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PHYSIOLOGICAL REVIEWS Vol. 78 No. 4 October 1998, pp. 1055-1085
Copyright ©1998 by the American Physiological Society
Department of Pathophysiology, Centre of Internal Medicine, University of Essen, School of Medicine, Essen, Germany
I. INTRODUCTION: THE CONCEPT OF MYOCARDIAL HIBERNATION AND ITS EVOLUTION
II. ACUTE ISCHEMIA
A. Development of Contractile Dysfunction in Acute Ischemia
B. Relation of Flow and Function During Acute Ischemia
C. Mechanisms of Acute Ischemic Contractile Dysfunction
III. SHORT-TERM HIBERNATION
A. Relation of Flow and Function During Short-Term Hibernation
B. Recovery of Function After Short-Term Hibernation
C. Metabolism of Short-Term Hibernating Myocardium
D. Inotropic and Coronary Reserve in Short-Term Hibernating Myocardium
E. Limits of Short-Term Hibernation
F. Mechanisms of Short-Term Hibernation
G. Events Triggering the Development of Short-Term Hibernation
H. Short-Term Hibernation Versus Ischemic Preconditioning
I. Short-Term Hibernation Versus Stunning
J. Morphology of Short-Term Hibernating Myocardium
IV. CHRONIC HIBERNATION
A. Clinical Scenarios With Chronic Hibernation
B. Relation of Flow and Function in Chronic Hibernation
C. Metabolism in Chronic Hibernation
D. Coronary Reserve and Inotropic Reserve in Chronic Hibernation
E. Morphology in Chronic Hibernation
F. Diagnosis of Chronic Hibernation
G. Therapy of Chronic Hibernation
V. CONCLUSIONS AND PERSPECTIVES
REFERENCES
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ABSTRACT |
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 Top References
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Heusch, Gerd. Hibernating Myocardium. Physiol. Rev. 78: 1055-1085, 1998. 
Decreased myocardial contraction occurs as a consequence of a reduction in blood flow. The concept of hibernation implies a downregulation of contractile function as an adaptation to a reduction in myocardial blood flow that serves to maintain myocardial integrity and viability during persistent ischemia. Unequivocal evidence for this concept exists in scenarios of myocardial ischemia that lasts for several hours, and sustained perfusion-contraction matching, recovery of energy and substrate metabolism, the potential for recruitment of inotropic reserve at the expense of metabolic recovery, and lack of necrosis are established criteria of short-term hibernation. The mechanisms of short-term hibernation, apart from reduced calcium responsiveness, are not clear at present. Experimental studies with chronic coronary stenosis lasting more than several hours have failed to continuously monitor flow and function. Nevertheless, a number of studies in chronic animal models and patients have demonstrated regional myocardial dysfunction at reduced resting blood flow that recovered upon reperfusion, consistent with chronic hibernation. Further studies are required to distinguish chronic hibernation from cumulative stunning. With a better understanding of the mechanisms underlying short-term hibernation, it is hoped that these adaptive responses can be recruited and reinforced to minimize the consequences of acute myocardial ischemia and delay impending infarction. Patients with chronic hibernation must be identified and undergo adequate reperfusion therapy.
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 refers to an adaptive reduction of myocardial contractile function in response to a reduction of myocardial blood flow. Thus, in the concept of myocardial hibernation, the observed reduction of myocardial contractile function is not regarded as the consequence of a sustained energetic deficit, but instead as a regulatory event that serves to avoid an energetic deficit and to maintain myocardial integrity and viability (95, 96). Whereas the term hibernation was initially borrowed from zoology as a paradigm to characterize the endogenous cardiac protection during ischemia, recent studies indicate that the serum of truly hibernating animals indeed contains a substance with opioid-like activity that acts to preserve the myocardial ultrastructure and to improve the functional recovery from ischemia when given to nonhibernating animals (24). Diamond et al. (51) were the first in 1978 to use the word hibernation in the introduction to an experimental study on postextrasystolic potentiation in ischemic dog myocardium. Somewhat vaguely, they concluded from the "sometimes dramatic improvement in segmental left ventricular function after coronary bypass surgery" that "ischemic noninfarcted myocardium can exist in a state of function hibernation." Surprisingly, these authors never used the word hibernation again, when subsequently studying patients with improved wall motion after coronary revascularization (170). In the early 1980s, Rahimtoola (161, 162) systematically reviewed the results of coronary bypass surgery trials and identified patients with coronary artery disease and chronic left ventricular dysfunction that improved upon revascularization. Based on these findings, he first proposed the pathophysiological concept of "hibernating myocardium." In that context, he more precisely used the term hibernating myocardium to characterize a situation of "a prolonged subacute or chronic stage of myocardial ischemia . . . in which myocardial contractility and metabolism and ventricular function are reduced to match the reduced blood supply," that is "a new state of equilibrium . . . whereby myocardial necrosis is prevented, and the myocardium is capable of returning to normal or near-normal function on restoration of an adequate blood supply" (162). Shortly thereafter, the concept of hibernating myocardium was further popularized by Braunwald and Rutherford (30), who emphasized the need for its recognition and therapy through revascularization. Initially, the concept of myocardial hibernation was based on clinical observations only. However, the clinical concept of hibernation quickly merged with a number of experimental observations. Also in the early 1980s, several laboratories found that the long-held concept of myocardial ischemia as an imbalance between myocardial blood flow (the major determinant of energy supply) and contractile function (the major determinant of energy demand) was not necessarily correct at the regional myocardial level. In fact, the reduction in regional contractile function was proportionate to the reduction in regional myocardial blood flow (33, 72, 73, 215, 217; for review, see Ref. 91). Consequently, mechanical function appeared to "downregulate" depending on the amount of blood flow that was available. To describe this phenomenon, Ross (169) introduced the term perfusion-contraction matching. Such perfusion-contraction matching could be sustained for a period of 5 h of moderate ischemia in conscious, chronically instrumented dogs with eventual full recovery of contractile function upon reperfusion (137). With reference to sustained perfusion-contraction matching, as demonstrated in experimental studies over several hours, Ross (169) defined "short-term hibernation" and distinguished it from "chronic hibernation," i.e., a hypothetical condition of chronic perfusion-contraction matching. Further experimental evidence for the concept of myocardial hibernation was gained from studies demonstrating the recovery of metabolic markers during ongoing persistent ischemia (63, 157). The concept of hibernating myocardium has subsequently stimulated discussion on myocardial ischemia and its definition in general. Rahimtoola (162) had already postulated that hibernating myocardium may not be "ischemic in the strict sense of the word." With reference to hibernating myocardium, Hearse (89) went on to propose a distinction between physiological ischemia ("a condition in which coronary flow is inadequate to permit