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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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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
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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).]
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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·g
1). 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 the phenomenon as well as the eventual availability of simple standard methods for its identification will most likely prove that hibernation is more common than currently recognized. Also, whereas the prevalence of hibernation in patients with coronary artery disease may not appear impressive at present, coronary artery disease per se is frequent and the leading cause of death in developed countries.
B. Relation of Flow and Function in Chronic Hibernation
When proposing the concept of hibernation, Rahimtoola (161, 162) reasonably assumed that the observed reduced regional contractile function that recovered upon revascularization must have reflected reduced resting blood flow (161, 162). More recently, this idea was challenged, and chronic hibernation was proposed not to result from chronic hypoperfusion, but from repeated episodes of ischemia and subsequent cumulative stunning (214). This as well as several other more complex patterns of flow and function in chronically dysfunctional myocardium have previously been hypothetically proposed by Bolli (23) (Fig. 12). The issue of hibernation versus cumulative stunning as the underlying mechanism of chronic yet reversible contractile dysfunction in patients with coronary artery disease has been and continues to be a matter of intense debate (165, 213).
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Consistent with the original concept of Rahimtoola (161, 162), qualitative studies using thallium scintigraphy (99, 160), 82Rb PET (135), or 13NH3 PET (125, 205, 208) demonstrated reduced regional myocardial perfusion at rest in patients with chronic regional contractile dysfunction which subsequently improved upon revascularization. Nuclear techniques, however, have certain limitations in terms of defining hibernation. Thallium and technetium sestamibi uptake closely correlate with the morphological integrity of the myocardium (48, 128, 141), and thallium reinjection identifies more or less the same viable and nonviable regions as glucose uptake measured with 18fluorodeoxyglucose (18FDG) PET (27). On the other hand, tracer uptake in these studies does not depend solely on perfusion; thus it is always normalized to a reference region that may or may not be normal and is subject to the partial volume effect, i.e., underestimates true regional activity in areas with reduced myocardial wall thickness. Therefore, the issue of perfusion-contraction matching in patients with chronic regional contractile function can only be resolved with absolute rather than relative regional myocardial blood flow and function data. More recently, absolute regional myocardial blood flow data are available from PET studies using either 13NH3 or H215O as flow tracers (Table 4). The majority of these studies clearly indicate a significant reduction in resting regional myocardial blood flow in those dysfunctional areas classified as hibernating myocardium as compared with intraindividual normal remote areas, with an average reduction in blood flow from baseline by 20-30%. Vanoverschelde et al. (214) observed a significant 19% reduction in resting blood flow in dysfunctional versus remote reference regions of the individual patients (Fig. 13), but they surprisingly reasoned that the observed dysfunction was not secondary to reduced resting blood flow, because blood flow was not significantly different in collateral-dependent myocardium of two subgroups of patients with and without contractile dysfunction (214). Subsequently, Marinho et al. using H215O (133) and Gerber et al. using 13NH3 (79) observed no significant reduction in resting blood flow in the dysfunctional area, both as compared with that in a remote reference region and as compared with normal flow values obtained from healthy volunteers. Clearly, in both studies, the observed reduction in regional contractile function appeared to be out of proportion to the observed changes in regional blood flow at rest, consistent with cumulative myocardial stunning rather than hibernation. In the study by Sun et al. (204), also no significant reduction in resting blood flow in the dysfunctional area as compared with that in the remote reference region and as compared with normal flow values in healthy volunteers was reported. However, in a critical reanalysis, Rahimtoola (165) demonstrated a significant reduction in resting blood flow as compared with that of the remote reference region when using data from those patients only in which blood flow for both regions were reported.
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The discrepant PET data on resting blood flow cannot easily be attributed to the admixture of scar tissue with low perfusion and otherwise normally perfused myocardium. This kind of dilution effect is more significant for 13NH3 than H215O flow measurements. On the other hand, H215O flow measurements may tend to overestimate flow at low flow (90) and in heterogeneously perfused myocardium (220), which was certainly the case in the studies including patients with myocardial infarction. However, reduced blood flow at rest has been demonstrated with 13NH3 (31, 43, 83, 136, 172, 199, 204, 214), H215O (42, 138), and [11C]acetate (220), and, vice versa, normal blood flow has been demonstrated with both 13NH3 (79) and H215O (133, 139). When weighing the controversial PET data on regional myocardial blood flow at rest, two critical limitations of any PET flow measurement must be emphasized. 1) The available normal blood flow values from healthy volunteers vary widely [1.02 ± 0.26 (SD) ml·g
1·min
1, n = 19 (42); 1.02 ± 0.25 ml·g
1·min
1, n = 25 (133); 0.88 ± 0.22 ml·g
1·min
1, n = 6 (79); 0.68 ± 0.16 ml·g
1·min
1, n = 12 (204)], and the subjects' ages also varied widely. In an individual patient, with reference to the reported broad range of normal flow values in volunteers, a 50% reduction in resting blood flow will go undetected. Also, the argument forwarded by Camici et al. (32) that even in the 10% minority of patients who had reduced blood flow at rest (133) this was within the range of normal blood flow as measured with microspheres (80) is not correct, because the myocardial sample size in the microspheres measurements was far smaller (0.2 g) than in the PET measurements (>>1 g), and blood flow inhomogeneity, as measured with microspheres, decreases with increasing sample size. Therefore, the comparison to an intraindividual reference region is preferable, even if a certain hyperemia there cannot be excluded. 2) Positron emission tomography flow measurements lack sufficient transmural resolution, and the lack of respiration and/or cardiac motion-gated measurements greatly enhances this problem. As a consequence, an observed 20% reduction in transmural blood flow in regions with chronic contractile dysfunction may well translate to a reduction in subendocardial blood flow as great as 40%, and subendocardial blood flow is the primary determinant of transmural wall function (72).
