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Molecular and Cellular Biochemistry 186: 195–199, 1998.© 1998 Kluwer Academic Publishers. Printed in the Netherlands.

Hibernating myocardium: Its pathophysiologyand clinical role

Roberto Ferrari,1, 2 Federica Ferrari,1 Massimo Benigno,1 Patrizia Pepi1

and Odoardo Visioli1

1Cattedra di Cardiologia, Universita’ degli Studi di Brescia, Brescia; 2Fondazione Clinica del Lavoro, Centro diFisiopatologia Cardiovascolare ‘S. Maugeri’, Gussago, Brescia, Italy

Abstract

Myocardial hibernation, as first defined by Rahimtoola, is a state of chronic contractile dysfunction in patients with coronaryartery disease which is fully reversible upon reperfusion. Clinical conditions consistent with the existence of myocardialhibernation include unstable and stable angina, myocardial infarction heart failure, and anomalous origin of coronary arteries.The mechanisms of hibernation are not known. Morphological alterations have been described in the hibernating area of patients,but these information are strongly affected by the diagnostic criteria utilized to screen patients. It has been postulated thathibernation is an adaptive phenomenon occurring during ischemia. In this context, downregulation of contraction is not regardedas a consequence of energetic deficit, but as a regulatory event aimed at reducing energy expenditure, thereby maintainingintegrity and viability. Thus, hibernation might bear a relationship to the phenomenon of low-flow perfusion-contractionmatching, or repetitive stunning or preconditioning. Clear-cut evidence for the mechanism of hibernation in the clinical settingseems likely to remain elusive, because of the nature of the studies needed to document it. Current experimental evidence supportsthe view that hibernation, stunning, preconditioning, or their coexistence can be responsible for regional myocardial contractiledysfunction which is reversible upon reperfusion. These are all adaptive and protective phenomena independent of theirterminology and strict definitions and do not always apply to the extremely complex situation of myocardial ischemia in man.(Mol Cell Biochem 186: 195–199, 1998)

Key words: hibernating myocardium, myocardial ischemia, heart failure, myocardial viability, ischemic cardiomyopathy

tion does not necessarily mean permanent or irreversible celldamage. Hypoperfused myocytes can remain viable butakinetic. This type of dysfunction has been called ‘hiber-nating myocardium’ [1].

The diagnosis of hibernation is clinically relevant becauseit has therapeutic implications, as regional and global leftventricular function due to hibernation will improve afterrevascularization and it is associated with improved survival[2]. The true clinical gold standard for hibernation is theimprovement in systolic function of dysfunctional myo-cardial segments after revascularization. Such a retrospectivestandard is, however, insufficient. An accurate prospectivediagnosis of patients with potentially reversible left vent-ricular dysfunction is essential for the identification of idealcandidates for revascularization procedures. Thus, the

Address for offprints: R. Ferrari, Cattedra di Cardiologia, Universita’ degli Studi di Brescia, c/o Spedali Civili, P.le Spedali Civili, 1, 25123 Brescia, Italy

Introduction

Differentiation of viable myocardium from non-viablemyocardium in patients with coronary artery disease and leftventricular dysfunction is an issue of clinical relevance in thisage of myocardial revascularization. Impaired left ventricularfunction may occur transiently during an attack of angina andis usually reversible. It may persist over hours or even daysin patients after an episode of ischemia followed by reper-fusion, leading to the so-called condition of ‘stunning’. Inpatients with persistent limitation of coronary flow, leftventricular dysfunction may be present over months or years,or indefinitely in subjects with fibrosis, scar formation andremodeling after myocardial infarction, leading to thesyndrome of heart failure. Chronic left ventricular dysfunc-

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hibernating myocardium poses a series of clinical issue. Thethree fundamental questions are: 1) how and with whataccuracy this entity can be recognized?; 2) how should it bebest treated? and 3) can reperfusion of hibernating myo-cardium be considered an alternative to transplantation?

