Ann Thorac Surg 2001;72:163-168
© 2001 The Society of Thoracic Surgeons
Original article: cardiovascular
Is chronically dysfunctional yet viable myocardium distal to a severe coronary stenosis hypoperfused?
G. Chad Hughes, MDa,
Carolyn K. Landolfo, MDb,
Bangliang Yin, MDa,
Timothy R. DeGrado, PhDc,
R. Edward Coleman, MDc,
Kevin P. Landolfo, MDa,
James E. Lowe, MDa
a Division of Cardiovascular and Thoracic Surgery, Duke University Medical Center, Durham, North Carolina, USA
b Division of Cardiology, Duke University Medical Center, Durham, North Carolina, USA
c Department of Radiology, Duke University Medical Center, Durham, North Carolina, USA
Accepted for publication April 3, 2001.
Address reprint requests to Dr Hughes, Duke University Medical Center, Box 3954, Durham, NC 27710
e-mail: chadh{at}acpub.duke.edu
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Abstract
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Background. Controversy exists regarding the perfusion status of chronically dysfunctional yet viable myocardium. Studies investigating the pathophysiology of this condition have reached different conclusions, with some suggesting that myocardial blood flow (MBF) in these regions is normal at rest with regional dysfunction resulting from repetitive stress-induced ischemia (stunned myocardium), whereas others have proposed that MBF is chronically reduced at rest (hibernating myocardium). However, adequately powered experimental studies investigating this question in an appropriate animal model using clinically available techniques have not been performed. Based on the mixed results of prior studies, we hypothesized that these chronically dysfunctional yet viable regions may actually represent a mixture of hibernation and stunning. Consequently, the purpose of this study was to quantitatively determine the distribution of MBF in left ventricular regions with chronically impaired resting function but preserved viability in a large population of animals with single-vessel coronary stenosis in an attempt to further elucidate the mechanism(s) responsible for chronic, reversible myocardial dysfunction.
Methods. Fifty-two adult mini-swine with 90% proximal left circumflex (LCx) stenosis underwent dynamic positron emission tomography (PET) with 13N-ammonia and 18F-fluorodeoxyglucose and dobutamine stress echocardiography (DSE) (5 to 40 µg/kg/min) 1 month after stenosis creation. Values of MBF and FDG uptake by PET and wall motion score index (WMSI) by DSE were compared using a standard 16-segment model.
Results. Of 312 possible LCx segments seen on PET, 303 (97.1%) were visualized by DSE. Of the 303 LCx segments, 279 (92.1%) had rest dysfunction (WMSI 
2) by DSE. One hundred eighty-two segments (60.1%) had decreased (< 85% reference) MBF at rest with preserved to increased (> 60% reference) FDG uptake and were classified as hibernating. Ninety-two segments (30.4%) had preserved MBF ( 85% reference) and were classified as stunned. Five segments (1.7%) with reduced (
60% reference) FDG uptake by PET and akinesis or dyskinesis at rest (WMSI 3) and no contractile reserve were considered infarcted. Hibernating segments had significantly higher FDG uptake at rest (360.7 ± 48.3 vs 212.3 ± 17.7% septal values; p < 0.001) than stunned segments consistent with greater resting ischemia. Likewise, mean rest WMSI was also worse in hibernating versus stunned segments (2.35 ± 0.04 vs 2.13 ± 0.04; p < 0.001). There was no difference in the percentage of hibernating versus stunned segments exhibiting contractile reserve during dobutamine infusion (55.5 vs 63.7%; p = 0.4), indicating similar degrees of viability.
Conclusions. Myocardial hibernation and stunning appear to frequently coexist in regions served by a stenotic coronary vessel. Hibernating regions appear to have greater resting ischemia based on higher values of FDG uptake and greater resting dysfunction. Reversible left ventricular dysfunction in the setting of chronic coronary artery disease is likely due to a combination of these two mechanisms.
