(Circulation. 1997;95:1900-1909.)
© 1997 American Heart Association, Inc.
Articles |
18F-2-Deoxyglucose Deposition and Regional Flow in Pigs With Chronically Dysfunctional Myocardium
Evidence for Transmural Variations in Chronic Hibernating Myocardium
From the Buffalo Veterans Administration Medical Center and the Departments of Medicine and Physiology and the Center for Positron Emission Tomography at the State University of New York at Buffalo School of Medicine and Biomedical Sciences.
Correspondence to James A. Fallavollita, MD, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Biomedical Research Building, Room 345, 3435 Main St, Buffalo, New York 14214.
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Abstract |
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Background Hibernating myocardium in patients with collateral-dependent myocardium is characterized by relative reductions in resting flow and increases in the uptake of 18F-2-deoxyglucose (FDG) in the fasting state. We performed the present study to examine whether these key physiological alterations could be produced in a porcine model of chronic coronary occlusion and to assess whether the adaptations consistent with hibernation varied across the myocardial wall.
Methods and Results We chronically instrumented pigs (n=18) with a fixed occluder on the proximal left anterior descending coronary artery (LAD). Three months later, ventricular function, regional myocardial perfusion, and FDG deposition (by excised tissue counting or positron emission tomography) were assessed in pigs after an overnight fast in the closed-chest anesthetized state. Total LAD occlusion with angiographic collaterals was present in the majority of animals. Left ventriculography showed severe anterior hypokinesis, and resting perfusion was significantly reduced in the hibernating LAD region in comparison with the normal remote regions (subendocardium: 0.80±0.06 versus 1.07±0.06 mL·min-1·g-1, P<.001; full-thickness: 0.87±0.04 versus 0.99±0.06 mL·min-1·g-1, P<.01). There was a twofold increase in full-thickness fasting FDG uptake in the dysfunctional LAD region (1.8±0.2 by positron emission tomography versus 1.9±0.1 by ex vivo counting). Ex vivo tissue counting revealed a pronounced transmural variation in FDG uptake in the hibernating region (LAD/normal), which averaged 2.5±0.2 in the subendocardium, 1.9±0.2 in the midmyocardium, and 1.4±0.1 in the subepicardium.
Conclusions These results demonstrate that pigs instrumented with a proximal LAD stenosis develop hibernating myocardium characterized by relative reductions in resting function and perfusion in association with increased uptake of FDG in the fasting state. The transmural variations in relative resting flow and FDG uptake suggest that myocardial adaptations consistent with hibernation are most pronounced in the subendocardial layers and vary in relation to local coronary flow reserve.
Key Words: ischemia • glucose • myocardial contraction • tomography • collateral circulation
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Introduction |
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An increasing effort is being made to identify patients with viable but chronically dysfunctional myocardium. Reversible dyssynergy can arise through a number of different mechanisms, including postischemic stunning and chronic hibernation.1 2 3 Metabolic imaging with positron emission tomography (PET) has been very helpful in identifying viability in patients with chronically dysfunctional myocardium. Both retrospective4 and prospective5 studies have demonstrated that the presence of a metabolic/flow mismatch with increased 18F-2-deoxyglucose (FDG) deposition relative to resting flow is predictive of viability and associated with an improvement in myocardial function after coronary bypass surgery. The extent to which this mismatch pattern reflects the effects of reduced resting flow as opposed to increases in relative FDG uptake is difficult to determine because of the variabilities in the techniques used to stimulate FDG uptake. In addition, whether the physiological adaptations observed in hibernating myocardium vary between the subendocardial and subepicardial layers of the heart remains unanswered because of the limited spatial resolution of clinical imaging modalities as well as the difficulties in reproducing the key physiological features of hibernating myocardium in a chronic animal model.
To investigate this in more detail, we used techniques in which transmural flow (microspheres) and FDG uptake (excised tissue counting) could be assessed in myocardial tissue samples from a chronic animal model of hibernating myocardium. We used a technique to provoke coronary collateral growth in pigs that was originally described by Millard6 ; the proximal left anterior descending coronary artery (LAD) was banded to a fixed dimension. Mills et al7 recently demonstrated that a similar animal model of chronic coronary stenosis is associated with some of the features of hibernating myocardium in humans, including reductions in resting myocardial perfusion and oxygen consumption in the absence of tissue necrosis. In the present study, we sought to determine whether myocardial function was reduced in this model and whether the dysfunctional myocardium had an increase in FDG deposition in the fasting state by PET imaging, as has been recently described in patients with hibernating myocardium.8 The second objective of our study was to determine whether there are transmural variations in perfusion and FDG deposition across the wall of hibernating regions. The results demonstrate that the magnitudes of resting flow reduction and fasting FDG uptake are critically related to local coronary flow reserve and that both changes are most pronounced in the subendocardium of pigs with chronic hibernation.
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Methods |
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The studies were conducted in farm-bred pigs. All experimental procedures and protocols conformed to institutional guidelines for the care and use of animals in research.