How hibernating can be explained

The molecular factors responsible for hibernation and for thechronically-depressed contractile function have not yet beendefined. The hypothesized mechanism of a down-regulatedcontractile performance matching the reduced energy supplyis, in part, supported by experimental and clinical studiesusing positron emission tomography (PET). These studiesshow that during prolonged underperfusion metabolism isshifted from FFA to glucose with the recruitment of gly-colysis. In humans, a mismatch of flow and glucose meta-bolism predicts recovery of mechanical function afterrevascularization. There is little data, however, to support ordisprove this theory that a perfect balance between reducedoxygen supply and contractile function prevents myocardialinjury [3]. This is because there are neither adequate animalmodels for chronic persistent ischemia nor any clinicalstudies showing whether hibernating myocardium is truly achronic condition.

If the above mechanism is the only one responsible forhibernation, this condition should occur in every patient withreduction of coronary flow. Obviously this is not the case.In addition, in clinical practice hibernation is often presentin patients with a history of acute ischemia, such as infarctionor prolonged angina pain. This complicates not only thedistinction between viable and non-viable myocardium, butalso the understanding of the pathophysiological mechanismunderlying hibernation.

Different hypotheses have been suggested for the factorresponsible for down-regulation of contraction duringhibernation. An early theory suggests that decrement incoronary perfusion pressure reduces sarcomere lengthbecause of distention in the adjacent coronary microvas-culature. Therefore, the extent of the contraction would bereduced by the Frank Starling mechanism. Several lines ofevidence argue against this suggestion. Another theoryconsiders that a reduction of energy stores might cause down-regulation of contraction. 31P-NMR studies in live animals,however, suggest that net ATP and CP stores are not depletedunless coronary flow is reduced to very low levels. Further-more, it has been shown that in hibernating myocardium, ATPlevels are normal [4]. Our own studies suggest that changesin intracellular pH, phosphate (Pi) and myocardial NAD/NADH ratio are responsible for contractile and possiblymetabolic down-regulation in hibernation [5–7].

Doubts exist whether this new metabolic state (hiber-

nation) should be considered a true ischemic condition. Instrict terms, ischemia is a condition that exists when fractionaluptake of oxygen is not sufficient to meet the rate of mito-chondria oxidation, which, in the heart, is largely determinedby the mechanical or physical activity of the myocytes [5].It is likely that in hibernating myocardium, the residual flowis able to deliver enough oxygen to meet the reduced rate ofmitochondrial oxidation. This concept will explain why, thehibernating myocardium does not produce lactate (a typicalmarker of ischemia) and shows indirect signs of metabolicactivity. It also explains the full recovery after reperfusion andthe retention of a contractile reserve. Thus, hibernation is nota state of chronic ischemia but it represents a new metabolicstate that is consequent to an ischemic condition but it is notactually ischemic. In strictly molecular terms, hibernationrepresents a chronic hypoperfusion of akinetic but aerobicmyocytes.

A difficult concept to conceive, in clinical terms, is howthe mechanism discussed above or some other unknownmechanism could provide an exact balance between energydemand and supply for months to years. This would probablyrequire subcellular adaptive changes to occur. As a result, thisfascinating problem is presently under investigation using amolecular biology approach. Unfortunately, the electro-physiological changes occurring in the hibernated zone arenot known at the present. An interesting hypothesis is that theischemia induced activation of ATP/ADP modulated K+

channels which could down-regulate contractility duringchronic left ventricular dysfunction.

Today, a number of methods are available to assess via-bility and contractile reserve in regions with hypokinetic orakinetic wall motion. These include cardiac imaging tech-niques that evaluate myocardial viability on the basis ofmyocardial perfusion, cell membrane integrity and metabolicactivity and the infusion of a low-dose positive inotropicagent during echocardiography to evaluate contractilereserve. These methods provide greater precision in theassessment of hibernation than can be achieved by analysisof coronary anatomy, regional function or specific electro-cardiographic changes. The single limits and advantages, andthe comparison of the results obtained by each technique,have recently been discussed in detail [8].