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Introduction
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Hibernating myocardium is defined as chronic, reversible left ventricular dysfunction at rest due to coronary artery disease [1, 2]. Other concepts inherent in the definition include a responsiveness to inotropic stimulation and improvement or normalization of function after revascularization [1, 2]. There are also certain pathognomonic histologic features associated with the condition, including loss of contractile material and glycogen accumulation within otherwise viable cardiomyocytes [3]. Despite agreement on the definition of hibernating myocardium, controversy exists regarding the underlying pathophysiology. This controversy centers on whether or not resting myocardial blood flow (MBF) is substantially reduced in the condition [4]. When originally described [5], hibernating myocardium was felt to be hypoperfused. Early experimental studies [6, 7] seemed to support this "smart heart" hypothesis [8] of myocardial function downregulation to match perfusion deficits. More recent work [9, 10] has suggested that resting blood blow may be normal or near normal and that resting dysfunction results from repetitive stunning. However, adequately powered experimental studies investigating this question in an appropriate animal model using clinically available techniques have not been performed.
We have recently developed an animal model of hibernating myocardium [11, 12] that appears to meet all of the criteria used to describe the condition, including chronic left ventricular dysfunction at rest, response of the dysfunctional myocardium to inotropic stimulation, and reversibility upon revascularization [1, 2]. In addition, electron microscopy (Fig 1) of these chronically dysfunctional yet viable regions reveals depletion of contractile material, glycogen accumulation, and numerous small mitochondria within viable cardiomyocytes, all of which are hallmarks of hibernating myocardium [1, 2]. Based on the mixed results of prior studies [6, 7, 9, 10], we hypothesized that these chronically dysfunctional yet viable regions may actually represent a mixture of hibernation and stunning (ie, some segments may have reduced MBF at rest whereas in others resting perfusion would be normal). Consequently, the purpose of this study was to quantitatively determine the distribution of MBF in left ventricular regions with chronically impaired resting function but preserved viability in a large population of animals with single-vessel coronary stenosis to further elucidate the mechanism(s) (hibernation vs repetitive stunning) responsible for chronic, reversible myocardial dysfunction.
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Fig 1. Electron microscopy of biopsy from hibernating left circumflex (LCx) region (original magnification 900x) in a representative animal 30 days after production of high-grade proximal LCx stenosis (see text for details). Note the loss of contractile elements within viable cardiomyocytes, large areas of glycogen accumulation in the regions of sarcomere loss, as well as numerous small mitochondria. These ultrastructural changes are pathognomonic of hibernating myocardium [1–3].
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Material and methods
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Fifty-two adult male mini-swine (40 kg) (Harlan-Sinclair, Indianapolis, IN) were used. The Animal Care and Use Committee of Duke University approved all procedures and protocols. Animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health.
Chronic ischemia model
All animals underwent creation of an experimental 90% stenosis of the proximal left circumflex (LCx) coronary artery as previously described [11, 12]. This model produces a highly reproducible area of reversible ischemia in the lateral and posteroinferior walls of the left ventricle supplied by the left circumflex coronary artery [11, 12]. Animals were medicated with aspirin (650 mg po qd) throughout the entire experiment.
Positron emission tomography (PET) and dobutamine stress echocardiography (DSE)
One month after stenosis creation, animals underwent PET and DSE to characterize segmental MBF, metabolism, and function. Dynamic PET emission imaging of the heart using 13N-ammonia and 18F-fluorodeoxyglucose (FDG) was performed as previously described [11, 12] to obtain regional estimates of MBF and glucose utilization. After an overnight fast, dynamic PET emission imaging of the heart was performed at rest for 20 minutes after a 30-second intravenous infusion of 13N-ammonia (15 to 20 mCi). A 40-minute delay followed for decay of 13N activity. Then, dynamic imaging of the heart for 60 minutes was performed after a 30-second infusion of FDG (10 mCi). All emission images were corrected for photon attenuation using a transmission scan. Time-activity curves of tracer concentration in the left ventricular myocardium were obtained from short-axis views averaged over eight sectors in three short-axis slices (basal, mid, and apical). Previously validated compartmental modeling techniques were applied to the time-activity curves to obtain regional estimates of myocardial blood flow (mL/g/min) and glucose utilization (nmol/g/min) [13, 14]. A lumped constant of 1.0 was assumed for the calculation of glucose utilization from fractional FDG uptake rate [15]. During the PET scans, animals were maintained under general anesthesia and mechanically ventilated as described previously [11, 12]. PET data were interpreted in a blinded manner using absolute values for blood flow (mL/g/min) and glucose utilization (nmol/g/min). For each study, sectors representing the nonischemic septum were used as the normal reference segments (Fig 2) [12].