Experimental Preparation
Juvenile pigs were fasted overnight. On the morning of surgery,
they were premedicated with a mixture of Telazol (tiletamine [50
mg/mL]/zolazepam [50 mg/mL])/ketamine [100 mg/mL] (0.037
mL/kg IM) and administered prophylactic antibiotics (50
mg/kg IV cephalothin and 5 mg/kg IM gentamicin). After endotracheal
intubation, they were mechanically ventilated, and a surgical plane of
anesthesia was maintained with a halothane (0.5% to 2%)
and oxygen (balance) mixture. A thoracotomy was performed in the fourth
left intercostal space and a limited pericardiotomy used to expose the
proximal LAD immediately before or after the first major diagonal
branch. The proximal LAD was dissected free and instrumented with a
5-mm-long Delran occluder with a fixed internal diameter of 1.5 to
2.25 mm (average±SEM, 1.6±0.1 mm) that was similar to that
previously described by Folts et al.9 To insert the
artery, a longitudinal groove was machined in the occluder, and the
artery was secured within the occluder with a silk ligature or
umbilical tape. The chest incision was closed in layers, the
intercostal nerves were infiltrated with 2% lidocaine for analgesia,
and the pneumothorax was evacuated. A single postoperative dose of
antibiotics was administered after the chest was closed, and
intramuscular analgesics (0.025 mg/kg IM butorphanol) were administered
postoperatively as required to alleviate pain. Animals were fully
recovered within 24 hours. They were group housed and fed a diet of
Pro-Lean (Agway Inc) ad libitum.
Experimental Protocols
Animals were returned to the laboratory for studies after 
3
to 4 months. The pigs were fasted overnight, and anesthesia
was induced with a mixture of Telazol/xylazine (100 mg/mL) (0.022 mL/kg
IM). After tracheal intubation, a surgical plane of
anesthesia was maintained with a halothane (0.5% to 1%)
and oxygen (balance) mixture supplemented with intramuscular doses of
Telazol/xylazine (0.011 mL/kg IM) as required. Cutdowns were used to
expose the left and right carotid arteries for catheter placement. The
left carotid artery was instrumented with an 8F introducer, through
which a 7F pigtail catheter was placed into the left ventricle.
Arterial pressure and reference withdrawal samples for
microsphere flow measurements were taken from the sideport of
the introducer. In 6 animals, microspheres were injected into
the left ventricle. In the remaining animals, a pigtail catheter was
placed retrograde into the left atrium for microsphere
injection. Catheters were placed in the jugular veins to administer
fluids (normal saline) and pharmacological agents throughout the study.
After completion of the instrumentation, the animals were administered
heparin (10 000 units IV), and hemodynamics were
allowed to equilibrate for 
30 minutes before the protocol was
started.
After the equilibration period, colored microspheres were
injected into the left atrium or left ventricle to allow assessment of
regional perfusion under resting conditions. After the initial flow
measurement was completed, myocardial function was assessed with
contrast left ventriculography. In 11 of the animals, responses to a
submaximal inotropic stimulus were assessed with an
intravenous infusion of epinephrine that was
titrated so that heart rate increased by 50 bpm above resting values
(0.32±0.04
µg·kg-1·min-1
IV). Once hemodynamics reached a steady state (10
minutes), a second microsphere flow measurement was performed,
followed by a left ventriculogram. The epinephrine was stopped,
and hemodynamics were allowed to return to baseline.
Pharmacological vasodilation was produced to assess regional
coronary flow reserve using an intravenous infusion
of adenosine (0.9
mg·kg-1·min-1
IV). Because this dose of adenosine was accompanied by
arterial hypotension, a simultaneous infusion
of phenylephrine (5.4±0.9
µg·kg-1·min-1
IV) was started and adjusted to restore mean arterial blood
pressure toward baseline levels. After completion of the last
microsphere injection, hemodynamics were
allowed to return to baseline, and selective coronary
angiography was performed to assess the anatomic severity of the LAD
stenosis as well as the angiographic extent of
collateralization.
Transmural Analysis of FDG by Ex Vivo Tissue
Counting
At 60 to 70 minutes after the last pharmacological
intervention, 9 animals (as well as a sham-operated control) were
heparinized (10 000 units IV), and 2 to 8 mCi of FDG was injected
intravenously as a rapid bolus. Arterial blood
samples (2 mL) were withdrawn at frequent intervals to characterize the
arterial FDG time-activity curve. At 45 minutes after the
administration of FDG, the heart was rapidly excised for tissue
sampling. The left ventricle was weighed, and a 1.5-cm-thick concentric
ring parallel to the atrioventricular groove and midway
between the occluder and apex was used for analysis of
microsphere perfusion and FDG deposition (average weight,
41.4±3.2 g). The concentric ring was radially divided into 11 to 15
full-thickness wedges, which were subsequently subdivided into three
layers of approximately equal thickness. Myocardial samples were placed
into tared vials, and positron emissions were quantified through direct
measurement of annihilation 
radiation at 511 keV in a germanium
well detector (Canberra Inc). Myocardial activity was expressed as
counts per minute per gram of wet weight of tissue.
Arterial blood samples were counted in a similar fashion
and normalized to the sample volume
(counts·min-1·mL of
blood-1). All tissue and blood samples were
decay corrected to the time of FDG administration. We performed Euler
integration of the arterial time-activity curves to
normalize tissue activity for differences in the administered FDG
activity among animals. Sample activities were subsequently divided by
the arterial input function to obtain the regional
deposition or retention fraction, as previously
described.4 10
Average values for FDG deposition in the hibernating LAD and control
regions were obtained by determining the weighted mean values for all
of the samples within a given region after the perfusion boundaries
were determined by analyzing the circumferential distribution of
myocardial perfusion during pharmacological vasodilation (see below).
Border samples between the hibernating region and normal regions were
excluded. Approximately half of the tissue samples were usually
supplied by the LAD perfusion territory (LAD, 18.6±2.2 g; normal,
16.1±2.7 g). After tissue activity had been counted, the myocardial
samples were frozen at -20°C for 48 hours to allow the FDG to
decay to background levels. They were subsequently processed to assess
regional myocardial perfusion in each tissue sample, as outlined
below.
