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Cardiovascular Research 1997 36(3):301-309; doi:10.1016/S0008-6363(97)00125-9
© 1997 by European Society of Cardiology
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Copyright © 1997, European Society of Cardiology

‘Myocardial hibernation’—questions and controversies1

Gerd Heuscha,*, Roberto Ferrarib, David J Hearsec, Tom J.C Ruigrokd and Rainer Schulza

aDepartment of Pathophysiology, University of Essen, Essen, Germany
bCentro di Fisiopatologia Cardiovascolare, Universita degli Studi di Brescia, Brescia, Italy
cThe Rayne Institute, St. Thomas' Hospital, London, UK
dHeart Lung Institute Utrecht and Interuniversity Cardiology Institute of the Netherlands, Utrecht, Netherlands

* Corresponding author. Abteilung für Pathophysiologie, Zentrum für Innere Medizin, Universitätsklinikum Essen, Hufelandstraße 55, 45122 Essen, Germany. Tel.: +49 (201) 7234480; fax: +49 (201) 7234481.

Received 9 September 1996; accepted 5 December 1996

KEYWORDS Hibernation; Myocardial ischemia; Contractile function


   1 What is hibernation?
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 1 What is hibernation?
2 Why is hibernation...
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The term ‘hibernation’ has been borrowed from zoology and implies an adaptive reduction of energy expenditure through reduced activity in a situation of reduced energy supply. In the context of coronary artery disease, myocardial hibernation was originally seen as a chronic, adaptive reduction of myocardial contractile function in response to a reduction of myocardial blood flow. It was also viewed as a condition where there would be a complete recovery of contractile function upon restoration of flow. Thus, in the concept of myocardial hibernation, the observed chronic reduction of myocardial contractile function was not regarded as the result of a persistent energetic deficit, but instead as a regulatory event which acted to avoid an ongoing energy deficit and thereby maintain myocardial integrity and viability.

The concept of myocardial hibernation did not originate in the laboratory, instead it was entirely founded on clinical grounds when, in the early eighties, Rahimtoola reviewed the results of coronary bypass surgery trials and identified a subset of patients with coronary artery disease and chronic left ventricular dysfunction that improved upon revascularization [1, 2]. Rahimtoola then popularized the term ‘hibernation’ previously coined by Diamond et al. [3]. Whereas originally the idea of an adaptive reduction of contractile function in response to a reduction in blood flow was straightforward and simple, the situation of chronic, yet reversible contractile dysfunction in the setting of coronary artery disease is now recognized to be enormously complex and controversial. The aim of this article is not to give definite answers to any questions, but rather to identify the most pressing questions and controversies in the field of hibernation.


   2 Why is hibernation important?
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 1 What is hibernation?
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The introduction of the concept of hibernation has challenged the traditional view that the extent of chronic contractile dysfunction reflects the amount of infarcted tissue. In hibernation, preservation of viability rather than the occurrence of necrosis accounts for the observed reduction in function. In view of the preserved viability, hibernation is a key issue in assessing the potential benefit from reperfusion/revascularization. Hibernating myocardium must be recognized and identified by appropriate diagnostic procedures and requires decisions by the responsible cardiologist for the selection of patients who will benefit from interventional reperfusion or surgical revascularization. Of course, hibernation is only one of several important aspects which must be considered in the selection of patients who will benefit from reperfusion or revascularization, and many patients with coronary artery disease and no evidence of hibernating myocardium will also benefit.


   3 What are the most pressing questions about hibernation?
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 1 What is hibernation?
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As mentioned above, the concept of chronic, yet reversible contractile dysfunction in the setting of coronary artery disease is now recognized as a complex and controversial scenario, and 10 key questions about hibernation will be discussed, but not necessarily answered in the following sections.

