'Myocardial hibernation'—questions and controversies

Time for primary review 44 days. 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. 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. 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. 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. 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 of The will and, by early this biochemical ischemia will towards If, as many the hibernating myocardium does maintain perfusion–contraction matching such that metabolism maintains a thereby the biochemical of ischemia as and energy it cannot be designated as However, Hearse that such myocardium could be considered as in the that, as a of some flow it is to maintain contractile function over the normal physiological In physiological ischemia, adaptive in perfusion–contraction matching to over extracardiac signals which would contractile function at the of biochemical ischemia. Thus, in attempting to answer the question of this it would that the hibernating at least most of the time, may not be but will be Unfortunately, on the of hibernation are only available from experimental studies on short-term hibernation. However, these should be of some long-term hibernation may have from an short-term hibernation. In experimental studies of short-term hibernation a of in particular the that some event may be to a heart to during a period of flow The nature and of such a is, controversial. to a ischemia was reported in studies with hearts in which there was a preceding of ischemia In these the early in contractile function was more and than in control hearts that did not have the brief of ischemia. The in contractile function during the brief of ischemia was by a in and the contractile was to a of myocardial during the ischemia reduced these values were when ischemia was not by ischemia. reperfusion following the ischemia, only a in the hearts with preceding ischemia. On the basis of these the proposed that the of myocardial hibernation requires an period of ischemia, during which the in initiate the in contractile function and the restoration of the between energy supply and energy demand. In studies, in swine hearts in as a of ischemia was reduced from to by a period of ischemia before the ischemia reduction in was also by a reduction in for preceding coronary artery occlusion The experimental studies thus far a important to an of ischemia as to the of a state with preserved viability during a period of ischemia. or not such an of ischemia a between hibernation and is at present few studies that the of hibernation does not a In a reduction of coronary in regional contractile function, but with and no in the of subendocardial to in coronary and were preserved and and were reduced when a ischemia was by a and continuously of flow reduction There clearly to be more on the and nature of in more chronic of hibernation. is not all hearts that are to a restriction of coronary flow are to and This the perfusion–contraction matching is the basis of hibernation, all hearts least for a it be the of the in the is the of hibernation in the human on the of hibernating myocardium in coronary artery disease patients are This is to the that the concept is and is not even which are more and in the field have diagnostic and and the the more are likely to However, is not sufficient to the of hibernation, it should be by a in ventricular function revascularization. Unfortunately, and until procedures for the of but myocardium are made it is likely to be almost to on the of occurrence and the relevance of hibernation in coronary artery disease diagnostic for the of hibernating myocardium are the of a between reduced flow and using PET Whereas a is a of recovery upon revascularization, a does not the existence of hibernation as the of will also a of reserve [24]. for hibernating myocardium are on the and of such as thallium and scintigraphy and evidence of viability well the above in from the existing it that hibernation may be more in than in In patients an acute myocardial in at least one myocardial on PET of hibernating myocardium of patients with an acute myocardial a reduction in the deficit using tomography between 5 and the with improved wall and of hibernating myocardium of the patients for cardiac have been to have hibernating myocardium In a of coronary bypass surgery with a stenosis or occlusion with or regional a identified patients with hibernating by regional resting flow, normal and, most importantly, significant recovery revascularization In a of patients over 5 of viability on the basis of rest Of only a this would an of The available on the of hibernation It is that the of the existence of the phenomenon as well as the of simple for its will that hibernation is more than at the present time, it is to than to The responsible for the and maintenance of hibernation are entirely at In experimental of short-term hibernation, in or appear to be The to of and in the of This is on the observation that the and also the of by of failed to the of short-term hibernation, perfusion–contraction matching, recovery of and the maintenance of myocardial viability It is not that, in the for of hibernation, has been to In hearts coronary results in and contractile any in In of short-term hibernating myocardium in has been shown to be this reduction is to a in rather than to any in of short-term hibernation into long-term hibernation has been in a of experimental 17, Whereas resting blood flow in the setting of chronic contractile dysfunction was normal [17]or almost normal coronary reserve was consistently impaired this that seen in the clinical situation where the extent of reduction in contractile function may be of proportion to the reduction in transmural blood flow at rest where coronary reserve is also reduced On the basis of such 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 but rather it is the result of repetitive episodes of stress- or exercise-induced ischemia which repetitive and therefore chronic However, it should be in that in none of the above experimental or clinical studies was flow or function continuously monitored to provide evidence for repetitive of ischemia with have far been reported in only one experimental study in the but even there not systematically [17]. study which the of hibernation as a of episodes of has not yet been Thus, to all available studies on potential of short-term hibernation are in the that no clearly have been However, from these studies has the but highly controversial that hibernation is the of repetitive The of this concept is that it the situation of in the of coronary flow. this is it is that it and the controversy be This is because it the concept that hibernation is a well adaptive phenomenon and it as a condition where metabolism is not in but to and partial As with studies of metabolism and function, adds its to the controversy