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Fig 2. Quantitative values of myocardial blood flow and glucose utilization by PET were obtained over eight sectors in three left ventricular short-axis slices. Sectors 2 through 4 correspond to the lateral and posteroinferior walls of the left ventricle and represent the left circumflex distribution. Sectors 6 through 8 were considered to represent the nonischemic septum. For the present study, only data from the base and mid slices were used due to variable perfusion of the apical lateral and posteroinferior walls by the left anterior descending and right coronary arteries in this animal model [11]. For each study, sectors 6 through 8 were used as the normal reference segments. 13N-ammonia and 18F-fluorodeoxyglucose activity within each of the individual left circumflex sectors were expressed as a percentage of the mean activity measured in the reference segments for each slice. Consequently, there were six left circumflex segments analyzed per animal and a total of 312 LCx segments analyzed for the entire study (six segments per animal x 52 animals).
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DSE was performed in 3-minute stages with incremental doses of dobutamine beginning with 5 µg/kg/min and increasing to 40 µg/kg/min as previously described [11, 12]. Based on a standard 16-segment model as proposed by the American Society of Echocardiography [16], wall motion was graded as: 1 = normal, 2 = hypokinetic, 3 = akinetic, or 4 = dyskinetic. Regional wall motion score index (WMSI) was calculated at rest, low dose, and peak stress. Using DSE, contractile reserve was defined as an improvement in systolic wall thickening (decrease in WMSI 1) with low-dose dobutamine in myocardial regions with hypocontractility (WMSI 2) at rest. Viable segments were considered ischemic if systolic wall motion deteriorated with stress (biphasic response) [17]. The basal and mid lateral, posterior, and inferior segments by dobutamine stress echo correspond to the same left circumflex segments as analyzed by PET. The reference PET segments are represented by the basal and mid anterior septum, mid septum, and inferior septum by echocardiography. Echos were interpreted by a cardiologist (C.K.L.) with expertise in stress echocardiography who was blinded to the PET data.
Left circumflex segment analysis
For the purpose of this study, each individual segment within the left circumflex distribution was prospectively defined as normal, infarcted, hibernating, or stunned based on the results of the PET and stress echo data. Normal segments were defined as those with normal rest and stress function (WMSI = 1) by dobutamine echocardiography. Infarcted segments were designated as those with akinesis or dyskinesis at rest (WMSI 3) with no contractile reserve by stress echo and FDG uptake by PET less than or equal to 60% of that within the normal reference segments [18]. Hibernating segments were defined as those with at least hypokinesis at rest by echocardiography (WMSI 2), and myocardial blood flow less than 85% and FDG uptake greater than 60% of that within the normal reference segments [18, 19]. Finally, segments were designated as stunned if wall motion by echo was at least hypokinetic at rest (WMSI 2), yet myocardial blood flow by PET was greater than or equal to 85% of reference values [20].
Statistical analysis
All data are presented as the mean ± standard error. Myocardial blood flow and glucose utilization by PET, as well as wall motion scores by DSE, were compared between reference and LCx segments using a paired Student’s t test with a Bonferroni correction for multiple comparisons. FDG uptake and wall motion scores were compared between hibernating and stunned segments using an unpaired Student’s t test with a Bonferroni correction. The percentage of hibernating and stunned segments exhibiting contractile reserve by DSE was compared using 
2 analysis. Statistical significance was considered at a p value less than 0.05.
