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(Circulation. 1997;96:3205-3214.)
© 1997 American Heart Association, Inc.

Articles

Pathophysiological Mechanisms of Chronic Reversible Left Ventricular Dysfunction due to Coronary Artery Disease (Hibernating Myocardium)

Paolo G. Camici, MD; William Wijns, MD; Marcel Borgers, PhD; Ranil De Silva, PhD; Roberto Ferrari, MD; Juhani Knuuti, MD; Adriaan A. Lammertsma, PhD; A. James Liedtke, MD; Giovanni Paternostro, MD, PhD; ; Stephen F. Vatner, MD

From the Medical Research Council–Cyclotron Unit and Royal Postgraduate Medical School, Hammersmith Hospital (P.G.C., R. De S., A.A.L., G.P.), London, UK; Cardiovascular Center (W.W.), OLV Ziekenhuis, Aalst, Belgium; Janssen Research Foundation (M.B.), Beerse, Belgium; Department of Cardiology (R.F.), University of Brescia, Italy; Turku PET Center (J.K.), Turku University Central Hospital, Finland; Cardiology Section (J.A.L.), University of Wisconsin, Madison; and Harvard University Medical School (S.F.V.), NERPRC, Southborough, Mass.

Correspondence to Paolo G. Camici, MD, Medical Research Council–Cyclotron Unit, Hammersmith Hospital, Ducane Rd, London W12 ONN, UK. E-mail paolo{at}cu.rpms.ac.uk

	Introduction

Top Introduction Historical Background Hibernating Myocardium: Current... Conclusions References

 
The long-term consequences of CAD remain a prominent clinical problem. Particularly with new therapeutic strategies that reduce the mortality associated with acute coronary syndromes, more patients suffer from the long-term sequelae of this condition. In this setting, the identification of those segments of myocardium that appear dysfunctional distal to coronary stenoses and that can improve after coronary revascularization is of considerable clinical importance. Although the diagnostic and therapeutic aspects of this problem are clearly defined, the pathophysiological mechanisms underlying the dysfunctional myocardium are controversial.

	Historical Background

Top Introduction Historical Background Hibernating Myocardium: Current... Conclusions References

 
It was demonstrated more than 20 years ago^{1 2} that resting wall-motion abnormalities in patients with CAD can improve after administration of an inotropic agent or after coronary bypass. An article published in 1978 by Diamond et al³ presaged the concept of hibernating myocardium: "Reports of sometimes dramatic improvement in segmental left ventricular function following coronary bypass surgery, although not universal, leaves the clear implication that ischemic non-infarcted myocardium can exist in a state of function hibernation." Rahimtoola, in an article published in 1985,⁴ popularized this concept and later suggested that "hibernating myocardium is a state of persistently impaired myocardial and left ventricular function at rest due to reduced coronary blood flow that can be partially or completely restored to normal either by improving blood flow or by reducing oxygen demand."⁵

Since the introduction of the term "hibernation,"^{3 4 5 6} the clinical importance of reversible left ventricular dysfunction has been widely accepted. The concept of an adaptive process that decreases myocardial oxygen consumption in the presence of either chronically or intermittently reduced oxygen delivery has generated considerable clinical and experimental interest.

Accordingly, our aims were to (1) review the current criteria of the definition of hibernating myocardium, (2) summarize recent clinical as well as experimental data pertaining to this subject, and (3) present a potentially improved and more inclusive definition of the underlying pathophysiology.

	Hibernating Myocardium: Current Criteria for Definition

Top Introduction Historical Background Hibernating Myocardium: Current... Conclusions References

 
It is currently believed that there are three main features that characterize hibernating myocardium:

1. Baseline MBF is chronically reduced by a sufficient magnitude to be responsible for the decrease in myocardial function.

2. There are consequences of tissue ischemia, eg, remodeling without necrosis.

3. A residual contractile reserve can be demonstrated in hibernating segments.

In addition, there are two other features that may not be part of the definition but have been attributed to hibernating myocardium:

4. Depressed myocardial function may recover rapidly on revascularization.

5. There is a lack of suitable animal models that simulate the condition.

MBF Is Chronically Reduced by a Sufficient Magnitude to Be Responsible for the Decreased Myocardial Function
The postulate of a long-term reduction of baseline MBF of sufficient magnitude to be responsible for the reduction in function is the conditio sine qua non for the definition of hibernating myocardium.

