hibernating myocardium: a historical perspective

Cardiovascular Drugs and Therapy 1992;6:267-271 © K|uwer Academic Publishers, Boston. Printed in U.S.A.

Hibernating Myocardium: A Historical Perspective Julio F. Tubau and Shahbudin H. Rahimtoola The Division of Cardiology, Department of Medicine, University of Southern California, Los Angeles, California

Summary. Hibernating myocardium refers to the presence of persistent myocardial and left ventricular dysfunction at rest, associated with conditions of severely reduced coronary blood flow. This left ventricular dysfunction probably repre- sents an adaptive mechanism preventing irreversible myocardial cell damage, since myocardial and left ventricular dysfunction in hibernating myocardium improve following the restoration of coronary blood flow. This review examines the evolution of the concept of hibernation from a clinical obser- vation to the potential underlying mechanisms recently proposed.

Cardiovasc Drugs Ther 1992;6:267-271

Key Words. hibernating myocardium, left ventricular dysfunction, coronary artery disease, myocardial metabolism

Ischemic myocardial dysfunction, defined as a tran- sient impairment of contractile function due to reduced coronary blood flow, has been well documented [1]. Persistent impairment of contractile function was initially believed to represent irreversible myocardial damage resulting from myocardial infarction [2]. This conceptual dichotomy was challenged in the 1970s by the sometimes surprising recovery of left ventricular asynergy following coronary revascularization [3]. Thus, some areas of myocardium exhibiting dysfunction at rest had to be viable, since they recover after the restoration of coronary flow.

Initial investigations focused on predicting which of these areas would recover function using a variety of interventions aimed at either increasing the contractile function, e.g., catecholamine administration and postextrasystolic potentiation, or reducing myocardial oxygen demand and/or increasing coronary blood flow with nitroglycerin. Subsequently, with the advent of nuclear cardiology, the development of trac- ers of myocardial perfusion and the ability to assess left ventricular function and wall motion, it became possible to gain better knowledge about the patho- physiology of these observations [4]. The work corre- lating myocardial perfusion with function, and sometimes with pathology, was pivotal in describing the presence of severe wall-motion abnormalities associated with coronary artery stenoses exceeding a 90% reduction of the coronary intraluminal diameter. The histopathology of these areas revealed a myocardium

exhibiting an increased amount of fibrosis but with preserved myocardial cell integrity.

In 1984, Rahimtoola proposed the concept of hibernating myocardium to describe "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 if the myocardial oxygen supply/demand relationship is favor- ably altered, either by improving blood flow and/or by reducing demand" [5].

This theory was based on clinical observations at the time when knowledge of the regulation of contractile function was for the most part incomplete. The concept was not universally accepted when first proposed [6]. However, with the description of stunned myocardium and the evidence of the existence of hibernating myocardium by Braunwald, the interest of cardiologists focused on the new concept of "persistent ischemic dysfunction" [7,8]. This theory described stunning as myocardial dysfunction following severe myocardial ischemia persisting despite the restoration of coronary flow to normal or near-normal levels. This contrasts with the concept of hibernating myocardium, where the coronary flow is severely reduced and function remains depressed in a commensu- rate measure to preserve viability.

The last decade has witnessed an explosion of research efforts in the area of stunned myocardium. This was due in part to the common occurrence of stunning after a myocardial infarction and, more recently, following coronary reperfusion with thrombol- ysis or angioplasty. However, the greatest impact was the development of reproducible experimental models of stunning [8].

In contrast, the efforts to develop a reproducible experimental model of hibernating myocardium have been less successful. Nevertheless, a body of clinical evidence pointed towards the common occurrence of left ventricular dysfunction that improved following an intervention [6]. The clinical entities often associated with hibernation are unstable and stable angina patients with moderate to severe wall-motion abnor-

Address for correspondence and reprint requests: Julio F. Tubau, M.D., LAC/USC, Cardiology Division, 2025 Zonal Avenue, Los Angeles, CA 90033.

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268 Tubau and Rahimtoola

malities undergoing coronary revascularization, and those with acute myocardial infarction and wall- motion abnormalities in other areas without evidence of infarction [6,8]. Other patients with ischemic car- diomyopathy and left ventricular dysfunction of unknown origin were also found to improve their left ventricular function and wall-motion abnormalities following revascularization. This improvement is con- sistent with left ventricular dysfunction secondary to hibernating myocardium [8,9].

