(Circulation. 1999;99:2798-2805.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Differential 18F-2-Deoxyglucose Uptake in Viable Dysfunctional Myocardium With Normal Resting Perfusion
Evidence for Chronic Stunning in Pigs
From the Department of Veterans Affairs, Western New York Health Care System and the Departments of Medicine and Physiology at the University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, NY.
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Abstract |
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Background—Viable, chronically dysfunctional myocardium can have normal or reduced resting flow. We previously produced hibernating myocardium with reduced resting flow in pigs with a chronic stenosis and hypothesized that hibernation is preceded by chronic stunning with normal resting perfusion.
Methods and Results—Pigs instrumented with a proximal left anterior descending coronary artery (LAD) stenosis were studied 1 or 2 months later in the closed-chest anesthetized state. Stenosis severity increased from 74±5% at 1 month to 83±6% at 2 months and was accompanied by anteroapical hypokinesis (wall motion score, 2.1±0.1 at 1 month and 1.5±0.3 at 2 months; normal=3). Resting perfusion was similar in normal and dysfunctional regions, but the deposition of 18F-2-deoxyglucose (FDG) varied. At 1 month, subendocardial FDG deposition by excised tissue counting was similar in each region (0.034±0.006 mL · g-1 · min-1 LAD region versus 0.032±0.004 mL · g-1 · min-1 in normal regions, P=NS). At 2 months, subendocardial FDG deposition was increased (0.084±0.025 mL · g-1 · min-1 LAD region versus 0.042±0.017 mL · g-1 · min-1 in normal regions, P<0.05). Increases in FDG uptake were inversely related to LAD subendocardial flow reserve during adenosine (3.5±0.6 at 1 month versus 1.4±0.2 at 2 months, P<0.01).
Conclusions—These data indicate a progression of physiological adaptations in pigs with viable, chronically dysfunctional myocardium. As coronary flow reserve decreases, fasting FDG uptake increases. Flow at rest remains normal, consistent with "chronic stunning," and contrasts with reduced flow and increased FDG characteristic of hibernating myocardium in similarly instrumented pigs after 3 months. This temporal progression of adaptations supports the hypothesis of a transition from a physiological phenotype of stunning to hibernation.
Key Words: stunning, myocardial • hibernation • fluorodeoxyglucose
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Introduction |
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Clinical studies have demonstrated a spectrum of physiological abnormalities that are associated with viable, chronically dysfunctional myocardium. At one extreme are patients in whom the dysfunction is associated with reduced resting flow and preserved metabolic uptake of 18F-2-deoxyglucose (FDG) that has been called "hibernating myocardium." At the other extreme are patients in whom regional dysfunction occurs with normal perfusion, referred to as chronically stunned. Chronically dysfunctional myocardium is undoubtedly related to episodes of acute ischemia in both conditions, but the interrelation between these 2 states remains unclear and is controversial.1 2 3 One possibility is that areas of reduced perfusion at rest may be the result of an admixture of viable tissue and subendocardial scar, partial volume effects in dysfunctional regions, or attenuation with conventional single photon tracers.2 3 Arguing against this are animal studies using microspheres to assess regional perfusion that have demonstrated chronic dysfunction with histologically viable myocardium and both reduced and normal resting flow.4 5 6 7 This suggests that coronary artery disease may result in both chronic stunning and hibernation. If so, there may be a transition from stunning to hibernation as stenosis severity increases and flow reserve is compromised, as we previously hypothesized during progressive ameroid stenosis in dogs.6 Because it would be difficult to resolve this issue in clinical studies because of the lack of information regarding the temporal progression of events and detailed histology, we studied pigs with a chronic LAD stenosis at time points before that at which we previously demonstrated hibernating myocardium (3 to 4 months).4 The results demonstrate a transition from chronic stunning to hibernation with variability in FDG uptake that appears to be related to regional coronary flow reserve.