Chronically dysfunctional segments are often characterized by defects on ²⁰¹Tl scintigraphy. ²⁰¹Tl is a potassium analogue that is initially extracted by the myocardium in proportion to flow and enables the assessment of directional changes of nutritive tissue perfusion⁷ as opposed to measurements of epicardial coronary flow by either thermodilution⁸ or Doppler catheter techniques.⁹ Tracer redistribution on late images (4 to 24 hours after injection), after a stress-redistribution, stress-redistribution-reinjection, or rest-redistribution protocol, can be defined as the delayed resolution of a defect present on the early image (10 minutes after injection) and requires integrity of sarcolemmal functions. This feature of ²⁰¹Tl is exploited successfully in the clinical setting to assess myocardial viability.⁷ In chronically dysfunctional segments, there is frequently evidence of stress-induced ischemia, which may or may not be followed by late redistribution of the tracer.¹⁰

Using the inert gas technique, Arani et al¹¹ demonstrated a reduced perfusion in dysfunctional collateral-dependent myocardium, suggesting the possibility of a long-term reduction in local metabolic demand. A factor that might contribute to artificially increasing the difference between hibernating and remote myocardium is the lack of partial volume correction in single-photon emission computed tomography studies. Because the less contractile hibernating segments are thinner, the radioactivity concentration will be seen as lower in these segments,¹² although this argument fails to explain ²⁰¹Tl redistribution at rest 4 hours after injection in the same territory that remains hypocontractile during that 4-hour period. In any case, absolute quantification of MBF (mL · min^-1 · g^-1) by use of any of the previously mentioned techniques is impossible due to the physical limitations of the imaging systems and the tracers available.

PET overcomes most of the physical limitations of previously available imaging systems by providing the means for accurate attenuation correction, thus enabling absolute quantification of the concentration of radiolabeled tracer in the organ of interest.¹³ Initial PET studies revealed that hibernating segments corresponded to areas with qualitatively reduced perfusion, assessed with ¹³N-labeled ammonia (¹³NH₃) in the presence of preserved uptake of FDG (flow/metabolism mismatch, a marker of tissue viability).¹⁴ Of course, as noted below, this could also reflect an admixture of scarred myocardium in the region of interest. As PET technology has advanced and rapid dynamic imaging has become possible, quantification of MBF has been achieved after the development of suitable tracer kinetic models. Grandin et al,¹⁵ using ¹³NH₃ with PET, found that chronically dysfunctioning segments that recovered after revascularization had baseline blood flow of 0.77±0.20 mL · min^-1 · g^-1, a figure slightly lower than that in normally contracting areas in the same patients (0.97±0.18 mL · min^-1 · g^-1). In the same study, in another group of patients with nonrecoverable dysfunction, baseline blood flow in normally contracting areas was 0.87±0.18 mL · min^-1 · g^-1, which is even closer to the value in hibernating segments. De Silva et al,¹⁶ using PET with ¹⁵O-labeled water (H₂¹⁵O) found almost identical blood flow values to those reported by Grandin et al¹⁵ both in hibernating (0.73±0.18 mL · min^-1 · g^-1) and normally contracting (0.97±0.22 mL · min^-1 · g^-1) segments. Recently, Maki et al¹⁷ also found similar results. In two other reports,^{18 19} patients with chronic left ventricular dysfunction were studied several months after acute myocardial infarction. In dysfunctional segments with flow/metabolism mismatch, MBF was higher than in dysfunctional, nonviable segments but lower than in remote, normally contracting segments. As in the study by Arani et al,¹¹ the latter two studies are limited by the lack of demonstration of functional recovery after revascularization and the potential dilutive effect of varying amounts of fibrosis within the dysfunctional areas. In some cases,²⁰ the regional differences in flow are sustained in part by a higher perfusion in remote myocardium, probably as a consequence of a higher oxygen consumption in these regions. These compensatory changes in flow distribution can be responsible for an apparent relative reduction of tracer content in the dysfunctional regions that, in the case of qualitative imaging, could be erroneously interpreted as an absolute flow reduction in the same segments. In addition to the limitations noted above, it must also be appreciated that there is both spatial and temporal heterogeneity of blood flow under normal conditions.²¹ The data alluded to above consistently show that baseline blood flow to hibernating myocardium in most cases is within the range of values measured by PET in the myocardium of normal human volunteers (Table). In addition, the same range of baseline flow distribution has been demonstrated in healthy conscious primates by radioactive microspheres (Fig 1).