Fasting FDG Uptake by In Vivo PET
At 1 week (8.0±1.1 days) before the terminal
physiological study, 9 animals underwent FDG
imaging by PET. Animals were fasted overnight, sedated with Telazol
(100 mg/mL)/xylazine (100 mg/mL) (0.022 mL/kg IM), and transported to
the PET suite. Supplemental doses of Telazol/xylazine (0.011 mL/kg IM)
were given as needed. The animals were positioned in a 31-slice ECAT
951/31-R PET scanner (Siemens/CTI) with a 10.8-cm axial field of view
and a resolution of 5.9 mm3 full-width-at-half-maximum
(Ramp filter 0.5 cycles/pixel cutoff). A 5-minute transmission scan was
used to confirm correct positioning, and then a 20-minute transmission
scan was performed with retractable 68Ge rod sources to
correct for attenuation. After blood glucose was measured, 5 to 10 mCi
FDG was administered via a cannulated ear vein as a slow bolus. Dynamic
imaging was begun at the time of tracer injection and continued for 54
minutes (8x15 seconds, 4x30 seconds, 10x300 seconds).
Regions of interest (n=4 for each territory) were drawn on single-frame transaxial images (summed final four dynamic frames, Hann filter, 0.3 cycles/pixel cutoff) in the midanteroapical wall corresponding to the LAD perfusion territory, with similar regions drawn in the posterolateral and inferior walls corresponding to the normal perfusion territory. Four additional regions were drawn in the left atrium and left ventricle for determination of arterial activity. Spillover into the blood pool was minimized by drawing small regions of interest approximately two full-widths-at-half-maximum away from the cardiac walls and using high spatial resolution images as the data source. The final quantitative time-activity curves for tissue regions and blood pool were obtained by copying each of the regions of interest on the full set of dynamic images (Ramp filter, 0.5 cycles/pixel cutoff) and extracting regions of interest values (µCi/mL) for each frame of data. The regions of interest for each territory (LAD, normal, blood pool) were averaged for subsequent analysis.
Decay-corrected tissue and blood time-activity curves were automatically analyzed using the technique of Patlak and Blasberg.11 The slope of the linear portion was determined by least-squares singular value decomposition fitting to the final 10 frames of data and is equal to the FDG utilization constant (K). The regional rate of metabolic glucose utilization (rMGU) was determined with the following equation: rMGU=K·Pglu/L, where Pglu is the plasma glucose and L is the lumped constant that corrects FDG kinetics for the metabolism of glucose in myocardium. The lumped constant was assumed to be 0.67.12 In seven of the animals, terminal physiological studies were performed as outlined above.
Left Ventriculography and Coronary Angiography
Myocardial function was assessed with contrast left
ventriculography performed in the left lateral projection. This
approximates a view that is similar to the shallow right anterior
oblique projection used for left ventriculography in humans.
Approximately 10 to 20 mL of warmed nonionic contrast (iohexol 365 mg
iodine/mL, Winthrop Pharmaceuticals) was hand injected over 3 to 6
seconds to visualize the left ventricle. Adequate images could not be
recorded for two ventriculograms due to failure of the fluoroscopy
unit. Fluoroscopic images were recorded and stored on Super VHS
tape for later playback and off-line analysis.
End-systolic and end-diastolic images of the left
ventricle were traced by two observers. Global ejection fraction was
calculated from digitized tracings using the area-length
method,13 and the measurements from each observer were
averaged. Each observer also graded regional wall motion in the
anterior wall using the following scoring system (3, normal; 2, mild
hypokinesis; 1, severe hypokinesis; and 0, akinesis). Dyskinesis was
not present under any condition.
Selective left and right coronary angiography was performed using a 7F Sones or a 7F Judkins right (4R) coronary catheter and hand injections of Renografin (Squibb Diagnostics). Images were recorded on Super VHS tape for later review. In cases in which antegrade filling of the LAD through the native vessels versus collaterals was in question, subselective left coronary injections were performed into the left circumflex and the LAD. Each series of angiograms was interpreted by two observers regarding the extent of collaterals (0, none; 1, faint opacification of the distal LAD; 2, delayed but complete opacification of the LAD; and 3, rapid, complete opacification of the LAD). Caliper measurements of magnified coronary angiograms were used to quantify the percent diameter reduction of the LAD stenosis in relation to the proximal and distal native vessels. The right coronary artery could not be engaged in 1 animal with a patent but stenotic LAD and in 1 animal with an occluded LAD that had grade 3 left-to-left collaterals.
Microsphere Flow Measurements
Regional perfusion was assessed with colored
microspheres (15-µm diameter, Dye-Trak, Triton Inc)
according to previously published techniques.14 Briefly,
microspheres suspended in saline with thimerosal (0.01%) and
Tween 80 (0.01%) were sonicated and vortex agitated before injection.
Approximately 3 to 5 million microspheres labeled with one of
four differently colored dyes (yellow, red, white, and blue) were
administered as a bolus through the left atrial or
ventricular catheter after confirmation of the position of
the catheter through the use of pressure tracings and fluoroscopy.
Immediately before injection, an arterial reference sample
was started from the left carotid artery at a withdrawal rate of 6
mL/min and continued for 90 seconds.