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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. Juvenile pigs (n=30) were fasted and premedicated with a mixture of Telazol (tiletamine 50 mg/mL and zolazepam 50 mg/mL) and ketamine (100 mg/mL) (0.037 mL/kg IM) and given prophylactic antibiotics (cephalothin 50 mg/kg IV and gentamicin 5 mg/kg IM). The pigs were intubated, and anesthesia was maintained with halothane (0.5% to 2%) and oxygen (balance). Through a thoracotomy (fourth left intercostal space), the proximal left anterior descending coronary artery (LAD) was exposed with a 1- to 2-cm limited pericardiotomy, leaving the rest of the pericardium intact. The LAD was dissected free and instrumented with a stenosis having a fixed ID of 1.5 mm.4 Five animals were sham-instrumented to determine whether surgery resulted in wall motion abnormalities. The incision was closed, and the pneumothorax was evacuated. A single postoperative dose of antibiotics was repeated after the chest was closed, and an intercostal nerve block (2% lidocaine) and analgesics (butorphanol 0.025 mg/kg IM) were given postoperatively to alleviate pain.
Experimental Protocol
Pigs were fasted overnight, and anesthesia was
induced with the Telazol/xylazine (100 mg/mL) mixture (0.022 mL/kg IM).
After intubation, anesthesia was maintained with halothane
(0.5% to 1%) and oxygen (balance) supplemented with additional
Telazol/xylazine (0.011 mL/kg IM PRN). A pigtail catheter was placed
retrogradely into the left atrium for pressure monitoring and
microsphere injection. A second catheter was placed into the
left ventricle for contrast ventriculography. Arterial
pressure and reference withdrawal samples for microspheres were
taken from a femoral artery catheter. Pharmacological agents were
administered through the jugular vein. Animals were heparinized (100
U/kg IV), and hemodynamics were allowed to equilibrate
for 30 minutes.
Colored microspheres were injected to assess regional perfusion
as previously described.4 After resting flow measurements,
myocardial function was assessed with contrast left ventriculography
using 10 to 15 mL of hand-injected nonionic contrast (iohexol, Winthrop
Pharmaceuticals Inc). Fluoroscopic images were recorded and stored
on Super VHS tape. Two observers graded anteroapical wall motion using
the scoring system 3=normal, 2=mild hypokinesis, 1=severe hypokinesis,
and 0=akinesis. Dyskinesis was not present under any condition. We
also quantified anteroapical wall motion using the centerline method as
previously described.8 Inotropic responsiveness was
assessed with a submaximal epinephrine infusion (0.38±0.05
µg · kg-1 ·
min-1 IV) titrated to increase the heart rate by
50 bpm. Finally, adenosine vasodilation was produced (0.9
mg · kg-1 ·
min-1 IV) with phenylephrine
(5.4±0.9 µg · kg-1 ·
min-1 IV) infused to maintain
arterial pressure. Stenosis severity and extent of
collateralization were determined by coronary
angiography.4
FDG Quantification by Ex Vivo Tissue Counting
An hour after the last pharmacological intervention (3 to 4
hours from study initiation), blood was obtained for
metabolic substrate levels. Enzymatic
colorimetric assays were used to quantify nonesterified
fatty acids (NEFA C, Wako Chemicals USA, Inc) and plasma glucose (Sigma
Diagnostics). A radioimmunoassay was used to quantify
insulin (Biotrak, Amersham International). We injected FDG (1 to 2 mCi)
as a rapid bolus and withdrew an arterial sample (1 mL/min)
to determine the integrated FDG time-activity curve. Forty-five minutes
later, the heart was rapidly excised. Flow and FDG deposition were
determined from a 1- to 1.5-cm midventricular ring. It was
divided into 9 to 12 full-thickness wedges, which were subdivided into
subendocardial, midmyocardial, and subepicardial layers. Samples were
placed into tared vials and weighed, and annihilation gamma radiation
at 511 keV was measured in a gamma counter (model 1470, Wallac
Inc).
Histology
Myocardial rings apical and basal to the ring used for
microsphere and FDG analyses were incubated in
triphenyltetrazolium chloride to exclude
myocardial necrosis. In addition, samples from the LAD and normal
regions were immersed in Z-fix (Anatech Ltd) for histology. Thin
sections were stained with Masson or Gomori trichrome stains.