View this table: [in this window] [in a new window]   Table 1. Resting MBF (mL · min-1 · g-1) in Normal Subjects Measured by PET

View larger version (19K): [in this window] [in a new window]   Figure 1. The frequency distribution (spatial heterogeneity) of MBF is analyzed in 1058 myocardial segments from 6 normal, conscious baboons with radioactive microspheres (top), 700 segments from 100 normal human subjects (middle), and 106 segments from 30 patients with CAD and chronic ventricular dysfunction by means of PET with 15O-labeled water (bottom). Note the similarity and the wide distribution of normal MBF values, ranging from 0.2 to 2.0 mL · min-1 · g-1, in normal baboons and normal human subjects. Also, note the analogy in distribution of MBF between normal subjects and patients with CAD and ventricular dysfunction, although the MBF distribution in dysfunctional segments is shifted to the left, suggesting that a greater proportion of these segments have low flows compared with normal subjects. (Reprinted with permission.36 108 )

Flow estimates within a given volume of interest are critically dependent on the mass of tissue that is actively participating in tracer exchange, as opposed to fibrous or scar tissue. In the presence of marked spatial tissue heterogeneity, such as occurs with ischemic injury, the measured flow value may represent a transmural average between several values ranging from very low in necrotic areas to normal in well-perfused zones. From these measurements, it is impossible to determine whether MBF, as reflected by tracer uptake, in viable myocytes is truly reduced or whether this is only an apparent phenomenon due to the fact that tracer uptake is the average between areas with extremely low uptake (scar tissue) and areas with more normal uptake (viable tissue).

Recent refinements of the H₂¹⁵O technique with PET have permitted incorporation of an estimate of the fraction of tissue within the volume of interest that is exchanging the freely diffusible tracer into the kinetic model.³⁴ This technique provides values of flow per gram of perfusable tissue (not per gram of region of interest).³⁵ Because the uptake of H₂¹⁵O in scar tissue is negligible compared with normal myocardium, in a myocardial region consisting of an admixture of viable and necrotic tissue, this model predominantly measures flow to the residual normal myocardium.^{16 34 35 36} At variance with the H₂¹⁵O technique, the flow measured with other tracers, eg, ¹³NH₃, represents an average flow per unit mass of tissue as with the microsphere technique.^{37 38} Another approach to avoid the dilutive effect of scar tissue is to select patients with CAD and chronic left ventricular dysfunction but without evidence of previous infarction. Marinho et al³⁶ measured MBF in 30 patients with chronic left ventricular dysfunction and previous infarction using H₂¹⁵O with PET. They found that baseline MBF in dysfunctional segments that recovered was comparable to that in normal segments (0.87±0.31 versus 0.92±0.25 mL · min^-1 · g^-1 of water-perfusable tissue). Comparable results were obtained by Gerber et al³⁹ using PET with ¹³NH₃. MBF in hibernating tissue was 0.84±0.27 mL · min^-1 · g^-1 and was not different from that measured in normal remote myocardium (0.82±0.22 mL · min^-1 · g^-1). It must be recognized that in both these studies, a small fraction (10%) of hibernating segments had blood flows <0.60 mL · min^-1 · g^-1, suggesting a reduced resting perfusion. However, as shown in Fig 1, a small fraction of myocardial segments in normal human subjects also have flows of <0.6 mL · min^-1 · g^-1. Similar results were obtained by Vanoverschelde et al,²⁰ Grandin et al,¹⁵ and Sambuceti et al.⁴⁰ Interestingly, Marin-Neto et al⁴¹ showed that in patients with reverse ²⁰¹Tl redistribution and evidence of tissue viability after ²⁰¹Tl reinjection, the simultaneous assessment of MBF with H₂¹⁵O and PET showed that in most (13 of 16) cases, resting PET flow values were in the normal range (ie, >0.70 mL · min^-1 · g^-1).