over the nature of hibernation. than a of do not for of short-term hibernation. In more long-term hibernation, have been partial coronary artery stenosis in the of was reduced and were these were of the stenosis myocardial from patients with prolonged contractile dysfunction that was by bypass and have been shown to be reduced and the as well as the small have been observed appeared to be and as and to a of these appear to be reversible In to such in the of and have been and it has been that these an together with the of in hibernating myocardium has been to of Thus, it is whether the seen in hibernating myocardium adaptive such as in any with it and an or whether the observed and possibly resolve these questions, are required that for the of the under there is an for studies of during and hibernation, and this can only be in animal This of hibernation is also by and controversy with that upon recovery may be or In a of short-term hibernation the heart, recovery of function has been shown to be and almost complete of reperfusion In in short-term hibernation, reperfusion is with and no recovery of function was observed the first even In studies, in conscious dogs in which a coronary stenosis was maintained for 5 and also in with a coronary stenosis for [13, was observed with recovery of function days. there are no experimental on recovery from long-term hibernation. In patients with hibernating the recovery of contractile function restoration of blood flow can also be subacute chronic However, as by et al. the situation is by the that the various clinical studies involved patients both with and myocardial different to regional contractile function, only the instantaneous function at time following and in most did not restoration of blood flow. Apart from such methodological the different recovery be to the extent of and the selection for patients with hibernating myocardium. It is that an of function can only be in the of in particular in the of a of with will have to recovery and therefore it will time appropriate selection in particular a response to a will identify patients with hibernating myocardium and of who are therefore to a recovery In that has a for recovery than or PET which myocardial viability. there is no consensus on the of recovery from hibernation, this is not there are at least key that would be to recovery are the of flow reduction and the for which that flow reduction is it is well that the and of are to the and of ischemia hibernation not ischemia in the it is likely to the of conditions, the nature of which determine the for the restoration of normal metabolism and function upon the restoration of normal flow. The of hibernation must also be a in the of hibernation results in either chronic adaptive or of the recovery from such chronic must It would that of the recovery issue will only be available when a of and studies of the above have been There is one clear consensus in the hibernation that we have a clinical phenomenon in of an experimental is its Apart from the that experimental of a clinical the available of myocardial hibernation would to be far from the clinical by experimental with are for the study of hibernation. for this the heart has the of hibernation The of this of course, well It is and of extracardiac with has surgical and least in hibernation is rather than The heart in with most animal in models, the of observation this limited observation period is clearly a when to long-term chronic hibernation, such acute may be in the and the for the of hibernation. such acute may provide with to the potential preservation of viability in myocardial The of hearts in rather then hearts has in terms of cost, time and the costs by the in chronically the for the study of coronary has thus far been limited to a of a time that clearly of the of hibernation in human despite the of in in no study thus far have myocardial blood flow and function been continuously monitored and and in only 3 studies with 5 and with has the recovery of function following reperfusion been 13, do not the but any of hibernation should chronically with a coronary stenosis a regional of flow, it should allow of flow and function, it should recovery of function following of the and it should provide over and this is an but a endeavour and may be the only of hibernation in its clinical may that hibernation is a simple of and, as such, should be with by a as a or interventional However, this may be a at the of the of cardiac However, available of the of hibernation there can be no this time, it is whether the should to hibernation or to a could be to or hibernation as to myocardial viability, as it were a than for diagnostic has not been in patients with hibernation or in of long-term hibernation. However, any prolonged will be of whether the hibernating myocardium has persistently reduced blood flow and cannot meet the energy with or whether the hibernating myocardium has only reduced coronary reserve and ischemia is by the hibernating myocardium is by a reduced resting flow, any increase in blood flow would be to contractile a response of contractile function to was of the of hibernation by Rahimtoola [1, 2]. If, the hibernating myocardium has normal resting flow, then an increase in flow not necessarily contractile function such that exercise-induced ischemia but none of these has yet been or The is more studies with In patients with coronary artery disease, is a primary for heart for of to the of only of patients will The have a high despite survival only In view of this situation it is not that myocardial revascularization has been before heart for patients with when a coronary revascularization has an of than and of heart failure about of to which will benefit from that a of myocardium is rather than and has the potential of recovery upon has a on the is no longer a of On the a significant survival benefit surgical revascularization only for patients with impaired the The for revascularization is not limited to the of or ischemia, but also to with of heart failure such as are the patients on the for in the of we can only that coronary revascularization may be in patients with is and survival is to that for heart patients The for reperfusion to be a left ventricular of than 10 and a PET demonstrating evidence of viability. of a contractile reserve with to be an of and early recovery of function surgery resolve the above questions and we more and this must experimental and clinical trials with the of a and to more and we more However, we must also that some of the and controversies may be of own of can from using experimental that do not the clinical can from using physiological measurements methodological limitations. The answer is and between and In this hibernation will be and will also and should be and, in this we are to the for a on the and thus a for the present between and at an the of the for and