Connective tissue staining was quantified with standard point counting
techniques.4
Data Analysis
Data are presented as mean±SEM. Flow and FDG in the LAD
and normally perfused regions represent weighted means for all
samples within a given region after the perfusion boundaries were
determined from the circumferential distribution of perfusion during
adenosine.4 Measurements in the normal and LAD
regions were compared by paired t tests. Differences during
pharmacological interventions were assessed with an ANOVA and
t tests with the Bonferroni correction for multiple
comparisons. Experimental groups were compared by use of unpaired
t tests. Values of P<0.05 were considered
significant.
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Results |
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All animals were in good health at the time of study. Infarctions >1% of left ventricular mass were present in 3 pigs, and they were excluded from analysis.
Regional Perfusion and Function in Chronically Stunned
Myocardium
The distributions of perfusion and hemodynamics at
rest, during submaximal epinephrine, and during pharmacological
vasodilation with adenosine are summarized in Figure 1
and Tables 1 and 2. Hemodynamic
parameters were similar between the 2 groups. Resting flow
was similar in the LAD and normally perfused remote regions. Figure 2 shows representative
left ventriculograms from each group. Despite normal values for resting
perfusion, anteroapical hypokinesis was present in animals with
significant stenoses (Table 3).
Anteroapical wall motion at 1 and 2 months was significantly reduced
compared with sham-operated animals (P<0.05). Connective
tissue was minimally increased in the LAD perfusion territory compared
with the normal region at both time points (LAD, 5.3±0.5% versus
4.3±0.3% at 1 month, P=0.05; LAD, 6.6±0.9% versus
4.2±0.4% at 2 months, P<0.05).
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Epinephrine increased heart rate and rate-pressure product
to a similar extent in the 1- and 2-month groups (Table 1
). Flow
in all myocardial layers increased and was accompanied by an
improvement in wall motion in the dysfunctional regions (Table 3). The distribution of perfusion during epinephrine was
similar in LAD and normal regions at 1 month, but the increase in
subendocardial flow in animals studied at 2 months was blunted, and
there was a reduction in the endocardial/epicardial flow ratio
(1.11±0.04 in normal versus 0.87±0.09 in LAD,
P<0.01).
Stenosis severity averaged 74±5% at 1 month, causing a
moderate restriction in vasodilated perfusion (full-thickness LAD flow,
3.87±0.40 versus 6.07±0.33 mL ·
min-1 · g-1 in the
normal region, P<0.001). Adenosine flows were
higher than those during epinephrine in each myocardial layer
(Figure 1, top). At 2 months, stenosis severity
increased by only a small amount, to 83±6% (P=NS versus 1
month), but there was a pronounced attenuation of pharmacological
vasodilator reserve (full-thickness LAD flow, 1.92±0.32 versus
5.36±0.55 mL · min-1 ·
g-1 in the normal region, P<0.001).
Flow in the LAD region during adenosine was similar to that
during epinephrine (Figure 1, bottom).
Regional Variations in Fasting FDG Deposition
The deposition of FDG relative to the normally perfused
myocardium for the 2 groups of animals is shown in Figure 3. At 1 month, there were no regional or
transmural differences in deposition between the dysfunctional LAD
region and the normally perfused myocardium (LAD
subendocardium, 0.034±0.006 versus 0.032±0.004 mL ·
g-1 · min-1 in
normal, P=NS). In contrast, at 2 months, FDG deposition was
increased in the LAD perfusion territory (LAD subendocardium,
0.084±0.023 versus 0.042±0.017 mL ·
g-1 · min-1 in
normal, P<0.05). The relative FDG deposition (LAD/normal)
varied transmurally in the animals studied at 2 months and was
significantly greater than 1 month on a full-thickness basis (2.0±0.3
versus 0.9±0.1, P<0.01) as well as in the inner 2 thirds
of the myocardial wall. Free fatty acids, plasma glucose, and insulin
were within the range expected for fasting animals (Table 4). There were no differences between 1
and 2 months. Although there was a wide range of fasting glucose
values, regression analysis revealed no correlation with FDG
uptake [relative FDG uptake=(0.029 · plasma glucose)+1.37,
r=0.09, P=NS].