Admittedly, the limited spatial resolution of the present generation of PET scanners permits measurement of average transmural MBF only. In the presence of flow restriction, subendocardial layers tend to have less flow than subepicardial layers. Therefore, a small reduction in average flow across the wall may still correspond to a more severe reduction in subendocardial blood flow. Whether or not subendocardial blood flow is reduced in patients with hibernating myocardium awaits verification by direct measurement. However, using the worst case scenario (zero reduction in subepicardial blood flow with ischemia), even a 20% reduction in transmural flow results in a 40% reduction in subendocardial blood flow and accounts for less functional impairment than seen in most patients with hibernating myocardium (Fig 2).^{42 43 44} This is noted as "worst case" because the most recent clinical studies using PET have not noted even a 20% reduction in transmural flow.^{36 39 40}

View larger version (18K): [in this window] [in a new window]   Figure 2. The regional MBF-function relationships are shown from prior studies in conscious dogs.42 43 44 Simultaneous measurements of regional subendocardial segmental shortening (measured with ultrasonic crystals) and blood flow at the same sites (measured with radioactive microspheres) were obtained during graded coronary constriction in the study by Vatner,42 whereas transmural wall thickening was correlated with transmural blood flow in the studies by Gallagher et al.43 44 One other difference is that in the study by Vatner,42 heart rate was held constant, whereas heart rate rose with progressive coronary constriction in the studies by Gallagher et al.43 44 It can be appreciated that even a 20% reduction in subendocardial blood flow is not expected to lead to an appreciable reduction in subendocardial function. Even in the case of transmural measurements, a 20% reduction in flow (which in dogs involves no decrease in subepicardial flow) accounts for a <40% reduction in function, which is far less severe than the functional impairment seen in most patients. (Reprinted with permission.42 43 44 )

It was noted that coronary vasodilator reserve was impaired in all stenotic regions, although the degree of impairment was more severe in stenotic regions with resting dysfunction.^{20 40} A unifying feature emanating from the available studies is the demonstration that chronically dysfunctional myocardium is characterized by a severe impairment of coronary vasodilator reserve. It has been demonstrated that in patients with CAD, flow reserve decreases as the degree of stenosis is increased and is abolished for stenoses 80% of the luminal diameter.⁴⁵ Under these circumstances, any increase in cardiac workload above baseline conditions cannot be met by an adequate increase in MBF, thus leading to myocardial ischemia. Therefore, in patients with severe CAD, the limited flow reserve leads to the development of myocardial ischemia even for small increases in oxygen demand such as those associated with ordinary daily activities.⁴⁶ Regardless of the blood flow level under baseline conditions, these patients will develop ischemia when oxygen demand is increased. Thus, intermittent episodes of ischemia and, consequently, postischemic stunning, which should occur frequently in patients with severe CAD, might play a role in the development of chronic reversible left ventricular dysfunction. Clearly, under these conditions, coronary revascularization could restore flow reserve and alleviate the chronic ischemic dysfunction.

There Are Consequences of Tissue Ischemia, eg, Remodeling Without Necrosis
Pathology
Histological studies^{20 47 48 49} on bioptic material obtained at the time of surgery, although showing no necrosis, have provided evidence for profound structural changes in chronically dysfunctional but viable myocardium. In a porcine model of coronary stenosis for 1 week, histological changes have been observed similar to those in patients with hibernating myocardium.⁵⁰ These changes can be summarized as follows: (1) A progressive loss of contractile proteins (sarcomeres) in a substantial number of cardiomyocytes occurs without loss of cell volume, which is clearly distinct from atrophic degeneration. The depletion of sarcomeres is initially seen at the cell center (perinuclear region) and may extend toward the periphery, involving all of the cytoplasm. Characteristically, the space previously occupied by sarcomeres is occupied by glycogen. (2) Numerous small mitochondria can be found in the areas adjacent to the glycogen-rich perinuclear zones. (3) Changes are present in the nuclei where heterochromatin is found evenly distributed over the nucleoplasm. (4) There is a substantial loss of sarcoplasmic reticulum. Organized sarcoplasmic reticulum is virtually absent; instead, a network of disorganized profiles of reticular membranes remains present in the myolytic areas. Fragments of rough endoplasmic reticulum are frequently encountered in cells undergoing such changes. The sarcolemma no longer projects protrusions (T tubules) into the cytoplasm. The above changes are suggestive of dedifferentiation because they resemble structural features of embryonic/fetal cardiomyocytes. The latter point is also supported by recent findings on the expression of three different structural proteins that are normally only present in fetal cells.^{51 52} As far as the extracellular space is concerned, mesenchymal cells are present in a slightly increased number and display well-preserved substructures. Interstitial collagen and ground substance are markedly increased and correlate with the degree of myocardial cell change.⁵³