After activity in tissue samples had decayed to background levels, the myocardial tissue samples were thawed and digested in 4 mol/L KOH with 2% Tween 80 and processed according to previously published techniques.14 The color dyes were eluted from the microspheres using a measured volume of dimethylformamide and aliquots placed in a multiple wavelength spectrophotometer (model U-2000, Hitachi Ltd). Absorbance was measured at the principal absorbance peak of each pure color dye. Corrections for the absorbance from overlapping spectra were performed using a matrix inversion technique.14 15 With the use of the absorbance and flow rate of the arterial reference sample and myocardial absorbance per unit sample weight, regional myocardial perfusion was calculated as follows14 15 : Qsample=Abssample*Qreference/Absreference, where Qsample is the flow (mL·min-1·g-1) in the tissue sample, Abssample is the absorbance of a given dye eluted from the tissue sample, Qreference is the reference blood sample withdrawal rate (mL/min), and Absreference is the absorbance of a given dye eluted from the blood reference.
Histological Analysis
A circumferential myocardial sample immediately basal to the
sample taken for FDG and flow analysis was immersed in Z-Fix
(Anatech Ltd), a buffered fixative containing 3.7% formaldehyde and
ionized zinc, for histology (n=9). Thin sections from the anterior and
posterior regions were stained with Masson's trichrome stain to
delineate connective tissue and fibroblasts from normal myocytes.
Connective tissue staining was quantified with standard point-counting
techniques using a 121-point grid at a magnification of x100 as the
grid was progressively moved across the myocardial wall from the
subendocardium to the subepicardium.16 Any epicardial fat
or connective tissue beyond the visceral pericardium was excluded from
analysis. Two full-thickness segments were analyzed in
the anterior and posterior regions from each heart. They were selected
to represent the area of greatest and least connective tissue
staining in each of the two regions. Connective tissue staining was
expressed as a percentage of the total across the myocardial wall.
Perivascular and endocardial connective tissue staining is included in
the reported results. The results represent the average of 30
fields from each region of a given heart.
Data Analysis
All data are presented as mean±SEM. Measurements of
perfusion, FDG, and connective tissue staining in the LAD region were
compared with corresponding measurements in the normally perfused
control region with the use of paired t tests. Differences
in flow and hemodynamics during pharmacological
interventions were initially assessed with the use of an ANOVA and
posthoc paired t tests with the Bonferroni correction for
multiple comparisons. The P<.05 level was taken as
significant.
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Results |
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All animals were in good health at the time of the study. Body weight increased from 7.9±0.6 kg at the time of instrumentation to 75±4 kg at the time of study (average growth interval, 107±5 days). Arterial blood gases immediately before resting measurements of myocardial perfusion were pH 7.41±0.01, PCO2 37±1 mm Hg, and PO2 453±27 mm Hg. Hematocrit levels averaged 0.34±0.01.
At the time of study, 11 animals had total LAD occlusion with
angiographic collaterals, and 5 had severe proximal LAD
stenoses (mean diameter stenosis severity of the group,
97±2%). In 1 animal (not included in the subsequent data), the
occluder was not secured, and it migrated off of the LAD. There was no
significant stenosis, and it served as a sham.
Representative left coronary angiograms and the
end-systolic and end-diastolic tracings of the
resting left lateral ventriculograms from an experimental animal and
the sham pig are shown in Fig 1
. Sources of angiographic
collaterals to the LAD included bridging vessels across the
stenosis and the circumflex artery (mean grade, 2.0±0.3,
usually to the mid-LAD) and the right coronary artery (mean
grade, 2.2±0.2, usually to the distal LAD). There were no angiographic
collaterals visible in the sham animal or in pigs with a patent LAD.
Analysis of the left ventriculograms revealed a resting
ejection fraction of 49±3%. Regional anterior wall motion was
severely depressed and usually exhibited akinesis or severe hypokinesis
(wall motion score, 0.7±0.2; normal wall motion, 3).
Histological sections taken from the anterior and
posterior regions did not show light microscopic evidence of myocardial
necrosis. Only occasional small islands of patchy fibrosis were seen. A
more consistent feature was a subtle, but generalized, increase
in the usual connective tissue staining in the LAD region. The extent
of connective tissue staining (including perivascular tissue) assessed
by point counting averaged 6.2±0.9% in the hibernating regions and
2.9±0.3% in the control region (P<.01).
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The distribution of perfusion at rest in the LAD and normal remote
region is shown in Fig 2. Corresponding measurements of
hemodynamics and myocardial perfusion are summarized in
Tables 1 and 2. Under resting conditions,
subendocardial perfusion in the LAD region of hibernating animals was
reduced by 24% compared with corresponding control region measurements
(0.80±0.06 versus 1.07±0.06
mL·min-1·g-1,
P<.001; Fig 2). Resting full-thickness flow was also lower
in the LAD region of hibernating animals (0.87±0.04 versus 0.99±0.06
mL·min-1·g-1
in the control region, P<.01).
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Fig 3 summarizes the effects of epinephrine and
adenosine on flow in hibernating and normal regions. During
submaximal inotropic stimulation with epinephrine, heart rate
increased from 85 to 137 bpm. There was no significant increase in left
ventricular ejection fraction (50±4% at rest to 56±6%,
n=10, P=NS), but the anteroapical wall motion score improved
(0.6±0.2 at rest to 1.2±0.2, P<.01). Pharmacological
vasodilation with adenosine produced no significant change in
heart rate or systolic blood pressure, but there was a 10%
decrease in mean arterial pressure (115±3 to 104±4
mm Hg, P=.01) compared with resting values. In the normally
perfused region, full-thickness flow increased an average of five times
over the resting values as well as increasing significantly in each of
the individual transmural layers. In contrast, there was an attenuation
of the flow increase in the hibernating LAD region. Full-thickness flow
during vasodilation was less than one third of that in the
corresponding normal region (1.51±0.13 versus 4.90±0.23
mL·min-1·g-1,
P<.001). Subendocardial flow reserve was markedly
attenuated, and perfusion did not increase above the corresponding
resting value (0.80±0.06
mL·min-1·g-1
at rest versus 1.05±0.15
mL·min-1·g-1
during adenosine, P=NS).