3.1 Does hibernation necessarily require a reduction of coronary flow?
When proposing the concept of hibernation, Rahimtoola reasonably assumed that the observed reduction of contractile function that recovered upon revascularization must have reflected a situation where there has been a reduction in resting blood flow [1, 2]. Experimental studies demonstrated a proportionate reduction in regional myocardial blood flow and contractile function in response to graded reductions in coronary flow in dog hearts which maintained viability during acute [4]and subacute ischemia [5]. On the basis of these studies John Ross introduced the concept of perfusion–contraction matching, and this was rapidly assumed to be the basis of hibernating myocardium [6]. The regulatory nature of perfusion–contraction matching was subsequently demonstrated by the recovery of aerobic myocardial metabolism during an ongoing period of flow reduction [7–9]. However, it should be noted that, different from the clinical situation, all experimental studies demonstrating perfusion–contraction matching have thus far been limited to observation periods of no more than 5 hours. Ross therefore proposed that it would be wise to make the distinction between ‘short-term’ hibernation, as observed in the experimental setting, versus ‘long-term’ hibernation, as seen in the clinical setting. Whereas perfusion–contraction matching of resting flow and function in short-term hibernation is unequivocal, the existence of this phenomenon in long-term hibernation is, as yet, unproven and cannot necessarily be assumed to exist.

There are only a few experimental studies that have attempted to investigate the nature of the transition process from short-term hibernation to long-term hibernation by subjecting swine or dogs to either a prolonged partial coronary artery stenosis [10–15]or a progressive narrowing of the coronary artery until complete occlusion using an ameroid constrictor [16–18]. Unfortunately, in none of these studies were regional myocardial flow and function continuously monitored and, more importantly, the recovery of function following the restoration of blood flow was demonstrated in only 3 studies [13, 15, 16]. When resting regional myocardial blood flow was measured in the above studies [12–14, 17, 18], it was found to be either reduced at the beginning [12, 13]and the end of the period of stenosis [12, 13, 18]or was normal [17]or almost normal at the beginning and the end of the period of stenosis [14]. However, the important observation was made, that at normal or almost normal resting blood flow, coronary reserve was consistently impaired [12, 14, 16–18]and, as a consequence, repetitive episodes of stress- or exercise-induced ischemia were likely to occur against this background of ‘normal’ flow [17]. In a study using chronically instrumented, conscious dogs equipped with an ameroid constrictor, the reduction in regional function exceeded that of regional blood flow before ameroid closure—supporting the idea of repetitive stunning—but following ameroid closure flow and function became more closely coupled and finally both returned towards control values [16].

Thus, in the experimental studies that did employ longer periods of contractile dysfunction there was no conclusive evidence for the maintenance of the perfusion–contraction matching phenomenon. However, with impaired coronary reserve it is assumed that at least some episodes of compromised blood supply occur, although this has not yet been systematically demonstrated.

Early qualitative studies have shown that, in patients with chronic regional contractile dysfunction which subsequently improved upon reperfusion/revascularization, there was a reduced regional myocardial blood flow at rest, as indicated by thallium scintigraphy [19]or positron emission tomography (PET) of 13NH3 [20, 21]. More recently, quantitative measurements of regional myocardial blood flow from PET studies using either 13NH3 [22–25]or H215O [26–29]have been reported in patients with hibernating myocardium. In such studies, resting blood flow was reduced by 19% [22], 33% [23], 27% [25], 21% [28], and 24% [29], respectively, but in another study flow was reduced by only about 5% [27], a flow reduction that appeared to be disproportionally small when compared to the observed reduction in regional contractile function, and in one study it was not reduced at all [24]. In seeking to reconcile these observations with existing concepts and recognizing that PET is the only available method to measure absolute regional myocardial blood flow in humans, it should be stressed that PET has significant limitations. Apart from the high costs and limited availability, PET can only provide an instantaneous flow estimate at a given moment in time, and it also lacks sufficient spatial resolution to resolve transmural differences in blood flow [30]. As a consequence, an observed 10–20% reduction in transmural blood flow in regions with chronic contractile dysfunction could well translate to a reduction in subendocardial blood flow as great as 40% [31], and subendocardial blood is the primary determinant of transmural wall function [31].Thus, although there is no clinical evidence to support the concept of perfusion–contraction matching of resting flow and function in the hibernating heart, the methodological power required to deny its existence is clearly not available.