It remains to be determined whether these histological changes are found in all patients with hibernating myocardium. Myocardial tissue characterized by such morphological changes is not likely to regain function immediately after revascularization but might require time to regain sufficient contractile material. However, the finding that some patients regain function rapidly whereas others have a delayed recovery suggests that the histological pattern cannot be the same in all patients with CAD and chronic left ventricular dysfunction.

Myocardial Metabolism
The study of myocardial metabolism can provide information regarding substrate utilization and the presence of myocardial ischemia, as well as the tissue response to hormonal stimulation. Qualitative studies performed during fasting conditions, using FDG and PET, have shown that chronically dysfunctional segments are characterized by an increased FDG signal relative to remote myocardium.⁵⁴ These data have been confirmed by two other groups performing quantitative measurements of myocardial FDG uptake.^{17 55} In normal subjects studied after overnight fasting, myocardial FDG uptake is extremely low (1 to 2 µmol/100 g per minute) due to the prevailing lipid utilization.⁵⁶ In the studies of Maki et al¹⁷ and Gerber et al,⁵⁵ FDG uptake was greater than in normal subjects not only in dysfunctional myocardium but also in remote myocardium. During hyperinsulinemic euglycemic clamp, segments with chronic dysfunction were shown to respond to insulin stimulation, albeit less than remote myocardium.^{17 36 55} Ferrari et al,⁵⁷ using simultaneous arterial and great cardiac vein sampling, demonstrated that chronically dysfunctional myocardium, which recovered after revascularization, showed net lactate extraction. Although net transmural extraction does not rule out subendocardial lactate production and ischemia,⁵⁸ increased glucose utilization in hibernating myocardium does not seem to represent increased anaerobic metabolism, as seen during ischemia,⁵⁶ but might be secondary to an increased expression of the GLUT-1 glucose transporter, as suggested recently.^{59 60} Oxygen consumption in chronically dysfunctional but viable myocardium has been measured with the use of ¹¹C-acetate and PET in three different studies,^{18 20 61} which demonstrated that oxidative metabolism was preserved.

In conclusion, although the studies on tissue metabolism in patients with CAD and chronic left ventricular dysfunction remain limited, there is no metabolic evidence for persistent ischemia in human hibernating myocardium.

A Residual Contractile Reserve Can Be Demonstrated in Hibernating Segments
Another feature of hibernating myocardium identified by different authors was the presence of residual contractile reserve.^{1 2 3 6 62 63} More recently, the demonstration of a recruitable contractile reserve by echocardiography during intravenous dobutamine infusion has been used to evaluate the presence of viable tissue in chronically dysfunctional regions,^{64 65 66 67 68} with an accuracy comparable to nuclear techniques.⁶⁹ As previously mentioned, in patients with chronic hibernation, the myocytes often show profound ultrastructural changes, including the loss of contractile myofilaments.^{47 48 49} Recent evidence seems to suggest that in patients with very low ejection fraction (24±7%) in whom these structural changes may be extreme, the absence of contractile apparatus may not permit a positive response to inotropic stimulation while myocytes are still viable.⁷⁰ Under these circumstances, other techniques that interrogate resting cell metabolism or membrane function can be expected to be more sensitive for the diagnosis of viability than stress echocardiography. Finally, because the computation of wall-motion score with echocardiography includes normal myocardium, this could account for some of the positive responses to dobutamine, particularly where normal segments are tethered to dysfunctional ones.