the organ to perform at a level sufficient to support the body over its full physiological range of activity") and biochemical ischemia ("a condition in which coronary blood flow is inadequate to permit the maintenance of a steady-state metabolism"). More recently, the concept of myocardial hibernation has been challenged. Vanoverschelde et al. (213) accepted the existence and adaptive nature of short-term hibernation but questioned the existence of perfusion-contraction matching over prolonged periods of time (chronic hibernation), since baseline flow in some studies both in patients with coronary artery disease and left ventricular dysfunction and in animal models with chronic coronary stenoses appeared to be not reduced to a sufficient extent to explain the observed reduction of contractile function (213). The present review therefore also distinguishes short-term hibernation from chronic hibernation and characterizes their essential features separately. Such distinction between short-term hibernation and chronic hibernation is certainly arbitrary in the sense that it uses laboratory hours rather than pathophysiology as criterion. Within the framework of this review, all experimental studies where the history of the observed contractile dysfunction is more or less known are discussed under short-term hibernation, and all clinical studies where the history of contractile dysfunction is not known are discussed under chronic hibernation. Also, for comparison, hibernation is contrasted with acute ischemia, stunning, and ischemic preconditioning. Both short-term hibernating and stunned myocardium are characterized by reversible contractile dysfunction. However, in short-term hibernating myocardium, blood flow is still reduced, whereas in stunned myocardium, blood flow is fully or almost fully restored (22, 23). Both short-term hibernation and ischemic preconditioning are cardioprotective phenomena. However, short-term hibernation is an adaptation to an ongoing blood flow reduction with absence of infarction. Ischemic preconditioning is the delay of infarct size development resulting from the temporal sequence of one or more short episodes of ischemia and reperfusion preceding a prolonged and severe ischemic insult (146). A. Development of Contractile Dysfunction in Acute Ischemia
Upon acute coronary artery occlusion, contractile function in the ischemic region rapidly ceases. In chronically instrumented, conscious dogs, within a few cardiac cycles systolic segment shortening and systolic wall thickening are reduced (hypokinesis), later abolished (akinesis), and within 30 s to 2 min replaced by paradoxic systolic segment lengthening and systolic wall thinning (dyskinesis, bulging) (206, 207). Electrophysiological changes in the surface electrocardiogram (ECG) occur only after the loss of systolic wall excursion, and changes in the local subendocardial ECG occur even later than those in the surface ECG (17). Thus loss of regional contractile function is a rapid, sensitive, and important consequence of regional myocardial ischemia. B. Relation of Flow and Function During Acute Ischemia
Because the microsphere technique requires steady-state conditions, regional myocardial blood flow data are available for no earlier than 2-3 min after the onset of ischemia, and therefore, no information exists on the relation of regional flow and function during this initial time. With acute coronary occlusion, there may be a transient state of imbalance between blood flow (the major determinant of energy supply) and contractile function (the major determinant of energy demand). However, even during the initial few minutes, the discharge of blood from the vascular capacitance into the microcirculation may serve to match flow and function. After a few minutes of ischemia, there is a consistent relation between the reduced regional myocardial blood flow and reduced function (Fig. 1) (33, 72, 73, 215, 217). The relationship between subendocardial blood flow and systolic wall thickening is particularly close (72), because the inner layers contribute most to transmural wall thickening (74). All these studies demonstrate that during steady-state ischemia, reductions in regional myocardial blood flow are associated with proportionate reductions in regional myocardial function. The paradigm of an imbalance between supply and demand therefore appears to no longer apply as soon as a steady state of reduced regional myocardial blood flow and reduced function has developed.
The relationship between regional myocardial blood flow and function during ischemia varies with the hemodynamic situation. During exercise in conscious dogs with different degrees of coronary stenosis, the relationship between systolic wall thickening and subendocardial or transmural myocardial blood flow is shifted. There is a higher blood flow for a given level of function during exercise as compared with resting conditions, but when myocardial blood flow is normalized for heart rate, i.e., expressed as blood flow per beat rather than blood flow per minute, the relationships at rest and during exercise are again superimposable (73). Similarly, in anesthetized pigs with constant-flow coronary hypoperfusion, the relationship between systolic wall thickening and subendocardial blood flow per minute is shifted to lower function values at increased heart rate; however, the relationships of systolic wall thickening and subendocardial blood flow per beat are superimposable and independent of heart rate (Fig. 2) (97). Such normalization to heart rate appears appropriate, since systolic wall thickening characterizes a representative single cardiac cycle, and therefore, blood flow should also be normalized to a single cardiac cycle. In fact, there is no study in the literature that shows a reduction in systolic wall thickening without a concomitant decrease in subendocardial blood flow per beat during myocardial ischemia. In a study designed to examine the sensitivity of systolic wall thickening for detecting ischemia, dogs with a subcritical coronary stenosis were subjected to treadmill exercise; with a slight reduction in systolic wall thickening, they had increased subendocardial blood flow per minute from the respective values at rest but decreased subendocardial blood flow per beat (120). Thus it appears that subendocardial blood flow per beat determines regional function of ischemic myocardium.
When equating perfusion-contraction matching, however, with an energetic supply-demand balance, a few caveats should be noted. Whereas regional blood flow is certainly the major determinant of oxygen supply as oxygen extraction is close to maximal and subject to little variation, anaerobic glycolysis may contribute to energy supply during myocardial ischemia (113, 153, 175). On the other hand, systolic wall excursion (segment shortening or wall thickening) does not account for wall tension, and wall tension even in akinetic myocardium may be surprisingly high (78) and contribute substantially to energy demand during ischemia. C. Mechanisms of Acute Ischemic Contractile Dysfunction
Adenosine 5'-triphosphate is well accepted to be the ultimate source of energy for the contractile process. Understandably then, the effect of acute myocardial ischemia on the concentration of ATP has been proposed as the mechanism of acute ischemic contractile dysfunction (88; see Table 1). A causal link between the appearance of regional ischemic contractile dysfunction and the loss of regional myocardial ATP, however, has never been proven experimentally. In the inner myocardial layers of anesthetized swine, the ATP concentration is reduced within 15 cardiac cycles after an acute reduction in myocardial blood flow; however, contractile dysfunction occurs even more rapidly, within the first few cardiac cycles (7).