Irrespective of whether resting blood flow is reduced or even whether it is reduced in proportion to the reduction in function, all available studies do agree that for hibernation to develop, blood flow must eventually be reduced, either persistently at rest or occasionally during stress. Thus, in attempting to answer the first question it would appear to us that in terms of myocardial blood flow and its distribution, the hibernating human heart, in contrast to many animal models, is likely to be in a highly dynamic state such that, at times, flow (as visualized by current technology) may appear to be near normal. However, looked at over a wider time frame, we believe that there must be periods when the delivery of flow will be insufficient to meet demand. This could, of course, occur by flow falling below its resting level or failing to increase because of an inadequate coronary reserve.

3.2 If hibernation involves a limitation of flow, does it induce ‘ischemia’?
If, as argued in the preceding paragraph, coronary flow in the hibernating heart fails to meet ‘demand’ under either resting or stress conditions, then it is of interest to ask whether we can designate the hibernating myocardium as an ‘ischemic’ syndrome? The answer to this superficially simple question requires a clear definition of ischemia, but surprisingly ischemia does not appear to have a clear definition and, as such, adds to the controversy over the nature of hibernation. In an attempt to address this problem, Hearse [32]invited 31 eminent cardiologists—all of whom were experts in ischemia—to provide a brief definitive definition of ischemia. The result was a multitude of differing and sometimes conflicting suggestions which ranged from just a few words to several hundred words in length! Of particular relevance to the present article, the definitions failed to provide a consensus on whether the hibernating myocardium should or should not be designated as ‘ischemic’.

In an attempt to draw together all the key elements of the various definitions into a unifying definition that would allow us to determine whether hibernation involved ischemia, Hearse [32]proposed that a fundamental distinction should be made between physiological and biochemical ischemia. He approached this by contrasting the effects of coronary flow restriction on the physiological function of the heart and the way in which, as an organ, it maintains the function and survival of the animal as a whole, versus the consequences of coronary flow restriction on the internal function and survival of the cardiac tissue, irrespective of any systemic consequences.

In biochemical ischemia, possibly in response to a series of complex and dominantly extracardiac neurohormonal signals (designed to ensure the maintenance of physiological cardiac pump function) the myocardium will transiently, at its own cost, endeavour to maintain contractile function despite an impairment of coronary supply. This failure of perfusion–contraction matching will result in the energy supply failing to match energy consumption and, as a consequence, cellular equilibrium (steady-state metabolism) will be sacrificed and this will initiate a cascade of increasingly severe metabolic perturbations. The cell will become metabolically distressed, and, unless interrupted by early reperfusion, this biochemical ischemia will inevitably progress towards cell death. If, as many believe, the hibernating myocardium does maintain perfusion–contraction matching such that metabolism maintains a steady state, thereby avoiding the biochemical signs of ischemia (such as lactate production and energy depletion) it cannot be designated as biochemically ischemic. However, Hearse [32]argued that such myocardium could be considered as physiologically ischemic in the sense that, as a consequence of some flow reduction, it is unable to maintain contractile function over the normal physiological range. In physiological ischemia, conservative adaptive responses inherent in perfusion–contraction matching manage to remain dominant over extracardiac signals which would promote contractile function at the cost of inducing biochemical ischemia.

Thus, in attempting to answer the question of this section, it would seem that the hibernating myocardium, at least most of the time, may not be biochemically ischemic, but will be physiologically ischemic.

3.3 How does hibernation develop, and does there have to be a ‘trigger’?
Unfortunately, data on possible factors determining the development of hibernation are only available from experimental studies on short-term hibernation. However, these findings should be of some use since long-term hibernation may have originated from an initial short-term hibernation. In reviewing experimental studies of short-term hibernation a number of common features emerge, in particular the possibility that some transient triggering event may be necessary to predispose a heart to hibernate during a period of flow reduction. The nature and importance of such a trigger is, however, controversial.