Depressed Myocardial Function May Recover Rapidly on Revascularization
The issue of functional recovery after revascularization of hibernating myocardium is complex. Evidence exists to support both early and late recovery. This may reflect different factors, including the amount of viable tissue in a dysfunctional region, the chronicity of CAD, and above all, the accompanying histological pattern. Evidence for an immediate recovery of function after coronary artery bypass grafting has been provided by Topol et al⁷¹ and La Canna et al.⁶⁵ However, it is important to note that some of the functional measurements were performed under the influence of anesthesia and shortly after surgery, which may also change the loading conditions of the heart. Other studies have shown recovery of function at various time points after revascularization, even as much as 10 weeks before maximal improvement could be demonstrated.^{72 73 74 75 76 77 78 79 80 81} Most importantly, as noted earlier, immediate recovery of function would be inconsistent with the pathognomonic histological changes observed in some hibernating segments. Failure to improve after revascularization may also be due to the occurrence of perioperative myocardial infarction in otherwise viable segments. Finally, as recently pointed out by Kaul,⁸² the degree of segmental dysfunction also depends on the transmural extension of fibrosis. In patients with fibrotic subendocardial layers but viable subepicardium, resting function, which is mainly dictated by the subendocardium, may not recover, but the segment may retain the ability to augment function on stimulation. A possible explanation that would reconcile these differences in the rate of recovery that have been observed could be heterogeneity among patients as well as heterogeneity of the disease process within the same heart.

Lack of Suitable Animal Models That Simulate the Condition
One of the major limitations for a better understanding of the mechanisms underlying myocardial hibernation is the absence of useful and relevant animal models. As pointed out by Ross,⁸³ there are no available animal models for studying chronic myocardial hibernation. The absence of animal models has not been due to the lack of effort. This by itself is a cogent argument against the possible pathophysiological concept of chronically reduced baseline MBF sufficient to reduce myocardial function. The principal limitations in animal models to date attempting to demonstrate chronically reduced blood flow can be placed in four categories: (1) coronary stenosis is not chronic; (2) coronary stenosis is chronic but necrosis might be present; (3) baseline MBF is not reduced sufficiently to account for the reduction of function; and (4) baseline MBF is not reduced, even slightly. As will become evident in the following discussion, the limitations may not be in the animal models but rather in the current definition of hibernating myocardium requiring baseline blood flow to be reduced substantially.

Coronary Stenosis Is Not Chronic
Because of the difficulty in producing long-term reductions in blood flow and chronic models of myocardial hibernation, a number of investigators have used acute models of myocardial hibernation. A study by Kitakaze and Marban⁸⁴ used an in vitro isolated heart in which reductions in flow and function were induced over a period of several hours. However, the extent to which results obtained in acute in vitro models can be extrapolated to the problem of chronic myocardial hibernation is questionable. Because of the difficulty in obtaining a steady-state reduction in coronary blood flow in the dog,⁸⁵ even for a few hours, due to the natural abundance of collateral vessels, several investigators have used the pig. Schulz and colleagues^{86 87 88} developed a model in the open-chest anesthetized pig with constant flow hypoperfusion for a 90-minute period, and they demonstrated parallel reductions in blood flow and function. These studies found acute perfusion-contraction matching, recovery of metabolic markers, inotropic reserve at the expense of metabolic recovery, and no tissue necrosis. Of course, it is not possible to predict whether some infarction might have been noted with longer periods of coronary stenosis. There is one report suggesting that this might indeed occur.⁸⁹ Chen et al⁹⁰ used a similar model but with stenosis induced for 24 hours, in which infarction was noted in some animals. However, these models suffer from the same problems as that of Kitakaze and Marban,⁸⁴ ie, how well do acute models of flow reduction simulate the situation of chronic CAD in humans?

Therefore, these studies that have been conducted in acute models have been referred to as short-term hibernation. Probably, it would be more correct to call these models short-term hypoperfusion/contraction matching because hibernation implies a chronic situation and there are major differences between the effects of acute coronary stenosis on the one hand and chronic myocardial dysfunction on the other.