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Our results indicate that pigs instrumented with an LAD stenosis for 1 or 2 months develop regional dysfunction in association with progressive reductions in coronary flow reserve. Resting flow in both groups is normal and consistent with a state of chronic myocardial stunning. Despite physiological features of chronic stunning at each time point, there were differential patterns of FDG uptake. This variability suggests that both coronary flow reserve and the length of time during which the heart is subjected to reversible ischemia are determinants of increased FDG uptake in viable dysfunctional myocardium.
Progression of Physiological Abnormalities in
Viable, Chronically Dysfunctional Myocardium
The present results taken together with those of our previous
study4 and results of others5 9 suggest that
there is a transition from stunning to hibernation, as was previously
reported in dogs with collateral-dependent myocardium and
limited collateral vasodilator reserve.6 Figure 4 shows the relation among flow at rest,
FDG uptake, and flow during vasodilation from our previous study in
relation to the present groups of animals. Figure 5 illustrates the relationship
between relative subendocardial flow (LAD/normal) and wall motion. The
present results of viable dysfunctional myocardium
associated with normal resting perfusion at 1 and 2 months are
consistent with findings in clinical studies.10 11
After 3 months, however, we observed reductions in resting flow and
increased FDG uptake that are consistent with findings in
humans with collateral-dependent, hibernating
myocardium.12 13 Importantly, dysfunction
preceded reductions in resting perfusion, which is in marked contrast
with experimental models in which flow is acutely reduced (short-term
hibernation).1 3 Thus, it seems likely that reductions in
resting flow are a result rather than a cause of chronic contractile
dysfunction.
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, values from
normally perfused myocardium. There was a progressive
increase in stenosis severity and reduction in regional wall
motion over time. Initially, dysfunctional myocardium had
normal perfusion and homogeneous FDG uptake. After 2
months, there was a further reduction in adenosine flow, and
although resting perfusion remained normal, FDG uptake increased. After
3 to 4 months, FDG remained regionally increased (P=NS
vs 2 months) and was accompanied by a reduction in resting flow that
was greatest in subendocardium. Thus, transition from chronic stunning
to hibernation was preceded by enhanced FDG uptake, and regional
dysfunction preceded reduction in resting flow. *P<0.05
vs normal, 
P<0.05 vs 1 month.
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One of the major factors responsible for the transition from stunning
to hibernation may be the physiological
significance of a stenosis. As illustrated in Figure 4, progression in stenosis severity was associated with a
transition from stunning to hibernation between 2 and 3 months.
Vasodilated subendocardial perfusion fell from 1.51±0.32 to 1.05±0.15
mL · min-1 ·
g-1 (P=0.16), with a corresponding
attenuation of stress-induced perfusion during submaximal
epinephrine infusion (1.67±0.37 at 2 months versus 0.84±0.11
mL · min-1 ·
g-1 at 3 months,4
P<0.05). Interestingly, the reduction in adenosine
flow reserve was unchanged because resting flow decreased in
hibernating myocardium (subendocardial adenosine
flow/resting flow, 1.4±0.2 at 2 months versus 1.3±0.2 at 3 months,
P=NS). These data support the hypothesis that hibernation
may reflect an adaptation that is induced once flow reserve is
critically compromised to minimize ischemia during subsequent
episodes of increased demand, as we have previously
speculated.14
Other possible explanations for the transition from chronic stunning to hibernation seem less likely. Complete coronary occlusion was infrequent in chronically stunned compared with hibernating pigs in our previous study4 (18% versus 73%), yet Mills et al5 demonstrated reduced resting flow in pigs when all of the stenoses were patent. The transition to hibernating myocardium cannot be explained by myocardial scar, because we found a similar regional increase in connective tissue in pigs with chronically stunned and hibernating myocardium (6.6±0.9% at 2 months versus 6.2±0.9% at 3 months,4 P=NS). Untested hypotheses include a downregulation of demand resulting from disassembly of the contractile apparatus in hibernating12 but not chronically stunned myocardium. Finally, time may be an independent determinant of whether hibernating myocardium develops.