A hibernation-like metabolic adaptation to a severe sustained (4 hours) low-flow ischemia was recently reported in studies with isolated buffer-perfused rabbit hearts in which there was a preceding short episode (10 min) of no-flow ischemia [33]. In these hearts, the early decline in contractile function was more pronounced and significantly faster than in control hearts that did not have the brief episode of no-flow ischemia. The rapid decline in contractile function during the brief episode of no-flow ischemia was accompanied by a greater decrease in interstitial [33]and intracellular [34]pH, and the contractile quiescence was attributed to a faster development of myocardial acidosis. Interestingly, interstitial [33]and intracellular [34]pH during the subsequent low-flow ischemia remained mildly reduced whereas these pH values were markedly decreased when low-flow ischemia was not preceded by no-flow ischemia. During reperfusion following the sustained ischemia, only a transient creatine kinase release occurred in the hearts with preceding no-flow ischemia. On the basis of these findings the authors proposed that the development of myocardial hibernation requires an initial period of no-flow ischemia, during which the rapid decrease in interstitial [33]and intracellular [34]pH initiate the decrease in contractile function and facilitate the restoration of the balance between energy supply and energy demand. In other studies, in anesthetized swine hearts in situ, infarct size arising as a consequence of sustained (90 min) low-flow ischemia was reduced from 13.2±9.8 to 6.8±6.0% by a short (10 min) period of no-flow ischemia immediately before the sustained ischemia [35]. A reduction in infarct size was also achieved by a 70% reduction in inflow for 30 min preceding 60 min total coronary artery occlusion [36]. The experimental studies described thus far attribute a potentially important role to an initial stimulus of severe ischemia as being critical to ‘triggering’ the development of a protective state with preserved viability during a subsequent period of sustained ischemia. Whether or not such an initial stimulus/‘trigger’ of severe ischemia represents a mandatory link between hibernation and ischemic preconditioning is unclear at present [37].

A few other studies suggested that the development of hibernation does not require a critical trigger. In anesthetized pigs a gradual slow reduction of coronary arterial inflow resulted in decreased regional contractile function, but with minimal lactate production and no decrease in the ratio of subendocardial creatine phosphate to ATP [38]. Also in anesthetized pigs, coronary venous pH and pCO2 were better preserved and lactate production and infarct size were reduced when a sustained severe ischemia was preceded by a slowly and continuously increasing severity of flow reduction [39].

There clearly needs to be much more investigation on the requirement and nature of triggering events, especially in more chronic models of hibernation.

3.4 What is the prevalence of hibernation and why isn't it more common?
One thing is clear: not all hearts that are subjected to a restriction of coronary flow are able to survive and recover. This raises the question: if perfusion–contraction matching is the basis of hibernation, why don't all ischemic hearts hibernate—at least for a while? Could it be the absence of the ‘trigger’ discussed in the previous section? What is the prevalence of hibernation in the human heart?

Not surprisingly, data on the incidence of hibernating myocardium in coronary artery disease patients are scanty. This is primarily due to the fact that the concept is relatively new and is not even unanimously accepted. Those groups which are more active and believers in the field have developed their own, personalized diagnostic and therapeutic approach, and the harder you look the more you are likely to find. However, diagnosis alone is not sufficient to confirm the incidence of hibernation, since it should always be confirmed retrospectively by a documented improvement in ventricular function after revascularization. Unfortunately, unless and until validated, standardized procedures for the recognition of dysfunctional but still viable myocardium are made routinely available, it is likely to be almost impossible to obtain data on the rate of occurrence and the relevance of hibernation in coronary artery disease patients.

Established diagnostic tests for the identification of hibernating myocardium are particularly the demonstration of a mismatch between reduced flow and enhanced glucose uptake using PET techniques [40, 41]and dobutamine echocardiography [42, 43]. Whereas a positive low-dose dobutamine test is a good predictor of functional recovery upon revascularization, a negative dobutamine test does not exclude the existence of hibernation as the associated loss of myofibrils will also induce a loss of inotropic reserve [24]. Other tests for hibernating myocardium are based on the uptake and retention of nuclear tracers such as thallium and sestamibi [44–46]. Sestamibi scintigraphy and histological evidence of viability correlate well (r = 0.89) [47].