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Results
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All 312 reference septal segments were seen by both PET and echocardiography. Of the 312 possible left circumflex segments seen on PET, 303 (97.1%) were visualized by dobutamine echocardiography, with the remainder not being visualized secondary to poor acoustic window. Two hundred seventy-nine (92.1%) of these 303 segments had rest dysfunction (WMSI 2) by DSE. Mean absolute resting MBF by PET for the 312 reference septal segments as a whole was 0.79 ± 0.01 mL/g/min versus 0.61 ± 0.01 mL/g/min for the corresponding LCx segments (p < 0.001). Mean FDG uptake for the septal segments was 58.1 ± 5.3 nmol/g/min versus 71.7 ± 4.2 nmol/g/min (p < 0.001) for the LCx segments. Using the previously outlined definitions of hibernating, stunned, infarcted, and normal, left circumflex segment analysis demonstrated 182 of the 303 segments (60.1%) to be hibernating, 92 (30.4%) to be stunned, five (1.7%) to be infarcted, and 24 (7.9%) to be normal (Fig 3). If the 24 left circumflex segments with normal function are excluded, then 65.2% (182 of 279 segments) of the dysfunctional segments were hibernating, 33.0% (92 of 279) were stunned, and 1.8% (5 of 279) infarcted. These findings support the hypothesis that chronically dysfunctional yet viable myocardium represents a mixture of predominantly hypoperfused (hibernating) and, to a lesser degree, normally perfused (stunned) myocardium.
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Fig 3. Individual LCx segment analysis. See text for details. Note that of all the chronically dysfunctional yet viable segments in the distribution of a highly stenotic left circumflex coronary vessel, approximately two-thirds were hypoperfused and considered hibernating, whereas one-third were normally perfused at rest and classified as stunned.
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Although statistical comparison of myocardial blood flow values by PET between groups are not valid, as the groups were defined on the basis of blood flow criteria, mean MBF values per group are presented for reference. Myocardial blood flow averaged 67.8 ± 0.9% of control septal values in the hibernating segments and 94.9 ± 0.7% in the stunned segments. Myocardial blood flow for the infarcted segments averaged 61.8 ± 9.2% of reference. FDG uptake by PET (Fig 4A) averaged 360.7 ± 48.3% of reference in the hibernating segments and 212.3 ± 17.7% in the stunned segments (p < 0.001). FDG uptake for the infarcted segments averaged 52.2 ± 4.2% of control.
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Fig 4. (A) FDG uptake by PET for hibernating, stunned, and infarcted LCx segments expressed as percent reference septal values (see text for details). The significantly higher values of FDG uptake (glucose utilization) in the hibernating versus stunned segments are consistent with a greater reduction in resting myocardial blood flow [24]. FDG uptake for the infarcted segments is shown for comparison, although statistical comparison with hibernating and stunned segments was not performed due to small (n = 5) number of infarcted segments. (B) Regional WMSI by echocardiography at rest for hibernating and stunned segments. WMSI = 1 is normal, with higher numbers indicating worsening wall motion (see text for details). As for FDG uptake, the hibernating segments had worse resting wall motion than stunned segments, also consistent with a greater reduction in basal myocardial perfusion [19]. (C) Percentage of hibernating versus stunned segments demonstrating contractile reserve during low-dose dobutamine infusion (see text for details). There was no difference in the percentage of hibernating versus stunned segments exhibiting contractile reserve during low-dose dobutamine infusion consistent with similar degrees of viability [17].
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Regional wall motion score index at rest for hibernating and stunned LCx segments is shown in Figure 4B. Resting wall motion score index was slightly, but significantly, worse in the hibernating segments (2.35 ± 0.04 vs 2.13 ± 0.4 for hibernating vs stunned segments; p < 0.001). By 2 analysis, there was no difference in the percentage of hibernating (55.5%) versus stunned (63.7%) segments demonstrating contractile reserve during low-dose dobutamine infusion (p = 0.4) (Fig 4C).