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Transmural Variations in FDG Deposition
The regional activity of FDG was systematically elevated in the
hibernating LAD region compared with the normally perfused posterior
regions. Fig 4 shows a representative
circumferential profile of FDG activity in subendocardial,
midmyocardial, and subepicardial layers. The hibernating LAD region
that encompasses the samples in the middle of this unrolled ring
demonstrates an increase in FDG deposition that is most marked in the
subendocardial samples and decreases toward the outer layers of the
heart. Although the magnitude of the increase in FDG varied, a similar
transmural pattern of FDG deposition was observed in each of the
animals with a chronic LAD stenosis. In full-thickness samples,
fasting FDG deposition averaged 24.3±3.8x103 cpm/g in
hibernating LAD regions versus 12.5±1.4x103 cpm/g in
normally perfused posterior regions (P<.01). There was a
more pronounced increase in FDG uptake in the subendocardium, which
averaged 36.9±6.8x103 cpm/g in hibernating versus
15.0±2.2x103 cpm/g in normally perfused remote regions
(P<.02). There was a uniform circumferential pattern in the
sham animal, whereas there was a mismatch between FDG and flow in the
LAD region of the hibernating animal.
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Fig 5 shows the average data from all 9 animals. Data
are expressed as the deposition [extraction (E)*flow
(F)]. This is equivalent to myocardial FDG activity in each region
divided by the integral of the arterial concentration-time
curve. Deposition of FDG was significantly increased in each of the
three transmural layers of the hibernating region compared with the
corresponding normally perfused region (P<.02) and was
greatest in the subendocardium. When expressed as a weighted average of
FDG activity across the entire myocardial wall, there was an
1.9-fold increase in FDG in hibernating versus normally perfused
myocardium. Fig 6 summarizes the relative
increase (LAD/normal remote region) in FDG deposition in relation to
the relative reduction in flow in each transmural layer for all of the
animals. The data were obtained by pooling samples in the hibernating
LAD region and dividing them by the corresponding values from the
normally perfused region. The deposition of FDG was inversely related
to the degree that resting perfusion was reduced and greatest in the
subendocardium.
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FDG Uptake by PET
FDG uptake was assessed after an overnight fast by dynamic imaging
with PET to exclude the possibility that prior pharmacological
stimulation (ie, epinephrine, adenosine, or
phenylephrine) may have produced transient ischemia
and the regional variations in FDG deposition we found through ex vivo
counting. A representative reconstructed short-axis PET
image is shown in Fig 7. Regional FDG uptake in the
anterior wall of the left ventricle, corresponding to the LAD perfusion
territory, was markedly increased compared with the normally perfused
inferoposterior region. After an overnight fast, plasma glucose
averaged 6.8±0.9 mmol/L. Fasting FDG uptake without antecedent
pharmacological stimulation was increased in the LAD region of each
animal, with an average 1.8±0.2-fold increase in FDG uptake in
comparison with normally perfused remote regions (LAD, 0.54±0.19
µCi/mL; normal regions, 0.30±0.09 µCi/mL; P<.05). The
relative increase in FDG uptake in hibernating versus normal regions by
in vivo imaging was in remarkable agreement with the full-thickness
values obtained from ex vivo tissue counting 1 hour after
pharmacological stimulation (Fig 8). The FDG rate
constant (K*100, 2.5±0.9 versus 1.3±0.4
min-1, P<.05) and the calculated
rate of metabolic glucose utilization (rMGU, 21±4 versus
11±3 µmol · min-1 · 100
g-1, P<.05) were also higher in
hibernating myocardium.
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Discussion |
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There are several important new findings from our study. First, pigs instrumented with a fixed proximal LAD occluder for 3 months develop a critical coronary stenosis or total occlusion with collateral-dependent myocardium that has regional dysfunction and is viable as assessed by histology. This model exhibits the key salient physiological features of hibernating myocardium found in humans. These include regional reductions in resting myocardial perfusion and an approximately twofold increase in FDG deposition in the fasting state as assessed by in vivo imaging with PET or ex vivo tissue counting. Second, although reductions in resting flow and increases in FDG deposition occurred in full-thickness myocardial samples, they were most pronounced in the subendocardial layers. This suggests that the propensity of a myocardial region to develop the intrinsic adaptation of hibernation may be critically related to its regional coronary flow reserve.