With the above caveats in mind, from the existing data, it appears that hibernation may be more common in unstable than in stable angina [2]. In patients studied 5–21 days after an acute myocardial infarction, 78% had perfusion–metabolism mismatch in at least one myocardial area on PET scanning, indicative of hibernating myocardium [48]. Likewise, 69% of patients with an acute myocardial infarction had a further reduction in the perfusion deficit using sestamibi tomography between 5 weeks and 7 months after the infarction, associated with improved wall motion and suggestive of hibernating myocardium [49].

About 11% of the patients referred for cardiac transplantation have been suggested to have hibernating myocardium [50, 51]. In a group of 50 coronary bypass surgery candidates with a severe LAD stenosis or occlusion with or without regional dysfunction, a principal component analysis identified 18 patients (i.e., 36%) with hibernating myocardium, characterized by low regional ejection fraction, moderately decreased resting flow, normal FDG uptake and, most importantly, significant recovery after revascularization [23]. In a total of 635 patients screened over 5 years, 165 had signs of viability on the basis of rest thallium-201 redistribution. Of these, only 55 had a positive low-dose dobutamine test; this would suggest an incidence of 8.6% (Ferrari, personal communication).

The available data on the prevalence of hibernation vary substantially. It is possible that the awareness of the possible existence of the phenomenon as well as the eventual availability of simple standard methods for its identification will prove that hibernation is more common than currently recognized. Certainly, at the present time, it is easier to miss than to find it!

3.5 What is known about the mechanism(s) of hibernation?
The mechanisms responsible for the development and maintenance of hibernation are entirely unclear at present. In experimental models of short-term hibernation, alterations in β-adrenoceptor density or affinity appear to be unimportant [52]. The same applies to activation of ATP-dependent potassium channels and increases in the concentration of interstitial adenosine. This conclusion is based on the observation that the ATP-dependent potassium channel blocker, glibenclamide, and also the increased catabolism of adenosine by intracoronary infusion of adenosine deaminase, failed to alter the characteristics of short-term hibernation, including perfusion–contraction matching, recovery of metabolic parameters, inotropic responsiveness, and the maintenance of myocardial viability [53]. It is not surprising that, in the search for possible mechanisms of hibernation, attention has been directed to calcium. In isolated buffer-perfused ferret hearts moderately decreased coronary perfusion results in decreased calcium transients and decreased contractile force without any change in high-energy phosphates [54]. In addition, overall calcium responsiveness of short-term hibernating myocardium in anesthetized pigs has been shown to be substantially reduced; however, this reduction is essentially attributable to a decrease in maximal developed force rather than to any decrease in calcium sensitivity [55].

Possible progression of short-term hibernation into long-term hibernation has been studied in a number of experimental preparations [10–15, 17, 18]. Whereas resting blood flow in the setting of chronic contractile dysfunction was normal [17]or almost normal [14], coronary reserve was consistently impaired [14, 17]. Encouragingly, this scenario resembles that seen in the clinical situation where the extent of reduction in contractile function may be out of proportion to the modest reduction in transmural blood flow at rest [22, 27]and where coronary reserve is also reduced [22, 27]. On the basis of such findings it has been proposed that hibernation is not an adaptive reduction of contractile function in response to a reduction of resting blood flow, as originally proposed by Rahimtoola, but rather it is the result of repetitive episodes of stress- or exercise-induced ischemia which cause repetitive and therefore chronic stunning [17, 22, 27]. However, it should be borne in mind that in none of the above experimental or clinical studies was flow or function continuously monitored to provide evidence for repetitive stunning. Episodes of stress-induced ischemia with subsequent stunning have so far been reported in only one experimental study in the pig, but even there not followed up systematically [17]. A study which successfully induced the phenotype of hibernation as a consequence of multiple controlled episodes of ischemia/reperfusion has not yet been reported.

Thus, to date, all available studies on potential mechanisms of short-term hibernation are negative, in the sense that no clearly defined mechanisms have been identified. However, from these studies has come the intriguing but highly controversial suggestion that hibernation is the product of repetitive stunning [57]. The attractive component of this concept is that it accommodates the situation of abnormal contraction in the face of near-normal coronary flow. Although this proposal is largely inferential, it is essential that it and the accompanying controversy be resolved. This is because it challenges the concept that hibernation is a well regulated adaptive phenomenon and repositions it as a pathological condition where metabolism is not in steady state, but subjected to alternating metabolic distress and partial recovery.