Coronary Stenosis Is Chronic but Necrosis Might Be Present
One of the major limitations of studies in patients with regional myocardial dysfunction is the possibility of contamination of healthy myocardium with focal areas of necrosis. It must be kept in mind that even a segment of myocardium that includes a small fraction of scar tissue will not function entirely normally. This problem has also plagued many of the animal models. This is particularly important in pigs with chronic coronary artery stenosis.^{91 92 93} For example, in these studies, the percentage of infarcted left ventricle ranged from 5% to 8% of the stenosis-dependent region. It must be emphasized that these figures are not insignificant and can affect regional measurements and be responsible for more severe reductions in both perfusion and function than warranted from the remaining viable myocardium.

Baseline MBF Is Reduced but Not Sufficiently to Account for the Reduction in Function
Several studies^{90 92 94} have noted modest reductions in flow of 25%. However, as pointed out in an earlier section of this review (Fig 2), these reductions in blood flow, under conditions of short-term coronary constriction,^{42 43 44} are not sufficient to reduce regional myocardial function by the same magnitude as in patients with hibernating myocardium and in addition may have been associated with sufficient myocardial necrosis to affect the baseline blood flow measurement. As noted earlier, there is both spatial and temporal heterogeneity of MBF under normal conditions.²¹ The data summarized above consistently show that baseline blood flow to hibernating myocardium in experimental models is within the range of values measured by PET in the myocardium of normal human volunteers (Table) and in the same range of baseline flow distribution that has been demonstrated in healthy conscious primates by radioactive microspheres (Fig 1).

Baseline MBF Is Not Reduced Even Slightly
A number of studies have proposed models of chronic coronary stenosis, mainly in pigs, resulting in hibernating myocardium.^{95 96} In these studies, flow reserve, as estimated by coronary velocity measurements, was acutely decreased by partial inflation of a hydraulic cuff around the anterior descending coronary artery but partially recovered thereafter. A third study from Liedtke's laboratory,⁹⁷ in addition to again observing the reduced flow reserve, also measured coronary flow with radioactive microspheres. Flow in these studies was essentially unchanged from prestenosis values. A recent study by McFalls et al⁹⁸ used a similar model in pigs as described by the Liedtke group,⁹⁷ except that the stenosis was maintained for 5 weeks. In that study, as was observed in a shorter-term study,⁹⁷ regional myocardial function was reduced without any demonstrable reduction of regional blood flow.

With the development of techniques for measurement of regional MBF and function in chronically instrumented, conscious animals,⁹⁹ it has become possible to undertake studies with chronic myocardial ischemia. Clearly, the most prevalent model used is the one of ameroid coronary constriction. This technique induces gradual constriction of a large coronary artery and, ultimately, complete occlusion of the vessel, generally over a 2- to 4-week period. The most clinically relevant model would be chronic coronary artery stenosis, or the ameroid model before complete closure of the coronary artery. Most studies using the ameroid technique suffer from one of two major limitations. As noted above, the coronary artery occludes totally after 4 to 6 weeks, and many of the prior studies concentrating on the development of coronary collaterals did not begin measurement of regional function and blood flow until after 4 weeks. A second limitation has been the use of the canine model of ameroid coronary artery constriction.¹⁰⁰ Because collateral systems are so well developed in the canine model, it is difficult to obtain a steady-state period of chronic myocardial ischemia. For example, in the study by Canty and Klocke¹⁰¹ examining ameroid-induced coronary occlusion in dogs, no absolute reduction in regional function could be demonstrated in the ameroid-dependent zone.