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Comment
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The term "myocardial hibernation" has been used to describe chronic, reversible left ventricular dysfunction at rest due to coronary artery disease [1, 2]. The pathophysiology underlying the condition, initially felt secondary to myocardial hypoperfusion [5], has been debated. The debate has stemmed, at least in part, from difficulties in reproducing this clinical state in an animal model [1]. Studies by Shen and Vatner [9] and Kudej and associates [10] using a porcine ameroid constrictor model found that myocardial blood flow in regions served by the occluded vessel was nearly normal at rest, with reduced myocardial flow reserve during stress. These findings supported the argument that myocardial hibernation results from repetitive stunning. Other chronic animal studies, however, have suggested that hibernating myocardium is hypoperfused at rest. Fallavollita and associates [21], utilizing a model similar to that of the present study, instrumented swine with a high-grade proximal left anterior descending (LAD) stenosis and found reduced resting MBF in regions with chronic dysfunction 3 to 4 months after instrumentation. Similar results have been published by others as well [22, 23]. The present study demonstrates that viable myocardial regions with chronically impaired resting function that are served by a highly stenotic epicardial coronary vessel may have reduced or normal myocardial blood flow at rest. In the model used, approximately two-thirds of the dysfunctional yet viable segments had reduced MBF and met the prospective definition of hibernating, while about one-third had preserved MBF and were considered stunned. Hibernating regions appear to have greater resting ischemia based on higher values of FDG uptake [24] and greater resting dysfunction [17].
More recently, Fallavollita and Canty [25] have demonstrated that resting MBF is normal in the dysfunctional regions 1 to 2 months after instrumentation in their LAD stenosis model. Based on their prior work demonstrating hypoperfusion in the dysfunctional regions 3 to 4 months after stenosis creation [21], they hypothesized a progression of physiological adaptation in viable, chronically dysfunctional myocardium with a transition from stunning to hibernation over time. Although the present study does not directly support this theory, it does demonstrate that myocardial hibernation and stunning may coexist in regions served by a chronically stenotic vessel, a condition likely necessary if a transition from stunning to hibernation is to occur. In addition, if a transition from stunning to hibernation does occur, the present study suggests that this transition may involve metabolic adaptation at the cellular level given the significantly greater FDG uptake in hibernating versus stunned myocardium. It is well known that under normal conditions nonesterified fatty acids are the preferred substrate of myocardium [24, 26] and account for up to 80% of myocardial energy production. However, during sublethal myocardial ischemia, the ß-oxidation of fatty acids diminishes concomitant with increased glucose extraction (Randle’s cycle), thus explaining the increased 18F-FDG uptake in hibernating versus stunned myocardium as demonstrated by PET in the present study [24, 26]. Potential metabolic alterations responsible for the transition from stunned to hibernating might involve increased glucose transporter (GLUT 1 and/or GLUT 4) production by the cardiac myocytes [27] or, alternatively, upregulation of specific glycolytic enzymes [28].
Both hibernating [3] and stunned myocardium [29] have been associated with characteristic structural alterations. These structural changes (Fig 1) include partial to complete loss of sarcomeres, glycogen accumulation, and increased numbers of mini-mitochondria within cardiomyocytes, among others [1–3, 29]. The slight, but significant, worsening of wall motion in the hibernating versus stunned segments in the present study suggests that greater structural alterations might be present in hibernating myocardium, again consistent with the theory of a transition from one phenotype to the other over time. A previous retrospective clinical study has suggested that cardiomyocyte degeneration is progressive in patients with hibernating myocardium [30], which is also consistent with this hypothesis. This may be significant, as patients with more advanced cardiomyocyte deterioration appear to have less return of function after surgical revascularization than those with less advanced changes [31, 32]. However, at least in the time course evaluated in this study, there was no difference in the percentage of hibernating versus stunned segments with recruitable inotropic reserve upon catecholamine stimulation, thus predicting an equal return of function after revascularization [33].
In summary, the results of this study suggest that myocardial hibernation and stunning may coexist in regions served by a highly stenotic epicardial coronary vessel. Reversible left ventricular dysfunction in the setting of chronic coronary artery disease appears due to a combination of these two mechanisms.
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Acknowledgments
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This work was supported in part by a grant from the National Institutes of Health and the National Heart, Lung, and Blood Institute (grant number 1 F32 HL09969-01) (G.C.H.). The authors would like to thank Michael Lowe for his expert technical assistance during all phases of the study. In addition, we would like to thank John Toptine for his technical assistance with dobutamine stress echocardiography, and Sharon Hamblen, Mary Traynor, and David Cherryholmes for their technical assistance with positron emission tomography.
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Abstract
Introduction