3.6 What does morphology tell us about hibernation?
As with studies of metabolism and function, morphology adds its contribution to the controversy over the nature of hibernation. Systematic morphological investigations, other than those indicating a lack of infarction, do not exist for models of short-term hibernation. In more long-term hibernation, however, morphological changes have been reported. With 24 hours partial coronary artery stenosis in pigs, the number of myofibrils was reduced while mitochondria and glycogen deposits were increased; these alterations were reversed 7 days after release of the stenosis [15]. Using myocardial biopsies from patients with prolonged contractile dysfunction that was reversed by bypass surgery, thin filament complexes and titin have been shown to be reduced and the remaining myofibrils, as well as the sarcoplasmic reticulum, disorganized. Numerous small ‘doughnut’-like mitochondria have been observed [58, 59]. Intracellular glycogen content appeared to be increased and extracellular matrix proteins (such as desmin, tubulin and vinculin) accumulated [58, 59]. Up to a certain degree of severity these degenerative alterations appear to be reversible [59]. In addition to such degenerative changes, particularly interesting changes in the distribution of titin and cardiotin have been observed, and it has been claimed that these changes reflect an embryonic phenotype pattern [60]. This, together with the expression of alpha-smooth muscle actin in hibernating myocardium has been suggested to represent hibernation-induced dedifferentiation of cardiomyocytes [60]. Thus, it is currently unclear whether the morphological changes seen in hibernating myocardium reflect adaptive atrophy such as occurs in any quiescent muscle (which might bring with it dedifferentiation and an embryonic phenotype pattern) or whether the observed changes reflect degenerative, pathological and possibly irreversible events. To resolve these questions, rigorous morphometric analyses are required that account for the undoubted heterogeneity of the tissue under study. Moreover, there is an obvious need for prospective studies of tissue taken before, during and after hibernation, and this can obviously only be performed in animal experiments.

3.7 What is known about recovery from hibernation?
This aspect of hibernation is also characterized by confusion and controversy with claim, that upon revascularization/reperfusion functional recovery may be instantaneous, rapid or very slow [61].

In a model of short-term hibernation employing the isolated, buffer-perfused rabbit heart, recovery of function has been shown to be immediate and almost complete within minutes of reperfusion [33]. In contrast, in anesthetized pigs [39, 55]with short-term hibernation, reperfusion is associated with severe stunning and no recovery of function was observed within the first 30 min [55]or even 2 hours [39]of reperfusion. In other studies, in conscious dogs in which a coronary stenosis was maintained for 5 hours [5], and also in anesthetized pigs with a coronary stenosis for 24 hours [13, 15], severe stunning was observed with full recovery of function requiring 7 days. Once again, there are no experimental data on recovery from long-term hibernation.

In patients with hibernating myocardium, the recovery of contractile function after restoration of blood flow can also be rapid [42, 62], subacute [23, 63]or chronic [61]. However, as pointed out by Camici et al. [56], the situation is complicated by the fact that the various clinical studies involved patients both with and without prior myocardial infarction, they used different methods to assess regional contractile function, they provided only the instantaneous function data at defined time points following reperfusion, and in most instances did not demonstrate adequate restoration of blood flow. Apart from such methodological considerations, the different recovery profiles might be related to the extent of morphological alterations and the selection procedure for identifying patients with hibernating myocardium. It is obvious that an immediate return of function can only be expected in the absence of morphological alterations, in particular in the absence of a loss of myofibrils. Conversely, with severe morphological alterations, structural repair will have to precede functional recovery and therefore it will require substantial time [58]. An appropriate selection procedure, in particular a positive inotropic response to a dobutamine challenge, will identify patients with hibernating myocardium and little loss of myofibrils who are therefore expected to show a fast recovery [42]. In that respect, dobutamine echocardiography has a higher specificity for functional recovery than scintigraphic techniques or PET which assess myocardial viability.