PET provides the capacity to quantitate non-invasivelyregional blood flow and to assess regional metabolic activityindependent of flow. In addition, it provides enhanced imageresolution and routine correction for body attenuation. In thisway it overcomes the two major limitations of thalliumimaging: poor resolution and photon attenuation. Viablemyocardium is identified by PET on the basis of enhancedor preserved metabolic activity in underperfused and dys-functional myocardial regions. Usually, the metabolic shiftfrom FFA to glucose is a marker of myocardial ischemia.These metabolic changes, however, may not apply to hiber-

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nating myocardium where a new state of perfusion-cont-raction coupling is achieved in the absence of ischemia. 18-F-flurodeoxyglucose (FDG) has emerged as a marker ofregional exogenous glucose utilization in hypoperfusedregions. FDG is a glucose analogue that undergoes the sametransport and phosphorylation of glucose but does not enterglycolysis or glycogen synthesis. An increase of FDG uptakein regions with reduced perfusion, the so-called FDG-bloodflow mismatch, provides a metabolic signal for identifyingviable myocardium [8].

Recently, absolute regional myocardial blood flow databecame available from PET studies using either 13NH3 orH215O as flow tracers. The majority of these studies clearlyshows a significant reduction in resting regional myocardialblood flow in those dysfunctional areas classified as hiber-nating myocardium as compared to intraindividual normalremote areas, with an average reduction in blood flow bybetween 20–30% of baseline. Others, however, failed to showa significant reduction in resting blood flow in the dys-functional area, both as compared to that in a remote referenceregion and as compared to normal flow values obtained fromhealthy volunteers [9–12]. This challenges the idea thathibernation is the result of chronic hypoperfusion and suggestthat repeated episodes of ischemia and subsequent com-mutative stunning may also be involved. While these argu-ments are important to explain the physiopathology, theyseem to be irrelevant from the clinical point of view ashibernation is always treated by revascularization.

Thallium myocardial imaging is an established and clin-ically important method to assess perfusion and sarcolemmalintegrity and hence to detect myocardial viability. Regionalthallium activity on redistribution images acquired eitherearly (3–4 h) or late (8–72 h) after stress is commonly usedto demonstrate the distribution of viable myocardial cells andthe extent of myocardial fibrosis. Different opinions exist onwhich protocol should be used for the detection of hibernatingmyocardium. This, obviously depends on the underlyingclinical question and on the meaning of the term hibernation.In our experience, the clinical question in a patient with leftventricular dysfunction, possibly due to hibernation, is oneof viability and not of inducible ischemia. Therefore, we userest-redistribution thallium imaging to discriminate viablefrom non-viable myocardium [13].

Low-dose dobutamine infusion to enhance regional syst-olic contraction during two-dimensional echocadiographyhas been successfully used to identify viable versus necroticmyocardium during the first week following successfulthrombolysis. Thus, this technique is able to unmask cont-ractile reserve in stunned myocardium in which coronaryflow has been restored. In patients with hibernating myo-cardium, with reduction of coronary blood flow severeenough to produce sustained regional contractile dysfunction,the administration of a positive inotropic agent has been

hampered by the risk of increasing myocardial demand in thesetting of exhausted coronary flow reserve, thereby pro-ducing myocardial ischemia and persistent regional dys-function. Despite this potential limitation, recent data suggestthat low-dose dobutamine echocardiography is a safe andaccurate method for assessing hibernating myocardium [14].We have evaluated its role in identifying hibernation in 33CAD patients with positive thallium rest-redistribution testand persistent left ventricular dysfunction [15]. Reversibledysfunction was identified by functional improvement ofakinetic areas immediately after surgical revascularization,detected by intraoperative epicardial echocardiography andboth 2 weeks and 3 months later, by means of transthoracicechocardiography. Infusion of dobutamine predicted revers-ible dysfunction in 178 of the 205 akinetic segments thatrecovered after surgery with a sensitivity of 86.8% andidentified 89 of the 109 segments that failed to recover witha specificity of 81.6%.