The presence of a temporal transition from chronic stunning to hibernation may help resolve some of the conflicting experimental data in clinical as well as animal studies that have resulted in varying speculation and conclusions regarding the relationship of these physiological entities.1 3 The role of PET in detecting reversible dyssynergy was originally described by Tillisch et al,15 who demonstrated that a mismatch pattern between FDG uptake and reduced regional flow predicted viability, whereas matched reductions in FDG uptake and resting flow were consistent with irreversibly damaged myocardium. Importantly, however, more than half of the patients in their study demonstrated reversible dyssynergy in the presence of normal resting flow consistent with stunning and, a priori, myocardial viability. In other studies, myocardium with normal resting flow constitutes a significant fraction of reversibly dyssynergic regions.10 11 16 Although the stability and chronicity of such changes remains to be established, our results support the notion that reversible dysfunction can occur with both normal and reduced resting flow.
Because animals were studied only once, we cannot delineate the mechanisms by which acute ischemia caused dysfunction in this model. Myocardial stunning has been demonstrated after brief occlusions17 as well as during demand-induced ischemia.18 Cyclical flow reductions due to platelet aggregates can result in transient coronary occlusion and has been reported distal to critical ameroid stenoses.19 20 Spontaneous demand-induced stunning has been demonstrated after physiological increases in myocardial oxygen demand in pigs with ameroid occluders.7 Either mechanism may have been the cause of repetitive ischemia leading to chronic dysfunction, and continuous monitoring will be required to assess their relative importance.
Fasting FDG Uptake in Viable Chronically Dysfunctional
Myocardium
Hibernating myocardium is accompanied by an increase
in FDG uptake in the fasting state compared with normally perfused
regions,4 13 yet FDG uptake is fairly uniform when
assessed after stimulation of uptake by glucose or
insulin.10 11 16 As illustrated in Figure 4, enhanced FDG uptake in the fasting state is also present in
chronically stunned pigs at 2 months and precedes the development of
reductions in resting flow. Clinical data regarding fasting FDG uptake
in chronically stunned myocardium are limited. Although it
was not the primary focus of their report, Camici et al21
found no regional variations in fasting FDG uptake before exercise
(fractional FDG uptake, 0.11±0.03 in coronary patients with
regional dysfunction and normal flow versus 0.07±0.04 in control
subjects, P=NS). These observations support the notion that
viable, chronically dysfunctional myocardium can be
associated with normal FDG uptake in the fasting state, as we found in
pigs instrumented for 1 month.
Although the factors responsible for the temporal variability in FDG
uptake in the present study are unclear, the uniform distribution
of FDG at 1 month suggests that the myocardial adaptations that lead to
an increase in glucose utilization are not simply related to resting
dysfunction. One possibility is that there is a temporal lag in the
development of increased FDG uptake, with stunning preceding changes in
glucose transport. Alternatively, changes in FDG uptake may be related
to the physiological significance of a
coronary stenosis. Huang et al22 found
fasting FDG uptake to increase with increasing stenosis
severity in patients with chronic coronary artery disease.
Because transmural FDG uptake is inversely related to adenosine
perfusion (Figure 4), the propensity for a region to develop
ischemia may determine whether FDG uptake is increased in the
fasting state. Frequent episodes of ischemia could result in
repetitive depletion of glycogen stores, and increased FDG may reflect
glycogen repletion. This is also consistent with the inverse
relation between fasting FDG uptake and regional coronary flow
reserve that we previously demonstrated in hibernating
myocardium.4 There could also be chronic
alterations in the expression of myocardial glucose transporters
induced in response to repetitive ischemia. Finally, there may
be a regional variation in the lumped constant for FDG that may not
reflect a true increase in glucose uptake.