Activation of ATP-dependent potassium channels by an ischemia-induced decrease in the myocardial ATP concentration, by an increase in the intracellular proton or lactate concentrations, or by activation of adenosine A1 receptors could increase potassium efflux, thereby reducing action potential duration and subsequent calcium influx into the myocyte (150). Decreased intracellular calcium concentration could then reduce contractile function and ATP consumption. Indeed, blockade of ATP-dependent potassium channels abolished the hypoxia-induced reduction of global left ventricular function in saline-perfused rat hearts (46). In contrast, in anesthetized swine in situ, blockade of ATP-dependent potassium channels prevented the ischemic reduction of action potential duration but did not alter ischemic contractile dysfunction or the myocardial ATP concentration (188). Apart from changes in the absolute concentration of myocardial ATP, decreases in the phosphorylation potential or the free energy change of ATP hydrolysis could be responsible for the decrease in contractile function. Indeed, the reduction in phosphorylation potential (41) or free energy change of ATP hydrolysis (104, 134) correlates well with the onset of contractile dysfunction, both in isolated, saline-perfused hearts and in regional ischemic myocardium. Other mediators proposed to play a role in the development of early ischemic contractile dysfunction are a decrease in the intracellular pH (101) or a disturbance in the calcium handling of the sarcoplasmic reticulum (112, 115). Decreased perfusion pressure reduces the calcium transient in isolated ferret hearts over a range of pressures (80-60 mmHg) that are not yet associated with alterations in pH and high-energy phosphates (Fig. 3) (109), and a collapse of the coronary arteries has also been suggested to be responsible for the decrease in contractile function early during ischemia in isolated, saline-perfused ferret hearts at 27°C (111). In contrast, in isolated, blood-perfused rat hearts at 37°C, the time course of development of contractile failure did not relate to that of coronary vascular collapse but did to that of metabolic processes, as reflected by oxygen consumption (71).
Apart from or in addition to the reduced calcium transient, the accumulation of Pi resulting from the ischemic breakdown of myocardial creatine phosphate and ATP is a possible candidate responsible for the early ischemic decrease in contractile function (117, 143). The increase in the concentration of Pi could reduce contractile function by direct binding to contractile proteins (171), by inhibition of the myofibrillar ATPase activity (181), and/or by desensitization of myofibrils for calcium (107). The ultimate mechanism of acute ischemic contractile dysfunction still remains unclear. A. Relation of Flow and Function During Short-Term Hibernation
In chronically instrumented, conscious dogs, a reduction in subendocardial blood flow by ~50% associated with a decrease in regional systolic wall thickening by 40% was maintained for 5 h without the development of necrosis at the site where function was measured, although some necrosis was noted in the papillary muscle. Regional contractile function recovered during reperfusion, but full recovery required 7 days (Fig. 4) (137). The relationship of flow and function during the prolonged (5 h) coronary stenosis was identical to that during a brief (few minutes) coronary stenosis, clearly indicating sustained perfusion-contraction matching.
Such sustained perfusion-contraction matching has become a hallmark of short-term hibernating myocardium (see Table 2). Interestingly, however, no subsequent study established and compared flow-function relationships during acute and more prolonged ischemia. Instead, perfusion-contraction matching was assumed to be present when perfusion and function measurements at consecutive time points could be plotted along the same relationship (34, 55, 100, 106, 189) or when the reductions in flow and function were roughly proportionate and stable (38, 182), and no necrosis was noted at the end of the experiment. Proportionate reductions in flow and function are not only seen with coronary hypoperfusion at rest, but also after sustained stress-induced ischemia when a combination of atrial pacing and intravenous norepinephrine was superimposed on mild resting hypoperfusion in anesthetized pigs. These findings, together with the lack of necrosis, indicate that the myocardium may also adapt to stress-induced ischemia (20). Not only the amount, but also the source of blood flow, may determine the level of perfusion-contraction matching. Anesthetized dogs subjected to 3-h partial coronary stenosis had better contractile function during ischemia than dogs with complete coronary occlusion and extensive collateralization, at almost identical subendocardial blood flow and in the absence of irreversible morphological injury (159).
Phenomenologically, the formal contraction pattern of ischemic myocardium, i.e., the extent of postejection wall thickening, also appears to provide information to help to distinguish irreversibly damaged from viable hibernating myocardium (168). The extent of postejection wall thickening at the end of a 90-min ischemic period in anesthetized pigs correlated inversely with the extent of necrosis and positively with myocardial creatine phosphate concentration, the dobutamine-recruitable inotropic reserve, and functional recovery upon reperfusion. Thus greater postejection wall thickening suggested that the hypoperfused myocardium was hibernating rather than irreversibly damaged. In some experimental studies, attempts have been made to investigate hibernation for longer than a few hours by subjecting dogs or pigs to either a prolonged partial coronary artery stenosis for a duration ranging from 1 day to 32 wk (25, 37-40, 62, 122, 123, 140, 142) or a progressive narrowing of the coronary artery by use of an ameroid constrictor (34, 195). Most of these studies, however, failed to continuously monitor myocardial blood flow and contractile function over the entire time period of coronary hypoperfusion. Liedtke and co-workers (25, 122, 123) used anesthetized pigs with measurements and placement of a coronary cuff occluder that reduced peak coronary blood flow velocity during an initial surgery and repeated measurements during a second surgery, 4-7 days later. Regional contractile function was reduced at the time of the second surgery, but in the single study in which flow data with microspheres were reported, the stenosis did not reduce resting flow, both during the first and the second surgeries (122). In contrast, studies in anesthetized, closed-chest pigs with a chronic ( This particular study was provocative because it refuted the idea that chronic hibernation exists at all, much less as an adaptive response to persistent hypoperfusion. Rather, Shen and Vatner (195) proposed that chronic dysfunction in a setting of coronary artery disease is a manifestation of cumulative stunning, an idea that has received widespread interest. This paper, however, has some limitations worth considering. 1) In this study, blood flow and function were not continuously monitored, and therefore, the history of the contractile dysfunction observed remains unknown. 2) Anecdotal episodes of excitement with subsequent dysfunction were reported, but they were neither systematically followed nor induced in a controlled fashion. 3) Interestingly, this same laboratory has previously reported that no prolonged dysfunction persists after such short (<2 min) episodes of ischemia, even with complete coronary occlusion in conscious dogs (154), and stunning in conscious pigs is even less pronounced than in conscious dogs (196). 