Clinical and Experimental Studies of Dysfunctional
Collateral-Dependent Myocardium
With the advent of clinical techniques to quantify myocardial
perfusion, a number of groups have demonstrated that relative and/or
absolute reductions in resting flow occur in patients who have a total
occlusion and collateral-dependent myocardium with regional
dysfunction at rest. The reductions in resting perfusion have been
difficult to attribute to tissue necrosis or acute ischemia,
and function has been shown to improve in patients who have undergone
surgical revascularization.4 8 17
These physiological features have led to the
description of this state as hibernating myocardium. Arani
et al18 found an absolute reduction in resting flow using
inert gas washout that averaged 0.51
mL·min-1·g-1
in collateral-dependent regions. This was not associated with
metabolic evidence of ischemia as reflected by
selective coronary venous sampling and was lower than the 95%
confidence interval for absolute flow in a normal population at a
similar level of double product. In more recent studies, flow in
patients with dysfunctional collateral-dependent myocardium
has been examined with the use of PET and resting flow has been
reported to be significantly lower than remote, normally perfused
regions in the same patient. The study by Vanoverschelde et
al17 reported resting flow to average 0.77
mL·min-1·g-1
in dysfunctional, collateral-dependent regions versus 0.95
mL·min-1·g-1
in remote regions. Mäki et al8 found resting flow to
average 0.81
mL·min-1·g-1
in dysfunctional regions versus 1.02
mL·min-1·g-1
in remote regions. In our porcine model, differences in full-thickness
microsphere flow measurements were very similar to the results
in patients with chronic coronary occlusion and averaged 0.87
mL·min-1·g-1
in dysfunctional regions versus 0.99
mL·min-1·g-1
in remote, normally perfused regions. By using microspheres, we
were also able to identify significant transmural variations in the
distribution of resting flow that are beyond currently available
clinical techniques to image myocardial perfusion. In dysfunctional
regions of pigs, reductions in resting flow were most pronounced in the
subendocardial layers, averaging 0.80
mL·min-1·g-1
versus 1.07
mL·min-1·g-1
in normal remote subendocardial regions. Thus, although speculative, it
seems likely that important transmural variations in flow may also
occur in humans with hibernating myocardium.
There has been limited success in reproducing the clinical findings of
hibernating myocardium in previous chronic animal models of
collateral-dependent myocardium. In dogs, this appears to
relate to the rapid maturation of the collateral circulation, which
usually produces no change in resting flow or
function19 20 and only a modest impairment in
coronary flow reserve. Such a limitation is frequently
manifested only during heavy exercise.21 In a previous
study, we attempted to circumvent this problem by surgically ligating
potential sources of epicardial collaterals in a chronic dog ameroid
model that resulted in relative reductions in flow and function for
several weeks that were consistent with
hibernation.22 Other researchers have used pigs to
circumvent the rapid and extensive collateralization that occurs in
dogs. Unfortunately, ameroid occlusion in mature pigs usually results
in some degree of tissue necrosis, making it difficult to interpret
relative changes in flow and/or function without correction for the
amount of infarcted tissue in the collateral-dependent
region.23 24 25 26 Only one study has been able to demonstrate a
reduction in regional myocardial function during ameroid occlusion in
the absence of potentially confounding tissue necrosis.27
In this study, serial measurements were used to demonstrate that
persistent reductions in wall thickening could be produced for a period
of 3 weeks. Unlike clinical studies of hibernating
myocardium, the dysfunction in this model was not
associated with significant reductions in resting flow. This contrasts
with the present findings in which resting flow in pigs was
systematically reduced. The differences may be due to the longer time
interval over which collateral-dependent myocardium is
present in our model, which would also be consistent with
the results of our previous study, in which there was a transition from
normal to reduced flow in dysfunctional collateral-dependent regions in
dogs.
FDG Uptake in Dysfunctional Collateral-Dependent
Myocardium
Tillisch et al4 demonstrated that a mismatch
pattern with reduced flow and increased FDG uptake was predictive of
functional recovery after surgical
revascularization. Interestingly, determining the
extent to which the mismatch is related to reduced flow or increased
FDG uptake has been complicated by the considerable variability in the
specific protocols that have been used to assess FDG uptake.
Enhancement of myocardial glucose (and FDG) uptake through stimulation
of the externalization of insulin-responsive myocardial glucose
transporters optimizes myocardial image characteristics to identify
viability. However, there may be pathophysiological
alterations unique to hibernating myocardium that can be
more optimally identified by examining FDG uptake in the unstimulated,
fasting state. In this regard, Mäki et al8 found
that the rMGU in the fasting state was 15 µmol·100
g-1·min-1 in
dysfunctional, collateral-dependent regions versus 11
µmol·100
g-1·min-1 in
normal regions. Likewise, a preliminary study by Gerber et
al28 found values of 14 µmol·100
g-1·min-1 in
dysfunctional collateral-dependent regions versus 7 µmol·100
g-1·min-1 in
normal remote regions. In both studies, stimulation of FDG uptake with
glucose and insulin increased rMGU but caused relative FDG uptake to be
lower in hibernating versus normally perfused remote regions. Our
findings in pigs in which FDG was also administered in the fasting
state are consistent with the observations in fasting humans.
In full-thickness dysfunctional regions, FDG uptake was increased by
1.9-fold through ex vivo counting and 1.8-fold through in vivo PET
imaging. Kinetic analysis of our PET data found the rMGU to
average 21 µmol·100
g-1·min-1 in
dysfunctional regions versus 11 µmol·100
g-1·min-1 in
remote regions.
We were also able to define the transmural variation in the distribution of FDG deposition through ex vivo tissue counting. In normal regions, the endocardium-to-epicardium ratio for FDG deposition was 1.35 and similar to the transmural gradient in resting perfusion, which was 1.20. This basal distribution favoring the subendocardium is similar to results in rat hearts29 as well as in anesthetized open-chest dogs.30 In contrast, there was a more pronounced variation across the myocardial wall of dysfunctional regions in the present study, and the endocardium-to-epicardium ratio for FDG increased to 2.4. Although there are no previous studies regarding transmural variations in FDG uptake in chronically dysfunctional myocardium, the pattern is similar to that recently reported by Zhang et al31 using in vivo NMR spectroscopy in dogs with severe left ventricular hypertrophy. They found that 2-deoxyglucose accumulation averaged 7.9 µmol/g in the subendocardium versus 3.3 µmol/g in the subepicardium (endocardium-to-epicardium ratio, 2.4). Whether these changes reflect intrinsic protective adaptations that are common to hibernating myocardium and hypertrophied hearts or are a reflection of chronic repetitive myocardial ischemia will require further study.