In our study echo-dobutamine predicted the immediatefunctional recovery after revascularization with higheraccuracy than thallium rest redistribution. On the contrary,scintigraphic imaging was better correlated than echo-dobutamine with long-term recovery of function [13]. Thisdiscrepancy stresses that the two tests have different clinicalsignificance as they explore two different aspects of the sameissue: viability and contractile reserve of the akinetic myo-cytes. We believe that demonstration of viability provides theultimate rationale for revascularization. Presence of cont-ractile reserve provides information on the overall operativerisk, thus overriding the additional concept that globalsystolic ejection fraction is a crucial determinant of surgicalrisk. Global ejection fraction, in fact, can be related todifferent pathophysiogical mechanisms.

How should hibernating myocardiumbest be treated?

It is clear that hibernating myocardium should be reperfused.It is our conviction, however, that, in a decision-makingprocess, several steps should be fulfilled before recom-mending myocardial revascularization. 1) the symptomaticstatus of the patient is important. This should not be limitedto the presence of angina pectoris or of inducible ischemia,but also to the presence of signs of heart failure in absenceof other symptoms. 2) coronary anatomy has to be suitablefor revascularization either by open-heart surgery or angio-plasty. 3) the extension and severity of the ventriculardysfunction has to justify an interventional procedure, the riskof which is not negligible. 4) the demonstration of viablemyocardium by one or more of the possible imaging modal-ities is essential, particularly to predict long-term recovery

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after revascularization. 5– the demonstration of a contractilereserve by low-dose dobutamine echocardiography is alsoimportant as it confirms viability and provides furtherinformation on the surgical risk.

No data exist regarding a possible pharmacologicaltreatment. Theoretically drugs which improve coronaryperfusion and protect the myocyte against ischemia might beuseful.

Can reperfusion of hibernatingmyocardium be considered as analternative to transplantation?

Revascularization of patients with end-stage ischemiccardiomyopathy and clinical manifestation of congestiveheart failure rather than angina may be considered analternative to transplantation. Data regarding this possibilityare few. In our study [15], one-third of patients had dyspneaas the only symptom, a severe reduction of ejection fractionand some of these patients were potential candidates fortransplantation. Examining the existing literature on revas-cularization of severe ischemic cardiomyopathies and poo-ling together the data, it seems that perioperative mortalityrate is between 15 and 20%, with 72–75% survival at 3 years.There is a clear improvement of symptoms and of globalejection fraction. Demonstration of viability, however, isessential for a positive outcome [16]. However, we believethat to answer this fundamental question we need a properclinical study of CAD patients awaiting transplantation inwhich large areas of hibernating myocardium have beendemonstrated. They should then be randomized to revas-cularization or standard medical therapy.

Conclusion

The discovery by Rahimtoola [1] that chronic left ventricularregional dysfunction due to prolonged hypoperfusion canrecover after full reperfusion has radically changed thecurrent pathophysiological concept of myocardial ischemiaand the actual treatment of CAD patients. We need, however,proper studies aimed to evaluate the role of the differentdiagnostic methodologies for detection of myocardial hiber-nation and to assess the clinical efficacy of revascularizationof hibernating myocardium in terms of reduction of morbidityand mortality. From the clinical point of view, attention andresources should be concentrated on those cases with largezones of hibernating myocardium in which the differentiationof viable from non-viable myocardium and the stratificationof operative risk is the real overriding clinical concern. It is

this subset of patients which will justify further investigationin this fascinating field and which hopefully, will improve ourtherapeutic possibilities.

Acknowledgements

This work was supported by the National Research Council(C.N.R) target project ‘Prevention and control of diseasefactors’ n. 91.00156 PF 41. The authors thank Miss RobertaBonetti for secretarial assistance in preparing the manuscript.

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