4) Most importantly, this study did not reproduce the morphological phenotype of hibernating myocardium (see sect. IIIJ), as published in a follow-up paper (194). Microinfarcts surrounded by only a small rim of cardiomyocytes with characteristic features of hibernation were found. Therefore, in this particular study, the observed contractile dysfunction may have indeed been the result of repetitive stress-induced ischemia with subsequent microinfarcts and cumulative stunning, but the methodological power to exclude persistent ischemia as a cause of hibernation is clearly lacking. Only two studies with controlled hypoperfusion and continuous monitoring of flow and function over 24 h are available, both so far only in abstract form. In one study in conscious pigs (116), a reduction in blood flow by 40% reduced systolic wall thickening by 70%. Surprisingly, upon post mortem examination, the hypoperfused tissue was a mixture of patchy necrosis with reduced blood flow and normal myocardium with normal blood flow (116). However, episodes of excitement cannot be excluded in conscious pigs continuously under study for 24 h, and such episodes of excitement have been shown to result in microinfarcts by this same laboratory, even with normal resting flow (194). In another study in anesthetized pigs (189), coronary blood flow was reduced by 45%, and this reduction in flow was maintained for 24 h. Perfusion-contraction matching was maintained for 90 min, but thereafter, contractile function was further reduced, despite constant flow. Apparently, with ischemia of longer than 90-min duration, additional factors acted to reduce contractile function. However, the close matching between myocardial contractile function and oxygen consumption was maintained, still supporting the concept of metabolic adaptation to prolonged ischemia (189). B. Recovery of Function After Short-Term Hibernation
In isolated, saline-perfused rat hearts subjected to global hypoperfusion for 2 h, there was almost complete recovery of developed pressure and rate-pressure product at 15-min reperfusion (174, 175). In isolated, saline-perfused rabbit hearts that were subjected to an initial 10-min no-flow and subsequent 4-h low-flow ischemia, there was also almost complete recovery of developed pressure at 60-min reperfusion (64, 65, 211). In isolated, blood-perfused piglet hearts subjected to 2-h reduction of coronary inflow by 90%, there was again almost complete recovery of left ventricular systolic pressure and the rate-pressure product at 30- and 60-min reperfusion (56, 151). In contrast to the above studies, all in vivo models of regional short-term hibernation in anesthetized pigs (94, 100, 152, 182) and dogs (159, 222) as well as in chronically instrumented pigs (37, 38) and dogs (137, 197) were invariably characterized by severe stunning during reperfusion. When full recovery of regional contractile function was followed, it required 7 days in conscious dogs with a preceding 5-h coronary stenosis (137) and again 7 days in conscious pigs with 24-h coronary stenosis (37, 38). The difference in time course of functional recovery points to important differences in models of short-term hibernation, with almost immediate recovery in isolated hearts subjected to global ischemia as compared with slow recovery in in situ hearts subjected to regional ischemia. C. Metabolism of Short-Term Hibernating Myocardium
1. Substrate metabolism
I. INTRODUCTION: THE CONCEPT OF MYOCARDIAL HIBERNATION AND ITS EVOLUTION
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II. ACUTE ISCHEMIA
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FIG. 1.
Relationship between mean transmural blood flow (normalized to that of a normal reference area) and systolic wall thickening (normalized to that during control conditions) in chronically instrumented, conscious dogs. A close, linear relationship exists, indicating perfusion-contraction matching. [From Gallagher et al. (72).]
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FIG. 2.
Relationship between endocardial blood flow per minute (top) and per beat (bottom), respectively, and systolic wall thickening (Wth) in anesthetized, open-chest pigs with heart rates of 122/min ( 
) and 55/min (
). At increased heart rate, systolic wall thickening is reduced at any given endocardial blood flow per minute. With normalization to a single cardiac cycle (bottom), relationships are superimposable, indicating perfusion-contraction matching at different heart rates. [From Indolfi et al. (97).]
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TABLE 1.
Potential mechanisms of acute ischemic contractile dysfunction
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FIG. 3.
Calcium transient and developed pressure (DP) at a coronary perfusion pressure of 80 mmHg (A) and 60 mmHg (B) in buffer-perfused ferret hearts. In C, data are means ± SE. At decreased coronary perfusion pressure, calcium transient and consequently developed pressure are reduced. [Ca2+]i, intracellular Ca2+ concentration. , Systolic; 
, diastolic. [From Kitakaze and Marban (109).]
III. SHORT-TERM HIBERNATION
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FIG. 4.
Systolic wall thickening (normalized to control conditions, means ± SD) during 5-h partial coronary stenosis and 7-day reperfusion in chronically instrumented conscious dogs. There is recovery of function back to control values, indicating maintenance of myocardial viability. * P < 0.05, ** P < 0.01 vs. control. [From Matsuzaki et al. (137).]
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TABLE 2.
Characterization of short-term hibernating myocardium
1 mo) fixed coronary stenosis revealed proportionate reductions in regional myocardial blood flow and oxygen consumption (142) and in regional myocardial blood flow and contractile function (62, 140) as compared with a nonstenotic reference region. Consecutive regional myocardial blood flow and function measurements are available from studies in anesthetized pigs with a coronary cuff occluder adjusted to reduce flow to 40-60% of baseline for 24 h (37, 38), and more recently also for 7 days and 4 wk in a number of pigs (39, 40). These consecutive measurements during early ischemia and after 24 h or 4 wk coronary stenosis indicate proportionate reductions in resting flow and function. However, because the pigs recovered from the initial surgery and were reanesthetized for the repeat study, major alterations in systemic hemodynamics and consequently in regional myocardial blood flow and function throughout the period of coronary stenosis cannot be excluded. In fact, variations in coronary blood flow between 25 and 59% of control were reported in a subset of pigs (37). Consecutive regional myocardial blood flow and function measurements are also available from two studies in conscious, chronically instrumented animals during the progressive development of a coronary ameroid stenosis (34, 195). In one study in dogs (34), there was a dissociation between almost normal subendocardial blood flow and reduced contractile function before coronary occlusion, consistent with the idea that repetitive episodes of ischemia had occurred, resulting in myocardial stunning. After complete coronary occlusion, however, regional myocardial blood flow and function were once more closely matched, i.e., reduced in a proportionate fashion before they finally returned to normal (34). Also, in pigs (195), regional myocardial blood flow at the maximum reduction of systolic wall thickening (by ~60% from baseline) after the ameroid constrictor implantation was not reduced significantly, although subendocardial blood flow was lower than in the contralateral reference area (0.92 ± 0.10 vs. 1.07 ± 0.12 ml·min
1·g1). Interestingly, in this study, episodes of spontaneous excitement were observed, resulting in contractile dysfunction with subsequent prolonged recovery. The authors therefore proposed that hibernation is not the consequence of a persistent reduction of blood flow, but a manifestation of repetitive stunning (195).
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FIG. 5.
Myocardial lactate consumption (means ± SD) during 3-h coronary stenosis in sedated closed-chest pigs. At 5-min ischemia, net lactate consumption is reversed to net lactate production that is subsequently once more attenuated. Pre, prestenosis. * P < 0.05, ** P < 0.01 vs. prestenosis. ## P < 0.01 vs. 5 min Post Stenosis. [From Fedele et al. (63).]