Positron emission tomography (PET), with its ability to assess myocardial perfusion and metabolism, allowed clinicians to diagnose hibernating myocardium by documenting the presence of reduced blood flow with preserved glucose uptake, a mismatch pattern, in areas of left ventricular asynergy [10]. This mismatch pattern by PET permitted the prediction of reversible wall-motion abnormalities as early as 1986 [10]. However, the mechanisms underlying the downregulation of myocardial function and many issues concerning hibernation remain unresolved.

Can the Heart Hibernate?

In order to answer this fundamental question, it is necessary to review the basic understanding of the relation between myocardial function, myocardial blood flow, and myocardial metabolism.

The concept of hibernation presupposes that a reduction in blood flow (the initial or triggering event) will be followed by a downregulation in function to a point at which the limited oxygen supply will enable the maintenance of the biochemical functions that sustain cell integrity [6].

Basic Principles

A series of landmark studies conducted in the 1970s revealed the close coupling between regional myocardial blood flow and myocardial function or wall thickening [1]. These initial studies, performed in dogs and using radiolabelled microspheres to measure regional blood flow and ultrasonic crystals to measure transmural wall thickening, obtained a fair correlation between these two parameters [11]. More recently, Ross and coworkers, as well as other investigators, refined these findings by examining flow and function across three layers of the myocardium. They demonstrated that transmural wall thickening was more closely determined by endocardial blood flow; in fact, flow deliv- ered to the outer layers of the myocardium was of lesser importance for determining myocardial function [11]. The relationship between blood flow and function in the intact animal is curvilinear, with a flat portion through which flow reductions are not associated with a decrease in function, followed by a steeper portion of the curve where a more proportional relationship between decreases in flow and function occurs [11].

Early experimental work in the biochemistry labo- ratories demonstrated the close coupling between mitochondrial oxygen utilization, or mitochondrial respi- ration, and the production of adenosine triphosphate (ATP) [12]. It was therefore hypothesized that ATP content was likely to be the determinant of mechanical function in conditions in which the blood flow was reduced. The applicability of these concepts to the intact heart would require significant technological advances. Most of the initial biochemical cardiac work was performed using biopsies of intact or infarcted tissues, and by rapidly cooling the specimens to avoid changes in the concentration of some of the high- energy compounds. The initial findings in experimental models provided, at best, discrepant results, suggesting that ATP was sometimes depleted and sometimes maintained in the early stages of severe ischemia [8]. Finally, computer advances allowed the application of the principles of nuclear magnetic reso- nance spectroscopy (MRS) to the experimental animal preparation. The nondestructive nature of phosphorous MRS allowed the repeated determination of high-energy compounds, namely, phosphocreatine, ATP, and inorganic phosphorous, in experiments where regional coronary blood flow was progressively reduced. These studies permitted the determination of static concentrations of ATP in an area of the myocardium but did not quantify its production and utilization, which would be more accurate. Nevertheless, it became apparent from these studies that ATP was not as closely related to flow or to mechanical function as previously thought [8]. It was hypothesized that since ATP is immediately replenished from the phosphocreatine pool, abrupt and/or severe ischemic in- sults are necessary for a significant reduction of ATP concentrations.

Following these observations, several investigators documented a close relationship between the ratio of phosphocreatine and inorganic phosphorus, or the ratio between phosphocreatine and ATP and myocardial blood flow and function, reflecting a close link between biochemistry and function in both the isolated perfused heart [13] and in the intact heart [14]. Recently, Path and coauthors confirmed that the best relationship between biochemistry and myocardial blood flow occurred in the subendocardial layers showing a transmural heterogeneity in the coupling of myocardial function, coronary blood flow, and myocardial metabolism [15]. It should be noted that the charac- teristics of such a relationship follow a pattern identi- cal to the one described for coronary blood flow and wall thickening (see above). Shown in Figure 1 are superimposed idealized plots of function and metabolism versus endocardial blood flow.