Methodological Limitations
Contrast ventriculography is widely used in the evaluation of
patients with coronary disease, but more sensitive techniques,
such as wall thickening, would quantify the extent to which flow and
function were dissociated. Although this would not have affected our
conclusions regarding the presence of stunned myocardium at
1 and 2 months, we cannot determine whether function was
disproportionately reduced compared with flow in hibernating pigs or
whether there is superimposed myocardial stunning.
Ischemia23 and pharmacological stimuli24 rapidly alter myocardial glucose uptake. Our previous study in similarly instrumented animals with hibernating myocardium showed nearly identical measurements of FDG uptake by ex vivo counting following a similar pharmacological protocol and in vivo PET imaging without preceding interventions.4 This agreement supports the notion that 1 hour was sufficient for any effect of adenosine or epinephrine on glucose uptake to return to baseline before FDG administration.
Clinical Implications
There is controversy regarding the
pathophysiological basis of viable, chronically
dysfunctional myocardium in patients with coronary
disease. Whereas dysfunction is a consequence of reversible
ischemia in both chronically stunned and hibernating
myocardium, our results demonstrate a progression in
abnormalities that is consistent with a temporal transition
from stunning to hibernation. This may be the result of progressive
reductions in coronary flow reserve (ie, the propensity of a
region to be subjected to ischemia). Alternatively, the
transition from stunning to hibernation may require time and thus be
dependent on the cumulative effects of reversible ischemia.
This may explain the variability of resting flow measurements reported
in experimental and clinical studies, in which coronary flow
reserve is not always quantified and the chronicity of reduced function
is largely unknown. Finally, enhanced fasting FDG uptake is not
specific for hibernation, nor is it systematically present in
chronically stunned myocardium. Nevertheless, the presence
of enhanced FDG uptake may identify viable regions with the lowest flow
reserve, in which revascularization to ameliorate
ischemia may be most beneficial.
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Acknowledgments |
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This study was supported by the American Heart Association, the Department of Veterans Affairs, the Albert and Elizabeth Rekate Fund, and the National Heart, Lung, and Blood Institute. We would like to thank Felicia Bosinski, Anne Coe, Susan Fopeano, Deana Gretka, Jennifer Mortellaro, Amy Johnson, and Rebeccah Young for their technical assistance.
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Footnotes |
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Reprint requests to James A. Fallavollita, MD, Biomedical Research Building, Room 347, University at Buffalo, 3435 Main St, Buffalo, NY 14214.
Received September 15, 1998; revision received February 11, 1999; accepted February 23, 1999.
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 P. Lynch, T.-C. Lee, J. A. Fallavollita, J. M. Canty Jr, and G. Suzuki Intracoronary Administration of AdvFGF-5 (Fibroblast Growth Factor-5) Ameliorates Left Ventricular Dysfunction and Prevents Myocyte Loss in Swine With Developing Collaterals and Ischemic Cardiomyopathy Circulation, September 11, 2007; 116(11_suppl): I-71 - I-76. [Abstract] [Full Text] [PDF]
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 M. D. Banas, S. Baldwa, G. Suzuki, J. M. Canty Jr., and J. A. Fallavollita Determinants of contractile reserve in viable, chronically dysfunctional myocardium Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2791 - H2797. [Abstract] [Full Text] [PDF]
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J. A. Fallavollita, B. J. Riegel, G. Suzuki, U. Valeti, and J. M. Canty Jr. Mechanism of sudden cardiac death in pigs with viable chronically dysfunctional myocardium and ischemic cardiomyopathy Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2688 - H2696. [Abstract] [Full Text] [PDF]
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V. Ovchinnikov, G. Suzuki, J. M. Canty Jr., and J. A. Fallavollita Blunted functional responses to pre- and postjunctional sympathetic stimulation in hibernating myocardium Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1719 - H1728. [Abstract] [Full Text] [PDF]
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H. Wiggers, H. Norrelund, S. S. Nielsen, N. H. Andersen, J. E. Nielsen-Kudsk, J. S. Christiansen, T. T. Nielsen, N. Moller, and H. E. Botker Influence of insulin and free fatty acids on contractile function in patients with chronically stunned and hibernating myocardium Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H938 - H946. [Abstract] [Full Text] [PDF]