2. Energy metabolism
Technically, all current information on energetics in short-term hibernation is derived from biopsy-based biochemical measurements or from nuclear magnetic resonance (NMR) spectroscopy. Neither of these techniques can distinguish between cardiomyocytes and other cells in the heart. Nuclear magnetic resonance spectroscopy permits kinetic analyses and measurement of changes in the free cytosolic concentrations, but only biochemical measurements provide data on absolute tissue contents. Thus the two techniques complement each other. Modest proportionate reductions in both coronary perfusion by ~50% and contractile function by ~30% were not associated with decreases in ATP and the creatine phosphate-to-Pi ratio (106, 180). However, these measures were only obtained during step changes in perfusion pressure of 10- (106) or 30-min duration (180) and not over a longer duration of ischemia. With moderate ischemia (myocardial blood flow on the average at 30% of control) over 5 h in anesthetized dogs, myocardial ATP content was initially decreased and then stabilized, in contrast to more severe ischemia (myocardial blood flow on the average at 10% of control) with progressive loss of ATP (149). Decreased ATP content over time was also observed during continued myocardial ischemia in isolated rat (174), rabbit (113), and piglet (55) hearts and in anesthetized pig (6, 157, 182) and dog (222) models of short-term hibernation. In contrast to the steady decline in ATP content, and like the attenuation of lactate production over time, the myocardial creatine phosphate content was significantly decreased immediately after the onset of ischemia but gradually recovered over time toward control values (Fig. 6) (157), whereas regional myocardial blood flow and contractile function were persistently reduced (6, 55, 157, 174, 182, 222). It is not clear why in one study in open-chest pigs lactate production was attenuated over time, but creatine phosphate content did not recover (177).
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In a more complex approach, simultaneous measurements of ATP, creatine phosphate, creatine, and Pi contents in freeze-clamped, saline-perfused guinea pig hearts permitted the calculation of the free energy change of ATP hydrolysis (76). The free energy change of ATP hydrolysis was markedly decreased at 10-min coronary hypoperfusion but, like creatine phosphate content, recovered back to control values during 60-min hypoperfusion. Similarly, in a porcine model of regional short-term hibernation, sequential biopsy-based measurements of ATP, creatine phosphate, creatine, and Pi revealed a decrease in the free energy change of ATP hydrolysis during early ischemia with a subsequent recovery during continued 90-min ischemia (134). Several explanations for the recovery of creatine phosphate content and the restoration of an energetic balance have been offered. In isolated, saline-perfused rat hearts, the recovery of creatine phosphate content during ongoing moderate low-flow ischemia was only observed in the presence of glycolytic substrate (175). On the other hand, in a porcine model of short-term hibernation, the anaerobic ATP production was insufficient to account for the recovery of creatine phosphate (6). Also, attenuation of lactate production during prolonged hypoperfusion is inconsistent with an important role of glycolytic ATP production for the recovery of creatine phosphate (6, 177, 182). Thus glycolytic ATP production may be necessary (but nevertheless insufficient) to allow metabolic adaptation to ischemia. Alternatively, in isolated, saline-perfused rabbit hearts, NMR spectroscopy revealed a recovery of creatine phosphate content and an attenuation of the reduction in the free energy change of ATP hydrolysis during 45-min severe hypoperfusion that could be related to open-system kinetics and a loss of adenine nucleotides through metabolism to and loss of adenosine (113). However, this explanation did not hold for moderate hypoperfusion, where there was no recovery of creatine phosphate content, in contrast to in situ preparations where only moderate ischemia can be sustained over longer periods of time without the development of necrosis (6, 182, 186). Whereas during the first few hours of ischemia loss of adenine nucleotides may be involved in the maintenance of an energetic balance, both ATP and creatine phosphate content were normal as compared with that in a remote reference region in pigs with chronic coronary stenosis and persistent reductions in regional myocardial blood flow and function (140). A specific inhibition of myofibrillar creatine kinase during prolonged moderate ischemia is also unlikely, because mitochondrial creatine kinase is more sensitive to ischemia and >2 h of total coronary occlusion is required before total creatine kinase activity is reduced (21). In an isolated, saline-perfused rat heart model of short-term hibernation, the creatine kinase equilibrium was maintained, as indicated by an unchanged ratio of the pseudo first-order rate constants of the forward and reverse creatine kinase reaction (174). Also, the increased energy utilization associated with a rapid breakdown of creatine phosphate during inotropic stimulation of short-term hibernating myocardium (94, 182) indicates a steady state of the creatine kinase reaction. Therefore, the most plausible explanation for the recovery of creatine phosphate content and the free energy change of ATP hydrolysis is indeed a downregulation of contractile function, i.e., energy demand. Glycolytic ATP production and loss of adenine nucleotides may contribute to the restoration of an energetic steady state, but probably play a relatively small role. In support of this view, pharmacological reduction of contractile function by intracoronary lidocaine prevented the decreases in ATP and creatine phosphate otherwise seen during a marked reduction in regional myocardial blood flow in anesthetized pigs (176).
D. Inotropic and Coronary Reserve in Short-Term Hibernating Myocardium
Although baseline contractile function is depressed, the hypoperfused myocardium retains its responsiveness to an inotropic challenge (Fig. 7) (182). When, after 85-90 min of sustained moderate regional ischemia (reduction of transmural blood flow by ~50%) in anesthetized pigs, dobutamine was infused selectively into the ischemic region, contractile function transiently increased, although regional blood flow remained reduced. Thus an energy reserve was available in the ischemic myocardium that was not used to maintain baseline function, but could be recruited to transiently increase contractile function during an inotropic challenge. These results strongly suggest that the decrease in contractile function secondary to a reduction in myocardial blood flow was not simply the consequence of a reduced energy supply, but rather reflected an active adaptive process of the myocardium. Imposition of an inotropic stimulus on the short-term hibernating myocardium disrupted this adaptive process, as indicated by the once more decreased myocardial creatine phosphate content and increased lactate production. An inotropic response of regional short-term hibernating myocardium to dobutamine at the expense of increased lactate production was subsequently confirmed, again in anesthetized pigs (38). Similarly, positive inotropic responses of porcine regional short-term hibernating myocardium were observed in response to postextrasystolic potentiation and intracoronary calcium (56, 94). In the latter case, enhanced regional contraction was again associated with increased lactate production and decreased creatine phosphate content (94).