Whilst there is no consensus on the rate of recovery from hibernation, this is not unexpected since there are at least two key variables that would be expected to influence recovery greatly. These are the severity of flow reduction and the duration for which that flow reduction is maintained. Certainly, it is well established that the severity and duration of stunning are related to the severity and duration of antecedent ischemia [64]. Although hibernation might not involve ischemia in the classical sense, it is likely to involve the establishment of new steady-state conditions, the nature of which might determine the time-course for the restoration of normal metabolism and function upon the restoration of normal flow. The duration of hibernation must also be a factor in determining the rate of recovery. If hibernation results in either chronic adaptive or degenerative changes of muscle structure, the recovery from such chronic changes must take time. It would seem that clarification of the recovery issue will only be available when a number of detailed and careful studies of the above variables have been completed.

3.8 How good are current animal models of hibernation?
There is probably one clear consensus in the hibernation field, namely that we have a clinical phenomenon in search of an experimental model—such is its complexity.

Apart from the reductionist approach that characterizes each experimental model of a clinical condition, the available models of myocardial hibernation would seem to be very far (possibly too far) from the clinical scenario. Almost by definition, experimental models with quiescent isolated cardiomyocytes are inappropriate for the study of hibernation. Perhaps for this reason, the isolated perfused heart has become the ‘lowest acceptable denominator’ of hibernation research. The limitations of this preparation are, of course, well known. It is denervated and free of extracardiac hormonal stimuli, often perfused with buffer, has suffered surgical trauma and (at least in hibernation studies) is usually globally rather than regionally ischemic.

The isolated heart preparation, in common with most large animal in situ models, shares the limitation of short observation periods. While this limited observation period is clearly a major disadvantage when trying to understand long-term chronic hibernation, such acute models may nonetheless be useful in studying the initial, ‘triggering’ events and the underlying mechanisms for the development of hibernation. Furthermore, such acute models may provide useful information with respect to the potential preservation of viability in evolving myocardial infarction.

The use of whole hearts in situ rather then isolated hearts has major implications in terms of cost, investigational time and complexity. Are the costs overweighed by the benefits?

Even in conscious, chronically instrumented animals, the time-frame for the study of coronary stenosis/hypoperfusion has thus far been limited to a maximum of 32 weeks [12], a time that clearly falls short of the duration of hibernation in human hearts. Also, despite the advantages of large in situ hearts, in no study thus far have myocardial blood flow and function been continuously monitored and related, and in only 3 studies (one with 5 hours and two with 24 hours hypoperfusion) has the recovery of function following reperfusion been documented [5, 13, 15].

We do not underestimate the difficulties, but ideally any model of hibernation should use conscious, chronically instrumented animals with a coronary stenosis inducing a regional limitation of flow, it should allow continuous monitoring of flow and function, it should demonstrate recovery of function following removal of the stenosis, and it should provide data over months and years. Certainly this is an ambitious, but (perhaps) a possible endeavour and may be the only means of truly understanding hibernation in its clinical sense.

3.9 What is the role of pharmacology in hibernation?
Some may say that hibernation is a simple problem of ‘plumbing’ and, as such, should be dealt with by a ‘plumber’ (otherwise known as a surgeon or interventional cardiologist). However, this may be a defeatist attitude, particularly at the dawn of the era of cardiac gene therapy. However, without available knowledge of the mechanisms of hibernation (see above), there can be no rational pharmacotherapy. At this time, it is paradoxically unclear whether the pharmacologist should seek to overcome hibernation or to mimic it. Possibly a drug could be developed to induce or reinforce hibernation so as to preserve myocardial viability, as it were a ‘cardioplegia-mimetic’.

To date, inotropic stimulation, other than for diagnostic purposes, has not been studied in patients with hibernation or in models of long-term hibernation. However, any prolonged inotropic stimulation will probably be detrimental [52], regardless of whether the hibernating myocardium has persistently reduced blood flow and cannot meet the enhanced energy demand associated with inotropic stimulation or whether the hibernating myocardium has only reduced coronary reserve and ischemia is induced by inotropic stimulation.