Relation Among Coronary Flow Reserve and
Chronic Hibernation
We and others have speculated that there may be a key link between
the severity to which coronary flow reserve is reduced and the
induction of adaptations consistent with chronic
hibernation.3 17 22 In humans with collateral-dependent
myocardium, there was an inverse relation between the
extent of myocardial dysfunction and regional coronary flow
reserve.17 Patients with regional dysfunction and relative
reductions in flow consistent with hibernating
myocardium had values of coronary flow reserve that
averaged 1.4. In contrast, in a subgroup of patients with
well-developed collaterals who exhibited near-normal function, the
values of resting flow and coronary flow reserve were the same
in collateral-dependent and remote regions. Because we found
significant variations in flow and FDG deposition across the myocardial
wall of the hibernating regions in our model, we evaluated whether
heterogeneity in local FDG uptake varied with respect
to coronary flow reserve. Fig 9 shows the
relation between coronary flow reserve as assessed through
microsphere flow measurements in individual myocardial examples
and regional FDG as assessed through ex vivo tissue counting. There was
an inverse relation between the magnitude of FDG deposition in the
fasting state and the reduction in coronary flow reserve.
Although speculative, these data suggest that the propensity of a
region to exhibit physiological adaptations
consistent with hibernation may be critically dependent on its
local flow reserve.
|
Methodological Limitations
Although the findings in our animal model are similar to findings
in patients with hibernating myocardium, a limitation that
must be acknowledged is that collateral growth is stimulated by a fixed
stenosis placed on the LAD of growing pigs, and this may not be
identical to an acquired stenosis in adult animals.
Nevertheless, the gradual increase in stenosis severity in this
model as opposed to ameroid models, in which the ameroid
stenosis reaches a total occlusion over only 2 to 3
weeks,22 may be a key reason why we were successful in
producing hibernating myocardium in the absence of
infarction.
Although we did not demonstrate that function could improve after surgical revascularization, all of our physiological findings are consistent with observations in humans that are predictive of functional recovery and submaximal inotropic stimulation improved anterior wall motion. We found a small increase in connective tissue staining by point counting, but the quantitative changes were actually somewhat less than those found in patients with clinically defined hibernating myocardium in whom function improved after revascularization.17 32 33
Finally, acute ischemia34 and pharmacological stimuli35 have been shown to rapidly alter myocardial glucose transport. Although glucose transport has been reported to be unchanged,36 decreased,36 37 or increased10 38 after ischemia, the similarity of FDG uptake obtained through in vivo imaging with PET (without antecedent pharmacological stimuli) and ex vivo counting suggests that a 1-hour time interval is adequate for glucose transport to return to baseline in our model.
Clinical Implications
Both the preservation of FDG uptake and a
flow-metabolism mismatch pattern are predictive of
reversible dyssynergy in chronically dysfunctional
myocardium. Our results suggest that alterations in
regional FDG uptake in the fasting state may be useful in identifying
the pathophysiological basis for regional
dysfunction. This may be of particular clinical importance when using
imaging modalities that cannot resolve transmural variations in tracer
uptake and trying to distinguish nontransmural scar from reversibly
dysfunctional myocardium.39 The results of our
study also suggest that the physiological
adaptations associated with hibernating myocardium,
including alterations in resting flow, flow reserve, and FDG uptake,
vary in magnitude across the myocardial wall in a way that may not be
detectable with currently available physiological
imaging modalities. We have preliminary evidence that there are also
transmural variations in candidate genes that may be responsible for
some of the physiological responses at the
molecular level.40 Whether hibernating
myocardium is an entity that can be distinguished from
chronic stunning will require further comparative studies in which
physiological and molecular responses can be
examined in chronic animal models.
|
Acknowledgments |
|---|
This work was supported by an Affiliate Grant-in-Aid from the American Heart Association; National Heart, Lung, and Blood Institute grant HL-55324; a Merit Review Award from the Department of Veterans Affairs; and the Albert and Elizabeth Rekate Fund. Dr Fallavollita is the recipient of a Clinician Scientist Award from the American Heart Association. We would like to thank all of the staff at the Center for Positron Emission Tomography and, in particular, Brian Murphy and David Wack for help with the kinetic analysis. Deana Gretka, Amy Johnson, Susan Fopeano, Felicia Bosinski, and Christopher Trojan provided technical assistance throughout this study. We would also like to thank Nina Goss and Karin Brady for their help in preparing the manuscript.
Received August 27, 1996; revision received November 4, 1996; accepted November 19, 1996.