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Persistent inotropic reserve in response to dobutamine was observed in the 1-wk coronary stenosis model in pigs which probably reflects cumulative stunning rather than hibernation (25). Persistent inotropic reserve in response to isoproterenol was also observed in conscious pigs with chronic ameroid constriction and normal resting flow at the time of the study, again a situation probably characterized by repeated stunning rather than hibernation (194). However, a persistent inotropic reserve in response to dobutamine was also apparent in anesthetized pigs with 24-h coronary stenosis and reduced resting flow. The inotropic response to dobutamine was typically biphasic (Fig. 8), with increased wall thickening at lower doses and contractile dysfunction at higher doses, and was associated with increased net lactate production (38). Importantly, this is the only study that not only demonstrated persistence of inotropic reserve at the expense of metabolic recovery, but also recovery of contractile function after removal of the stenosis over 7 days. Recently, with the use of the same model, an enhancement of the inotropic response to low-dose dobutamine with the addition of nitroglycerin was reported, suggesting that inotropic reserve is in part dependent on coronary reserve (127).
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A similar disruption of the developing metabolic balance after prolonged moderate ischemia is also observed upon a chronotropic challenge (6). Increasing heart rate by atrial pacing in this particular study, however, increased the severity of ischemia and reduced regional myocardial blood flow, function, and creatine phosphate content and increased lactate production. Because the severity of ischemia was increased, the observed metabolic deterioration during pacing does not demonstrate active adaptation of energy demand during the preceding more moderate ischemia as conclusively as that during the imposition of an inotropic challenge at an unchanged blood flow.
In the studies by Liedtke and co-workers (25, 122), reactive hyperemia was reduced after placement of the stenosis during the initial surgery, but it had recovered toward control values by the time of the repeat study 4-7 days later, again suggesting that this is a model of cumulative stunning rather than hibernation. An attenuated but persistent coronary reserve, elicited by adenosine (62, 142) or carbocromen (34), was found in the final study after chronic, fixed coronary stenosis in pigs (62, 142) or progressive ameroid stenosis in dogs (34). The persistence of flow reserve was not surprising in the study in dogs in which resting flow and function had completely recovered back to baseline (34). There was little subendocardial flow reserve in one study with a chronic fixed coronary stenosis in pigs (62) but substantial flow reserve in another study when adenosine was coadministered with phenylephrine to avoid a decrease in perfusion pressure (142). To explain the persistence of coronary reserve at reduced resting flow, the authors speculated that subendocardial flow reduction caused subendocardial contractile dysfunction which, in turn, constrained subepicardial contractile function by tethering, leading finally to a reduction of subepicardial blood flow (142).
E. Limits of Short-Term Hibernation
The development of a delicate balance between regional myocardial blood flow and function during early ischemia is disturbed by subsequent unfavorable alterations in supply and demand. When in anesthetized pigs after 5 min of ischemia, at a blood flow reduction compatible with the development of myocardial hibernation over 90 min, energy supply was further reduced by a further reduction of myocardial blood flow, necrosis developed, as indicated by lack of triphenyltetrazolium chloride (TTC) staining (Fig. 9). The lower limit of transmural myocardial blood flow compatible with the development of short-term myocardial hibernation over 90 min coronary hypoperfusion corresponded to ~50% of baseline in this experimental setting; the lower limit of subendocardial blood flow corresponded to 25% of baseline (Fig. 9) (186). Also, a further increase in energy demand by continuous inotropic stimulation with dobutamine for 85 min induced necrosis (Fig. 10) (186). Thus both a further reduction in energy supply by an increasing severity of ischemia and an enhanced energy expenditure by continuous inotropic stimulation can impair the development of short-term myocardial hibernation and precipitate myocardial infarction. Whether or not infarction is indeed precipitated depends on the severity and duration of flow reduction (see above) as well as on the strength and duration of the inotropic and/or chronotropic challenge. With a protocol of only mildly reduced baseline flow and only 30-min atrial pacing and intravenous norepinephrine in anesthetized pigs, the myocardium was still able to adapt, and no infarction occurred (20).
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F. Mechanisms of Short-Term Hibernation
The mechanisms responsible for the development of short-term myocardial hibernation remain largely unclear at present. There were no alterations in the 
-adrenoceptor density or affinity in anesthetized pigs with regional short-term hibernation for 90 min (186). However, more detailed analyses of the adrenergic signal transduction cascade are lacking.
1. ATP-dependent potassium channels
As mentioned in section IIC, the ischemia-induced activation of ATP-dependent potassium channels might increase potassium efflux, thereby reducing action potential duration and subsequently calcium influx into the cardiomyocyte. Decreased intracellular calcium concentration could then reduce contractile function and ATP consumption, leading to the new equilibrium between supply and demand that characterizes myocardial hibernation. Indeed, the monophasic action potential duration shortens during hypoxia (46) and ischemia (188), and this shortening of action potential duration is prevented by blockade of ATP-dependent potassium channels with glibenclamide. However, blockade of ATP-dependent potassium channels with glibenclamide during 2-h low-flow ischemia in isolated piglet hearts and 90-min low-flow ischemia in isolated rabbit hearts had no effect on the proportionate reductions in ventricular function and coronary perfusion and on the recovery of function, ATP and creatine phosphate content during reperfusion (151). Glibenclamide also failed to alter contractile function, metabolic parameters, or myocardial viability in an in situ porcine model of regional short-term hibernation (188). Consequently, activation of ATP-dependent potassium channels appears, therefore, not to be involved in the development of short-term myocardial hibernation (151, 188). However, two recent studies indicated that it is not the sarcolemmal but the mitochondrial ATP-dependent potassium channels and the mitochondrial redox state that are important in cardioprotection (77, 124). It therefore seems important to study such mitochondrial ATP-dependent potassium channels also in hibernation.2. Adenosine
Endogenous adenosine that is released during ischemia might, through a number of secondary mechanisms, such as inhibition of adenylate cyclase activity, inhibition of norepinephrine release from sympathetic nerve endings, or inhibition of L-type calcium channels, attenuate the decrease in myocardial high-energy phosphates and the increase in intracellular calcium concentration, thereby preserving myocardial viability during ischemia. However, a role for endogenous adenosine in the development of hibernation has been excluded. Adenosine receptor antagonism with 8-sulfophenyltheophylline in isolated piglet hearts subjected to 2 h of low-flow ischemia had no effect on the proportionate reductions in ventricular function and coronary perfusion and on the recovery of function, ATP, and creatine phosphate content during reperfusion (151). Also, in an in situ model of regional short-term hibernation, contractile function, metabolic parameters, and myocardial viability were not altered by increased catabolism of endogenous adenosine by infusion of adenosine deaminase (188).3. Calcium transient and responsiveness
The calcium transient during short episodes (~10 min) of moderate coronary hypoperfusion is either unchanged (67) or slightly decreased, in proportion to the reduction in perfusion pressure (109, 110, 130). Measurements of intracellular calcium kinetics are not available for more prolonged coronary hypoperfusion. However, isolated adult rat cardiomyocytes maintained viability during 48-h hypoxia, and this adaption was associated with reduced calcium transients and contractile function (200). In a porcine model of regional short-term hibernating myocardium, after 90 min of ischemia, at a time when lactate production was attenuated and the creatine phosphate content was restored to a value no longer significantly different from the respective control value, the maximal contractile responses to graded intracoronary calcium infusion and to postextrasystolic potentiation were decreased. However, the relationships between the fractional increases in regional contractile function and dose of added intracoronary calcium (Fig. 11) and the postextrasystolic time interval, respectively, were not different. Thus overall calcium responsiveness of short-term hibernating myocardium was substantially reduced. The reduction of calcium responsiveness was, however, attributable to a decrease in maximal developed force and not to a decrease in calcium sensitivity (94). The source and nature of the factor(s) that decreases calcium responsiveness in short-term hibernating myocardium are not clear at present. In this respect, it was proposed that hypoxic endothelial cells release an as yet unidentified factor that inhibits the contraction of isolated adult rat cardiomyocytes without any effect on the calcium transient (193).