The body of work described in the previous para- graphs reflects relatively acute changes, in a matter of minutes, in conditions with severe reductions of blood flow and function, and where evidence of cell viability was not uniformly sought. Thus the question

A Perspective on Hiber~tating Myocardium 269

RELATION BETWEEN FLOW, FUNCTION AND METABOLISM

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0

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0 . 000 0 .005 0 .010

Relative Subendocardial Flow

, 0.0 0 .015 0 .020

(ml/g/beat)

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Fig. 1. Idealized plot relating endocardial blood.flow (microspheres) and function expressed as a percentage of wall thickening (left y axis) (modeled after Ross [11]). Plotted along the right y axis is the relation between myocardial metabolism, expressed as a fraction of phosphocreatine (PCr) over ATP, versus endocardial blood.flow (modeled after Keller and Cannon [13]). The relative y axes are arbitrary and the two plots are superimposed to emphasize their similarity. Note that both graphs exhibit a.fiat portion, with little change with mild degrees of blood=flow reduction, followed by steeper por- tions where .flow, function, and metabolism decline more rapidly.

remains whether the above-described mechanisms can be used by the heart to chronically downregulate its function in order to adapt to a reduced blood supply.

We will first examine experimental evidence where conditions of severe regional reduction in blood flow were maintained for a period of hours. The "chronic- ity" of these experiments is far from perfect but should be considered valid, since it has been shown that myocardial cell death will occur around 60 minutes after coronary blood flow cessation.

The best evidence that the whole heart can hibernate has recently been provided by experiments in an isolated neonate piglet heart model [16]. These authors monitored function and myocardial metabolism at baseline and continuously for 2 hours after a severe reduction in coronary blood flow to 10% of control. The isolated heart adapted to blood-flow deprivation by a reduction in function and myocardial oxygen demand. The left ventricular pressure fell, the intrinsic heart rate markedly decreased, and concomitantly, myocardial glucose utilization fell and lactate production ensued. The authors concluded that an 80% reduction in function and myocardial oxygen demand was responsible for the preservation of ATP concentration and glycogen stores to 75% of baseline. The preservation of cell viability was indirectly supported by the lack of myocardial contracture, as determined by preserved left ventricular diastolic compliance [17], although no direct evidence of ultrastructural integ-

rity was provided. This important contribution would seem to support the theoretical ability of the isolated heart to mimic hibernating species (bears, marmots, and others). It should be emphasized, however, that these hearts were devoid of hormonal or neuronal influences, and they did not have to sustain a cardiac output. In addition, the limited but persistent blood flow was capable of washing out metabolites that may otherwise have irreversibly damaged myocardial cells.

Similarly, Keller et al. demonstrated a downregulation of function associated with global coronary flow reductions in isolated perfused rat-heart experiments [13]. The authors believe this to be a good model of myocardial hibernation, but the applicability of water-perfused models to human pathology has sometimes been questioned.

Two separate experimental studies in the intact heart with prolonged regional ischemia, also limited to a few hours, seem to support the ability of the heart to downregulate its function in a regional fashion. One of the studies was performed in an instrumented dog, and chronic ischemia of moderate severity was maintained for 5 hours, followed by reperfusion. These authors demonstrated a persistent impairment in wall thickening or function that normalized over a week, with minimal evidence of cell necrosis [17]. Fedele et al., using a pig model, maintained 3 hours of prolonged reduction in flow (equivalent to 80% coronary stenosis) and observed a decrease in wall thickening that reached a steady state while regional myocardial oxygen consumption decreased concomitantly and re- mained reduced. In contrast, coronary venous pH and lactate production, although initially showing biochemical evidence of ischemia over approximately 1 hour, subsequently normalized [18]. The same hypothesis of "true" hibernation seems supported by the stabilization of ATP and total purine loss from the myocardium during sustained partial ischemia in the dog heart [19], or in patients with severe stenosis of the left anterior descending coronary ar tery [20].

Thus, these data support the intrinsic ability of the isolated heart to hibernate, as well as that of regional hibernation in the intact heart.

Requirements for Hibernation Subendocardial cell death was felt to occur when ATP levels fall below a critical level (<1 ~mol/g wet weight) [21]. More recently, however, the ATP gener- ated from glycolysis has been shown to have greater importance in predicting myocardial contracture than the absolute tissue concentration of ATP [22]. PET studies suggest that anaerobic metabolism, as as- sessed by lSF deoxyglucose uptake or minimal but rel- evant preservation of oxidative metabolism, may gen- erate enough ATP (about 10% of control) to sustain tissue viability. Experimental studies indicate that to

270 Tubau and Rahimtoola

maintain these metabolic conditions it is necessary for the regional coronary blood flow to remain between 20 and 40% of normal [10].