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G. Heusch and R. Schulz Hibernating Myocardium: New Answers, Still More Questions! Circ. Res., November 15, 2002; 91(10): 863 - 865. [Full Text] [PDF]
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S. A. Thomas, J. A. Fallavollita, G. Suzuki, M. Borgers, and J. M. Canty Jr Dissociation of Regional Adaptations to Ischemia and Global Myolysis in an Accelerated Swine Model of Chronic Hibernating Myocardium Circ. Res., November 15, 2002; 91(10): 970 - 977. [Abstract] [Full Text] [PDF]
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 A. J. Luisi Jr, J. A. Fallavollita, G. Suzuki, and J. M. Canty Jr Spatial Inhomogeneity of Sympathetic Nerve Function in Hibernating Myocardium Circulation, August 13, 2002; 106(7): 779 - 781. [Abstract] [Full Text] [PDF]
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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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B. L. Gerber, S. Laycock, J. A. Melin, M. Borgers, W. Flameng, and J.-L. J. Vanoverschelde Myocardial Blood Flow, Metabolism, and Inotropic Reserve in Dogs with Dysfunctional Noninfarcted Collateral-Dependent Myocardium J. Nucl. Med., April 1, 2002; 43(4): 556 - 565. [Abstract] [Full Text] [PDF]
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C. Q. Shi, L. H. Young, E. Daher, E. V.R. DiBella, Y.-H. Liu, E. N. Heller, S. Zoghbi, F. J.Th. Wackers, R. Soufer, and A. J. Sinusas Correlation of Myocardial p-123I-Iodophenylpentadecanoic Acid Retention with 18F-FDG Accumulation During Experimental Low-Flow Ischemia J. Nucl. Med., March 1, 2002; 43(3): 421 - 431. [Abstract] [Full Text] [PDF]
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G.C. Hughes Cellular models of hibernating myocardium: implications for future research Cardiovasc Res, August 1, 2001; 51(2): 191 - 193. [Full Text] [PDF]
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 G. C. Hughes, C. K. Landolfo, B. Yin, T. R. DeGrado, R. E. Coleman, K. P. Landolfo, and J. E. Lowe Is chronically dysfunctional yet viable myocardium distal to a severe coronary stenosis hypoperfused? Ann. Thorac. Surg., July 1, 2001; 72(1): 163 - 168. [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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P. G. Camici and D. P. Dutka Repetitive stunning, hibernation, and heart failure: contribution of PET to establishing a link Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H929 - H936. [Full Text] [PDF]
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A. Tawakol, H. A. Skopicki, S. A. Abraham, N. M. Alpert, A. J. Fischman, M. H. Picard, and H. Gewirtz Evidence of reduced resting blood flow in viable myocardial regions with chronic asynergy J. Am. Coll. Cardiol., December 1, 2000; 36(7): 2146 - 2153. [Abstract] [Full Text] [PDF]
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R Schulz and G Heusch Hibernating myocardium Heart, December 1, 2000; 84(6): 587 - 594. [Full Text]
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J. A. Fallavollita Spatial Heterogeneity in Fasting and Insulin-Stimulated 18F-2-Deoxyglucose Uptake in Pigs With Hibernating Myocardium Circulation, August 22, 2000; 102(8): 908 - 914. [Abstract] [Full Text] [PDF]
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J. M. Canty Jr. Nitric Oxide and Short-Term Hibernation : Friend or Foe? Circ. Res., July 21, 2000; 87(2): 85 - 87. [Full Text] [PDF]
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J. A. Fallavollita, C. Trojan, and J. M. Canty Jr. Transmural distribution of FDG uptake in stunned myocardium Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H102 - H109. [Abstract] [Full Text] [PDF]
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A. J. Sherman, F. J. Klocke, R. S. Decker, M. L. Decker, K. A. Kozlowski, K. R. Harris, S. Hedjbeli, Y. Yaroshenko, S. Nakamura, M. A. Parker, et al. Myofibrillar disruption in hypocontractile myocardium showing perfusion-contraction matches and mismatches Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1320 - H1334. [Abstract] [Full Text] [PDF]
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H. Lim, J. A. Fallavollita, R. Hard, C. W. Kerr, and J. M. Canty Jr Profound Apoptosis-Mediated Regional Myocyte Loss and Compensatory Hypertrophy in Pigs With Hibernating Myocardium Circulation, December 7, 1999; 100(23): 2380 - 2386. [Abstract] [Full Text] [PDF]
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J. A. Fallavollita, S. Jacob, R. F. Young, and J. M. Canty Jr. Regional alterations in SR Ca2+-ATPase, phospholamban, and HSP-70 expression in chronic hibernating myocardium Am J Physiol Heart Circ Physiol, October 1, 1999; 277(4): H1418 - H1428. [Abstract] [Full Text] [PDF]
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S. A. Thomas, J. A. Fallavollita, T.-C. Lee, J. Feng, and J. M. Canty Jr Absence of Troponin I Degradation or Altered Sarcoplasmic Reticulum Uptake Protein Expression After Reversible Ischemia in Swine Circ. Res., September 3, 1999; 85(5): 446 - 456. [Abstract] [Full Text] [PDF]
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J. M. Canty Jr. and J. A. Fallavollita Resting myocardial flow in hibernating myocardium: validating animal models of human pathophysiology Am J Physiol Heart Circ Physiol, July 1, 1999; 277(1): H417 - H422. [Full Text] [PDF]
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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]
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S. Firoozan, K. Wei, A. Linka, D. Skyba, N. C. Goodman, and S. Kaul A canine model of chronic ischemic cardiomyopathy: characterization of regional flow-function relations Am J Physiol Heart Circ Physiol, February 1, 1999; 276(2): H446 - H455. [Abstract] [Full Text] [PDF]
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 E. R. Schwarz, T. Reffelmann, F. Schoendube, B. Herrmanns, R. Chakupurakal, H. Doerge, T. Schuetz, M. Foresti, B. J. Messmer, P. W. Radke, et al. Hypoxic Hypoperfusion Fails to Induce Myocardial Hibernation in Anesthetized Swine Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 1999; 4(4): 235 - 247. [Abstract] [PDF]
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G. HEUSCH Hibernating Myocardium Physiol Rev, October 1, 1998; 78(4): 1055 - 1085. [Abstract] [Full Text] [PDF]
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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]
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D. J Duncker, R. Schulz, R. Ferrari, D. Garcia-Dorado, C. Guarnieri, G. Heusch, and P. D Verdouw "Myocardial stunning": remaining questions Cardiovasc Res, June 1, 1998; 38(3): 549 - 558. [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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