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The expression of calcium regulatory proteins (sarcoplasmic calcium ATPase, phospholamban, calsequestrin, and troponin inhibitor) is not altered during 90-min short-term hibernation in anesthetized pigs (126). In biopsies from human hibernating myocardium, phospholamban expression on the mRNA and protein level was even markedly decreased, excluding a significant involvement of the sarcoplasmic reticulum in the reduced excitation-contraction coupling (47). Thus, whereas most studies on the mechanisms of hibernation have been negative so far, calcium transient and calcium responsiveness are decreased in short-term hibernation, and these findings fit well into the concept that a biochemical signal reduces contractile activity and, in consequence, energy expenditure. However, which biochemical signal reduces calcium transient and calcium responsiveness is not clear at present.
G. Events Triggering the Development of Short-Term Hibernation
Hibernation-like metabolic adaptation to a severe sustained (4 h) low-flow ischemia was reported in studies with isolated, buffer-perfused rabbit hearts in which there was a preceding short episode (10 min) of no-flow ischemia (65). 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 (65) and intracellular (211) pH, and the contractile quiescence was attributed to a faster development of myocardial acidosis. During reperfusion after the sustained ischemia, only a transient creatine kinase release occurred. On the basis of these findings, it was proposed that the development of myocardial hibernation requires an initial period of severe ischemia, during which the rapid decrease in interstitial (65) and intracellular (211) pH, which initiates the decrease in contractile function, facilitates the restoration of the balance between energy supply and energy demand. The protection provided by the initial period of no-flow ischemia was associated with increased expression of 72-kDa heat shock protein, but a cause-effect relationship was not at all established (64). In other studies, in anesthetized pig hearts in situ, infarct size resulting from sustained (90 min) low-flow ischemia was also reduced by a short (10 min) period of no-flow ischemia immediately before the sustained ischemia (184). These experimental studies attributed 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, less severe ischemia. These studies might also serve as models of hibernating myocardium after an acute myocardial infarction where an initial total coronary artery occlusion of short duration is followed by spontaneous or therapeutic thrombolysis, however with a persistent coronary stenosis.
In contrast to the above studies, better preservation of coronary venous pH and PCO2 as well as less lactate production and reduced infarct size were demonstrated in anesthetized pigs when a sustained episode of severe ischemia was preceded by a period of gradual but continuous flow reduction (100). Also in anesthetized pigs, a gradual decrease in coronary blood flow was associated with a parallel decrease in regional contractile function, attenuated lactate production, and ATP depletion, suggesting that downregulation of myocardial energy requirements can keep pace with the gradual decline in coronary blood flow (5). Thus both an initial intense stimulus of severe flow reduction and a gradually developing moderate flow reduction appear able to facilitate an adaptive response of the myocardium. In any case, the development of hibernation appears to require a triggering event, be that an initial episode of severe ischemia with profound metabolic alterations or a slow, gradual increasing intensity of ischemia. The lack of such a triggering event may be the reason why not all hearts hibernate (93).
H. Short-Term Hibernation Versus Ischemic Preconditioning
Ischemic preconditioning, i.e., the delay of infarct size development resulting from prolonged and severe myocardial ischemia by one or more preceding short episodes of ischemia and reperfusion (146), is the most powerful cardioprotective maneuver known so far. Myocardial ATP and creatine phosphate contents remain somewhat higher in preconditioned hearts than in hearts subjected to prolonged ischemia without ischemic preconditioning (108, 147). Also, glycolysis and lactate production have been reported to be attenuated in ischemic preconditioned hearts (9, 219), although this remains controversial (102). As discussed in section IIIG, a brief episode of no-flow myocardial ischemia without intermittent reperfusion increased the tolerance to sustained low-flow ischemia. Activation of ATP-dependent potassium channels and endogenous adenosine are involved in the infarct size-reducing effect of ischemic preconditioning (185, 187), but not in short-term myocardial hibernation (188). The observed reduction in infarct size by the initial period of no-flow ischemia, like in classical ischemic preconditioning (185), was abolished by blockade of ATP-dependent potassium channels with glibenclamide (184). Therefore, this cardioprotective effect relates to ischemic preconditioning rather than to myocardial hibernation. This view is also supported by the fact that the protection provided by the initial short episode of no-flow ischemia is associated with increased expression of 72-kDa heat shock protein (64), which is also associated with ischemic preconditioning (132, 221). On the other hand, expression of heat-shock proteins may simply be an epiphenomenon.
Despite certain similarities between ischemic preconditioning and myocardial hibernation, those two cardioprotective phenomena appear to be different in nature.
I. Short-Term Hibernation Versus Stunning
Hibernation and stunning, although often confused, are clearly different phenomena (23, 129). Both the short-term hibernating and the stunned myocardium are characterized by reversible contractile dysfunction. In short-term hibernating myocardium, blood flow is still reduced, whereas in stunned myocardium, blood flow is fully or almost fully restored by reperfusion (22, 23). Interestingly, in a recent study in chronically, instrumented conscious dogs, proportionate reductions of regional contractile function and myocardial oxygen consumption persisted into the reperfusion period after 2 h of partial coronary stenosis and were also observed after a protocol of 15 repetitive 2-min complete coronary occlusions with 8-min reperfusion each (197).