Certain stimuli can transiently improve the function of hibernating myocardium. However, repeated stimulation and "awakening" of hibernating myocardium may counterbalance its protective effect and may result in irreversible myocardial damage. It is possible that, in addition to the minimal blood flow requirements, the hibernating heart should not re- spond completely to prolonged, high dose catecholamine stimulation. One way this can be achieved is if the rest of the myocardium is able to maintain cardiac output within the normal range and there is no need to reflex sympathetic stimulation. An alternative mechanism could be the downregulation of the adrenergic receptors of the hibernating region.

Mechanisms for Downregulation of Myocardial Function

Few investigators have attempted to elucidate the mechanisms underlying the impairment of myocardial function in hibernating myocardium. The ATP levels were only mildly depressed in presumably hibernating myocardium in animal experiments and in humans, but it has been suggested that there is a preferential depletion of subendocardial ATP, which is better cou- pled to mechanical function [23].

More recently, it has been possible to measure intracellular cytosolic calcium in isolated perfused hearts. These studies point to a reduction in calcium availability in the hibernating myocardium and indicate that perhaps limitation of both flow and of calcium availability may explain the functional impairment of hibernating myocardium [23].

Clinical Prevalence of Hibernating Myocardium

Hibernating myocardium has been described in asso- ciation with several clinical syndromes, but its exact prevalence is unknown. Berger showed a 30-40% inci- dence of wall-motion abnormalities in patients with stable and unstable angina symptoms, respectively, which reversed after coronary artery revascularization [24]. Shelbert found flow/metabolism mismatch with PET in 42% of patients with resting segmental wall-motion abnormalities, presumably representing hibernating myocardium [10]. Thallium defects at rest or defects persisting after stress-redistribution studies associated with wall-motion abnormalities were once felt to represent myocardial infarction. How- ever, several studies have demonstrated that a large number (>50%) of those areas with fixed perfusion defects exhibit improved wall motion or thallium uptake after revascularization procedures [10,24]. Other investigators have shown that about 35-45% of thai-

lium defects persisting on the standard redistribution images after 3-4 hours of exercise exhibit delayed thallium uptake and accumulate 18F deoxyglucose by PET, suggesting myocardial viability [10]. Finally, some investigators showed that 50% of patients pre- senting for percutaneous angioplasty had segmental wall-motion abnormalities and 73% of them improved after successful balloon dilation immediately or after a period of days or weeks [6,25].

Future Directions

The significant limitations in the current experimental models of myocardial hibernation are likely to stimu- late the development of new models, as well as studies in humans in the following research endeavors:

1. More reliable and widely available methods to diagnose hibernating myocardium are required. As of now, PET, with its ability to determine coronary blood flow and myocardial metabolism, may be the best tool for detecting viable myocardium. How- ever, due to its cost and complex requirements, its availability is limited to few centers.

2. The hypothesis that flow and/or calcium availability are important with regard to the basic mechanisms of hibernation needs testing in humans and in experimental models.

3. Why the improvement in function following revascularization of hibernating myocardium is so vari- able needs investigation. It is likely that in certain cases hibernating myocardium undergoes a period of stunning [19,25], but whether stunning is part and parcel of the recovery of hibernating myocardium is not known.

Finally, if reproducible experimental models of hibernation are developed and if its clinical detection is common, a myriad of investigations will be possible, including investigations of the mechanisms that trig- ger the downregulation of function. One of the hy- potheses postulates a blood flow threshold, which, although plausible, remains unproven in true hibernation [8]; another proposes a biofeedback mechanism through either neuronal or bioactive substances at a local level. Other important issues concern, first, the changes in the adrenergic receptor numbers and their responsiveness and, second, the histopathology of hibernation. The latter problem is likely to be more complex than presently thought. Information on those important issues may help in understanding the time lag in the recovery of function of the hibernating myocardium.

References

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A Perspective on Hibernating Myocardium 271

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hibernating myocardium: a historical perspective

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