Recently, Shen and Vatner¹⁰² investigated the effects of ameroid coronary constriction in the pig. Measurements of regional MBF and function were performed both in the ameroid-dependent as well as in the nonischemic zone. Other key features of that study were the documentation that the constricted coronary artery remained patent, the absence of significant myocardial infarction (another potential problem in the porcine ameroid model), the daily measurement of regional myocardial function, and full documentation that collateralization was not complete. Under these conditions, a 56% decrease in regional myocardial function was observed in the collateral-dependent region, suggestive of severe chronic myocardial ischemia. However, when regional blood flow was measured at the same sites with radioactive microspheres, there was no significant reduction in blood flow. Thus, the myocardium distal to the ameroid was characterized by many features of hibernating myocardium, ie, chronically and severely reduced contractile function distal to a coronary stenosis in the absence of infarction and clear inotropic reserve in response to isoproterenol and histological evidence characteristic of hibernating myocardium,¹⁰³ but it did not demonstrate a reduction in MBF. Rather, multiple episodes of myocardial stunning were observed in response to spontaneous increases in activity and agitation. This supports the hypothesis derived from previous human studies²⁰ that myocardial hibernation may in fact be the culmination of multiple episodes of myocardial stunning. However, it is important to note that the studies by Shen et al,^{102 103} used a chronic model of only 3 to 4 weeks' duration, far less time than the clinical situation of chronic CAD-induced dysfunction albeit sufficiently long to simulate the development of hibernation using the correct zoological definition. More recent studies by McFalls et al⁹⁸ in pigs with stenosis for 5 weeks and Gerber et al¹⁰⁴ in dogs with chronically reduced regional function after 6 months of chronic coronary stenosis also demonstrated no significant reduction in regional MBF.

	Conclusions

Top Introduction Historical Background Hibernating Myocardium: Current... Conclusions References

 
There is consensus that regional and global ventricular function in patients with CAD can improve after revascularization. With regard to the speed of functional recovery after revascularization, there is evidence supporting both immediate and delayed recovery. As we discussed previously, heterogeneity among patients and within the hearts of individual patients in addition to the lack of uniformity of the study protocol can contribute to the speed of recovery. It is generally agreed that there is no substantial tissue necrosis, which is consistent with the recovery of function, although pathognomonic morphological changes have been demonstrated. It is also generally agreed that there is a residual contractile reserve, which is also consistent with the recovery of function and absence of necrosis.

Altogether, there is little evidence to support the hypothesis that baseline blood flow is reduced by an amount sufficient to be responsible for the impaired function. Human studies have demonstrated that if there is a reduction in transmural flow in hibernating segments, it is modest at best and is within the range of flows obtainable in normal human subjects. This view is supported by the lack of animal models demonstrating chronically reduced blood flow of sufficient magnitude to account for the functional impairment distal to a chronic coronary stenosis. One unifying feature emanating from most animal and human studies is the demonstration that chronically dysfunctional myocardium is characterized by a severe impairment of coronary vasodilator reserve. Under these circumstances, any increase in cardiac workload above baseline conditions cannot be met by an adequate increase in MBF, thus leading to myocardial ischemia, albeit this may often be painless.¹⁰⁵ It is likely that in patients with severe CAD, the limited flow reserve leads to the development of myocardial ischemia even for small increases of oxygen demand, such as those associated with ordinary daily activities. Therefore, regardless of the blood flow level under baseline conditions, these patients logically will develop ischemia when oxygen demand is increased. From this premise, it follows that these episodes of ischemia, which might be frequent, will be followed by periods of postischemic stunning and that the final effect could be cumulative. However, the concept of repetitive stunning resulting in chronic dysfunction, suggested as a possibility years ago by Braunwald and Kloner¹⁰⁶ and more recently by Bolli,¹⁰⁷ has never been tested systematically, although experimental support for this point of view does exist.¹⁰⁸ Under these conditions, coronary revascularization will restore flow reserve and alleviate the chronic ischemic dysfunction.

Therefore, the term hibernating myocardium aptly describes chronic reversible left ventricular dysfunction due to CAD. However, this condition is not necessarily associated with a reduced baseline blood flow but is characterized by impairment of coronary vasodilator reserve.

	Selected Abbreviations and Acronyms

 

CAD = coronary artery disease FDG = 18F-fluorodeoxyglucose MBF = myocardial blood flow PET = positron emission tomography

	Acknowledgments

 
The stimulus for this review was a meeting held at the CIBA Foundation in London on October 9, 1995. The meeting was jointly sponsored by the European Community Concerted Action on "Positron Emission Tomography investigations of cellular regeneration and degeneration" and by the Working Group on Coronary Circulation of the European Society of Cardiology.

	References

Top Introduction Historical Background Hibernating Myocardium: Current... Conclusions References

 
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