If the hibernating myocardium is characterized by a reduced resting flow, any increase in blood flow would be expected to attenuate contractile dysfunction. Indeed, a positive response of contractile function to nitroglycerine was part of the original description of hibernation by Rahimtoola [1, 2]. If, however, the hibernating myocardium has normal resting flow, then an increase in flow might not necessarily improve contractile function [65]. Under such circumstances, substances that attenuate exercise-induced ischemia might alleviate cumulative stunning, but once again, none of these hypotheses has yet been studied experimentally or clinically. The need is clear: more studies with better models.

3.10 Could diagnosis of hibernation avoid unnecessary heart transplantation?
In patients with coronary artery disease, cardiomyopathy is a primary indication for heart transplantation, accounting for 40–50% of transplantations performed [66, 67]. Due to the severe shortage of donor hearts, only 10% of eligible patients will undergo transplantation. The others have a high mortality despite aggressive medical therapy, 2-year survival being only 31% [68].

In view of this situation it is not surprising that myocardial revascularization has often been offered before heart transplantation for patients with severe ischemic cardiomyopathy. Cardiac surgeons, however, remain concerned when a patient undergoing coronary revascularization has an ejection fraction of less than 30% and symptoms of heart failure without angina [69]. They complain about lack of criteria to predict which patient will benefit from reperfusion.

Knowing that a large portion of dysfunctional myocardium is viable rather than fibrotic and has the potential of functional recovery upon reperfusion, has shed a completely new light on the entire issue. Low ejection fraction is no longer a prognostic indicator of survival. On the contrary, often a significant survival benefit after surgical revascularization occurs only for patients with severely impaired ejection fraction [70]—the worse you are, the better you get!.

The indication for revascularization is not limited to the presence of angina pectoris or inducible ischemia, but also extends to those with signs of heart failure such as dyspnea. These are indeed the patients on the waiting list for transplantation!

At present, in the absence of large randomized trials, we can only say that coronary revascularization may be performed in selected patients with severe ischemic cardiomyopathy awaiting transplantation. Operative mortality is acceptable and 3-year survival is comparable to that achieved for heart transplant patients [50]. The best predictor for successful reperfusion seems to be a left ventricular end-diastolic pressure of less than 10 mmHg and a PET scan demonstrating evidence of viability. Demonstration of a contractile reserve with dobutamine echocardiography seems to be an excellent predictor of operative risk and early recovery of function after surgery [42].


   4 Where do we go from here?
Top
 1 What is hibernation?
 2 Why is hibernation...
 3 What are the...
 4 Where do we...
References
 
To resolve the above questions and controversies, we undoubtedly need more research, and this must involve developing better ideas, better experimental models and controlled clinical trials with the establishment of a registry and database. Obviously, to perform more and better research we need more research funding. However, we must also concede that some of the problems and controversies may be of our own making. Lack of agreement can arise from laboratory scientists using experimental models that do not adequately mimic the clinical situation. Likewise, problems can arise from clinicians using physiological measurements without considering their methodological limitations. The answer is clear—better communication and collaboration between basic scientists and clinicians. In this way, hibernation research will be improved. Meaningful national and international collaboration will also help and should be fostered and, in this connection, we are grateful to the EU Biomed II Concerted Action program for providing a grant on the ‘New Ischemic Syndromes’ and thus a platform for the present interaction between basic scientists and clinicians at an international level.

Time for primary review 44 days.


   Acknowledgements
 
We thank the other members of the EU Biomed II Concerted Action ‘New Ischemic Syndromes’ (C. Ceconi, M. Galinanes, D. Garcia-Dorado, C. Guarnieri, S. Haunsø, D. Kremastinos, J.W. de Jong, P. Menasché, M. Ovize, H.M. Piper, P.A. Poole-Wilson, K. Schwartz, P. Verdouw, D. Yellon) for their comments and suggestions.


   Notes
 
1 On behalf of participants of the EEC Biomed Concerted Action "The New Ischaemic Syndromes". Back


   References
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