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G. Heusch, R. Schulz, and S. H. Rahimtoola Myocardial hibernation: a delicate balance Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H984 - H999. [Abstract] [Full Text] [PDF]
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 J J Bax, E E van der Wall, and M Harbinson Radionuclide techniques for the assessment of myocardial viability and hibernation Heart, August 1, 2004; 90(suppl_5): v26 - v33. [Full Text] [PDF]
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 J. Milei, C. G. Fraga, D. R. Grana, R. Ferreira, and G. Ambrosio Ultrastructural evidence of increased tolerance of hibernating myocardium to cardioplegic ischemia-reperfusion injury J. Am. Coll. Cardiol., June 16, 2004; 43(12): 2329 - 2336. [Abstract] [Full Text] [PDF]
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J. M. Canty Jr, G. Suzuki, M. D. Banas, F. Verheyen, M. Borgers, and J. A. Fallavollita Hibernating Myocardium: Chronically Adapted to Ischemia but Vulnerable to Sudden Death Circ. Res., April 30, 2004; 94(8): 1142 - 1149. [Abstract] [Full Text] [PDF]
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V. Bito, F. R. Heinzel, F. Weidemann, C. Dommke, J. van der Velden, E. Verbeken, P. Claus, B. Bijnens, I. De Scheerder, G. J.M. Stienen, et al. Cellular Mechanisms of Contractile Dysfunction in Hibernating Myocardium Circ. Res., April 2, 2004; 94(6): 794 - 801. [Abstract] [Full Text] [PDF]
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 M. Pitt, D. Dutka, D. Pagano, P. Camici, and R. Bonser The natural history of myocardium awaiting revascularisation in patients with impaired left ventricular function Eur. Heart J., March 2, 2004; 25(6): 500 - 507. [Abstract] [Full Text] [PDF]
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 G. A. Krombach, M. Saeed, C. B. Higgins, V. Novikov, and M. F. Wendland Contrast-enhanced MR Delineation of Stunned Myocardium with Administration of MnCl2 in Rats Radiology, January 1, 2004; 230(1): 183 - 190. [Abstract] [Full Text] [PDF]
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R. Southworth and P. B. Garlick Dobutamine responsiveness, PET mismatch, and lack of necrosis in low-flow ischemia: is this hibernation in the isolated rat heart? Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H316 - H324. [Abstract] [Full Text] [PDF]
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 G. C. Hughes, M. J. Post, M. Simons, and B. H. Annex Translational Physiology: Porcine models of human coronary artery disease: implications for preclinical trials of therapeutic angiogenesis J Appl Physiol, May 1, 2003; 94(5): 1689 - 1701. [Abstract] [Full Text] [PDF]
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 A. F.L. Schinkel, J. J. Bax, R. van Domburg, A. Elhendy, R. Valkema, E. C. Vourvouri, F. B. Sozzi, J. R.T.C. Roelandt, and D. Poldermans Dobutamine-Induced Contractile Reserve in Stunned, Hibernating, and Scarred Myocardium in Patients with Ischemic Cardiomyopathy J. Nucl. Med., February 1, 2003; 44(2): 127 - 133. [Abstract] [Full Text] [PDF]
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 P. G Camici and O. E Rimoldi Myocardial blood flow in patients with hibernating myocardium Cardiovasc Res, February 1, 2003; 57(2): 302 - 311. [Abstract] [Full Text] [PDF]
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O. M. Muhling, Y. Wang, P. Panse, M. Jerosch-Herold, M. M. Cayton, L.S. Wann, M. M. Mirhoseini, and N. M. Wilke Transmyocardial laser revascularization preserves regional myocardial perfusion: an MRI first pass perfusion study Cardiovasc Res, January 1, 2003; 57(1): 63 - 70. [Abstract] [Full Text] [PDF]
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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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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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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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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]
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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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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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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. 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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