms our previous report of a pronounced transmural gradient in FDG uptake in hibernating myocardium (endo/epi ratio=2.56±0.19) and an inverse correlation of FDG uptake and local flow reserve in individual samples.2 This is consistent with our previous observations that the physiological and molecular adaptations found in hibernating myocardium vary across the myocardial wall.6 Insulin clamp increased FDG uptake in both hibernating and normal regions, resulting in a more homogeneous distribution throughout the left ventricle. This was associated with a loss of the transmural gradient in viable, chronically dysfunctional myocardium and a loss of the correlation between FDG uptake and local coronary flow reserve.
Spatial Heterogeneity of Flow and FDG
Uptake
A close correlation between flow and metabolism during
increases in myocardial oxygen demand has been well
documented,12 but the relative dispersion of flow and FDG
has not been previously examined. The RD of resting flow,
adenosine flow, and FDG uptake in the present study were
nearly equivalent (RD=0.15 to 0.16, mean sample weight 0.92±0.02 g,
n=276) and similar to that reported for resting flow in 1-g samples
with radioactive microspheres in awake baboons
(RD=0.17).13 14 Under fasting conditions, a modest
transmural gradient in FDG uptake was present in normally perfused
myocardium (endo/epi ratio=1.25±0.03), closely
approximating the gradient in resting perfusion (endo/epi
ratio=1.24±0.02). Similar findings have been previously
reported.15 Although the transmural gradients in resting
flow and FDG uptake suggest that they may be matched, absolute resting
flow and FDG uptake were not correlated under fasting conditions
(Figure 4, upper graph). However, when resting flow and FDG
uptake were normalized to the average value per region,16
a significant correlation was present (Figure 7). Nevertheless, this relation accounted
for only a small portion of the variability
(r2=0.13), suggesting that factors
other than those responsible for the local regulation of perfusion
determine myocardial glucose uptake. A similar normalized result was
reported in anesthetized dogs with the use of
3H-2-deoxyglucose and radioactive
microspheres (mean r2=0.24,
range 0.11 to 0.59).16 These findings in normal and
chronically dysfunctional myocardium appear to be
consistent with the weak relation between flow and FDG uptake
at moderate levels of acute ischemia17 and support
the contention that in contrast to other metabolic
substrates, delivery is not the primary determinant of FDG/glucose
uptake.17
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Methodological Limitations
All animals underwent interventions that resulted in
subendocardial ischemia (as evidenced by reductions in
subendocardial perfusion) before FDG administration. Since
ischemia is known to stimulate glucose (and FDG) uptake,
regional and transmural differences in the FDG uptake could simply
reflect antecedent ischemia. However, PET studies in pigs with
hibernating myocardium provided quantitatively similar
regional variations in FDG uptake when compared with animals that
underwent a protocol nearly identical to the present fasting
studies (LAD/normal, 1.8±0.2 by PET versus 1.9±0.1 by ex vivo
counting).2 This similarity suggests that a 1-hour
interval after pharmacological interventions is adequate for glucose
(and FDG) uptake to return to baseline.
Chronically dysfunctional myocardium with the physiological features of hibernating myocardium developed in normal pigs in the absence of risk factors known to be associated with coronary artery disease. Specifically, insulin resistance, which is present in patients with coronary artery disease,18 is unlikely to be a feature of this porcine model. Further studies will be required to determine the impact of insulin resistance on FDG distribution in viable, chronically dysfunctional myocardium in humans.
Clinical Implications
FDG uptake in the fasting state was regionally increased in
viable, chronically dysfunctional myocardium in comparison
to regions with normal coronary flow reserve. In contrast, FDG
uptake during insulin clamp resulted in homogeneous uptake.
Thus, imaging in the fasting state would accentuate the
"flow-metabolism mismatch" between hibernating and
normal myocardium.1 However, imaging in the
fasting state would limit the technical quality of the images and
complicate the placement of regions of interest caused by the
similarity of FDG activity between normal regions and the blood pool.
In addition, FDG uptake in the fasting state was associated with
greater spatial heterogeneity in viable, chronically
dysfunctional myocardium, potentially limiting the size of
regions of interest. Since insulin-stimulated FDG uptake is normal in
hibernating myocardium, our data would support the
assessment of myocardial viability with imaging during insulin
clamp.
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Acknowledgments |
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This study was supported by Clinician Scientist and Affiliate Grant-in-Aid awards from the American Heart Association and a Merit Review Award from the Department of Veterans Affairs. The author would like to thank Dr John Canty for his constructive critiques of the manuscript and Deana Gretka, Jennifer Mortellaro, Amy Johnson, Susan Fopeano, Anne Coe, Felicia Bosinski, and Randy Bassett for technical assistance.
Received December 21, 1999; revision received March 10, 2000; accepted March 22, 2000.
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J. A. Fallavollita, M. Logue, and J. M. Canty Jr. Coronary patency and its relation to contractile reserve in hibernating myocardium Cardiovasc Res, July 1, 2002; 55(1): 131 - 140. [Abstract] [Full Text] [PDF]
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A. Elsasser, K.-D. Muller, W. Skwara, C. Bode, W. Kubler, and A. M. Vogt Severe energy deprivation of human hibernating myocardium as possible common pathomechanism of contractile dysfunction, structural degeneration and cell death J. Am. Coll. Cardiol., April 3, 2002; 39(7): 1189 - 1198. [Abstract] [Full Text] [PDF]
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J. A. Fallavollita, M. Logue, and J. M. Canty Jr. Stability of hibernating myocardium in pigs with a chronic left anterior descending coronary artery stenosis: absence of progressive fibrosis in the setting of stable reductions in flow, function and coronary flow reserve J. Am. Coll. Cardiol., June 1, 2001; 37(7): 1989 - 1995. [Abstract] [Full Text] [PDF]
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J. A. Fallavollita and J. M. Canty Jr. Ischemic cardiomyopathy in pigs with two-vessel occlusion and viable, chronically dysfunctional myocardium Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1370 - H1379. [Abstract] [Full Text] [PDF]
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