To distinguish short-term hibernating from stunned myocardium, regional myocardial blood flow must be measured (23). Alternatively, the metabolic changes associated with an inotropic challenge must be analyzed. The recruitment of an inotropic reserve in short-term hibernating myocardium was at the expense of metabolic deterioration (94, 182), whereas in stunned myocardium, no metabolic deterioration occurred during inotropic stimulation (4, 8, 81). In addition, whereas prolonged inotropic stimulation can cause infarction in short-term hibernating myocardium (186), it does not cause necrosis in stunned myocardium (178). Thus distinction of hibernation and stunning is possible, and it is therefore mandatory that this distinction is done in all pertinent studies.
J. Morphology of Short-Term Hibernating Myocardium
The ultrastructure of reversibly injured myocardium quickly recovers upon reperfusion, and the structural restoration precedes its functional recovery. Therefore, stunned myocardium is characterized by virtually normal morphology (179). No necrosis and only minimal structural abnormalities were seen in the studies by Liedtke and co-workers (25, 122, 123), supporting the idea that this model represents cumulative stunning rather than hibernation. With chronic coronary stenosis for 24 h, minimal patchy necrosis (1-6% of the area at risk) was found with TTC staining and histology in a minority of pigs (37, 38), and findings were similar when the stenosis was maintained for 7 days or 4 wk in a few pigs (39, 40). Electron microscopy revealed loss of myofilaments and sarcomeres and an increased number of glycogen deposits (37). No necrosis but patchy fibrosis and a more generalized increase in connective tissue (to ~2-fold of that in the normal remote myocardium) were found in pigs with chronic coronary stenosis and persistently reduced myocardial blood flow for more than 1 mo (62, 140, 142). These morphological alterations are similar to those seen in goats with chronic atrial fibrillation, apart from the interstitial fibrosis that is not seen with chronic atrial fibrillation (13).
The coronary microcirculation exhibits hypertrophy of the smaller microvessels and atrophy and reduced protein synthesis of larger microvessels (142). In the study in conscious pigs with a chronic ameroid constrictor and no reduction in regional blood flow at the time of peak dysfunction, post mortem histology revealed multifocal areas of fibrosis, surrounded by only a small rim of cells with myofibrillar lysis and increased amounts of glycogen that were similar to the phenotype of human hibernating myocardium (194).
Thus it appears that loss of myofilaments, increased amounts of glycogen deposits, and increased connective fibrotic tissue are characteristic of those preparations that definitely or most likely had persistent reductions in regional myocardial blood flow and function. These regional morphological alterations were also associated with a typical left ventricular remodeling response, as reflected by an increase in left ventricular volume and muscle mass (39). Repetitive stress-induced ischemia either induces no morphological alterations (122) or, when too frequent and/or severe, patchy necrosis (194).
Characteristic features of apoptosis, i.e., programmed nonnecrotic cell death, have been observed in rat and rabbit cardiomyocytes in settings of myocardial ischemia and reperfusion (69, 82, 103). No increase in the expression of proapoptotic proteins (Fas, Bak) was found with 90-min regional short-term hibernation in pigs (45), but in pigs with chronic (>24 h) coronary artery stenosis, clear evidence for apoptosis was obtained from both in situ labeling with terminal deoxynucleotidyl transferase and ex vivo demonstration of DNA laddering on electrophoresis (40). The apoptosis had a patchy distribution and was predominantly seen in the subendocardium (affecting ~10% of the subendocardium at risk). Apoptosis was seen already with 24-h coronary stenosis, and the incidence of apoptosis was not further increased with 7-day or 4-wk coronary stenosis. The incidence of apoptosis correlated to the severity of coronary hypoperfusion and was higher in pigs that also had patchy infarction than in pigs without infarction (40). Therefore, programmed death of some cardiomyocytes might contribute to hibernation by shunting the available energy supply to the still viable cardiomyocytes and improve the likelihood of their survival, but this is entirely speculative at present (92).
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IV. CHRONIC HIBERNATION |
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A. Clinical Scenarios With Chronic Hibernation
Hibernation over months or years (chronic hibernation), as initially proposed by Rahimtoola (162), is a state of chronic contractile dysfunction in patients with coronary artery disease that is fully reversible upon reperfusion and can only be inferred from clinical studies. Clinical syndromes consistent with the existence of myocardial hibernation include unstable and stable angina (27, 35, 66, 163, 172), acute myocardial infarction (36, 144, 163), left ventricular dysfunction and/or congestive heart failure (3, 125), and the anomalous left coronary artery from the pulmonary artery (ALCAPA) syndrome (166, 167, 198) (Table 3).
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Not surprisingly, data on the prevalence of hibernating myocardium in patients with coronary artery disease are scanty. This is primarily due to the fact that the concept is relatively new and is not even unanimously accepted. Research groups that are more active in the field have developed their own, customized diagnostic and therapeutic approach to hibernation, and there is certainly a positive selection bias in groups with an interest in hibernation. Consequently, to increase objectivity, the diagnosis of hibernation 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 will be almost impossible to obtain data on the prevalence and relevance of hibernation in patients with coronary artery disease.
With these caveats in mind, based on the existing data, it appears that hibernation may be more common in unstable than in stable angina (163). In 41 patients studied 5-21 days after an acute myocardial infarction, 78% had reduced regional contractile function and blood flow, associated with increased glucose uptake (perfusion-metabolism mismatch) in at least one myocardial area on PET scanning, indicative of hibernating myocardium, and 32% of these patients had a large area of perfusion-metabolism mismatch (1). Likewise, 69% of patients with an acute myocardial infarction had a further reduction in the perfusion deficit using technetium sestamibi tomography between 5 wk and 7 mo after the infarction, associated with improved wall motion and suggestive of hibernating myocardium (75).
In a group of 50 coronary bypass surgery candidates with a severe left anterior descending artery 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, and, most importantly, significant recovery after revascularization (199). In patients with myocardial infarction, areas with reduced perfusion at rest and preserved glucose utilization, consistent with hibernation, are more frequently found shortly after the acute event and become less frequent with increasing time thereafter (70). About 11% of the patients referred for cardiac transplantation have been suggested to have hibernating myocardium (164). In a total of 635 patients screened over 5 yr, 165 had signs of viability on the basis of rest-201 thallium redistribution. Of these, only 55 had a positive low-dose dobutamine test; this would suggest an incidence of ~10% (R. Ferrari, personal communication) (93). However, it is possible that the prevalence of hibernation would be higher when using a high-dose dobutamine test.
Although part of the original definition and currently the best retrospective proof of hibernation, the use of recovery of function upon revascularization as the criterion of hibernation may nevertheless underestimate the prevalence of hibernation. Tethering to infarcted areas may prevent the recovery of function in reperfused myocardium, and long-term changes in contractile or other regulatory proteins may require gene therapy rather than or in addition to revascularization.
Thus the available data on the prevalence of hibernation vary substantially. The awareness of the possible existence of th