Apart from these technical concerns related to flow measurements with PET, only one of the above studies provided blood flow data after revascularization, and in this study, there was improvement in flow in areas with improvement of function (220). Also, in all of the above but one single study (199), wall motion scores were used, and no absolute data on regional contractile function were provided. To resolve the controversial issue of perfusion-contraction matching in chronically dysfunctional myocardium, quantitative data on both regional myocardial blood flow and contractile function before and after revascularization, and possibly with better transmural resolution than currently available are required.
C. Metabolism in Chronic Hibernation
Information on energy metabolism in patients with chronic hibernation, e.g., from biopsies taken during operative revascularization or from NMR spectroscopy, is not available.
Preserved metabolic activity in chronically dysfunctional myocardium was initially demonstrated in a more or less qualitative fashion from 18FDG uptake using PET (15, 27, 125, 135, 201, 205, 208). More recently, however, also quantitative data on glucose utilization during a standardized hyperinsulinemic euglycemic clamp have become available. In such studies, the glucose utilization of healthy volunteers varied from 0.50 ± 0.18 (204) or 0.53 ± 0.11 (79) to 0.71 ± 0.14 (133) µmol·min
1·g
1. Interestingly, in those two studies that observed no reduction in myocardial blood flow at rest, the glucose utilization of dysfunctional myocardium was lower than that in healthy volunteers (79, 133), although not different from that in a remote reference region of the individual patients in one study (133). In contrast, in studies with a reduction in resting blood flow in the dysfunctional myocardium, glucose utilization was not different from that of myocardium in healthy volunteers (204) as well as not different from that of a remote reference region (83, 138, 204). Also, the free fatty acid uptake in regions with chronic dysfunction but preserved viability was not different from that of remote reference regions (139).
During recruitment of inotropic reserve with intravenous dobutamine in the dysfunctional region, glucose utilization, as measured by 18FDG PET, was increased, whereas it was decreased in normal myocardium (204). In addition, increased anaerobic glycolysis with a significant reduction of net lactate uptake and even net production in some patients, as measured from the arteriocoronary venous differences, was seen in hibernating myocardium during recruitment of inotropic reserve with intracoronary dobutamine (Fig. 14) (98).
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An overall measure of oxidative metabolism is derived from the clearance kinetics of [11C]acetate using PET. The rate constant of acetate clearance in areas with chronic hibernation was reduced (42, 43, 214), largely in relation to the reduced blood flow (42, 87). Recruitment of inotropic reserve in such hypoperfused but viable myocardium was associated with increased oxidative metabolism, as indicated by an increase in the rate constant of acetate clearance (87).
D. Coronary Reserve and Inotropic Reserve in Chronic Hibernation
Quite consistently, coronary reserve, i.e., the ratio of myocardial blood flow during dipyridamole-induced hyperemia to resting blood flow, was reduced in those chronically dysfunctional areas that had reduced blood flow at rest (136, 172, 214). Recruitment of vasodilator reserve with dipyridamole can also result in improved wall motion score in a number of dysfunctional segments, along an upsloping flow-function relationship (210). A significant inverse relationship between the degree of contractile dysfunction and coronary reserve prompted Vanoverschelde et al. (214) to propose that repeated episodes of ischemia might occur in myocardium that is not capable of increasing its blood flow sufficiently and that repeated episodes of ischemia might induce cumulative stunning.
Also quite consistently, persistent inotropic reserve, i.e., improved regional wall motion in response to dobutamine, was reported from a number of studies in patients with chronic hibernation (79, 87, 98, 201, 204). The recruitment of inotropic reserve was associated with increased oxidative metabolism, as evident from the increased rate constant of [11C]acetate clearance (87), increased glucose utilization (204), and increased anaerobic glycolysis, as evident from reduced net lactate uptake (Fig. 14) (98). Those dysfunctional myocardial regions that responded to dobutamine with increased function also had persistent adenosine-recruitable coronary reserve (201), and the increase in function with dobutamine was associated with increased flow (119, 204). Persistent inotropic reserve, however, is also observed in chronically dysfunctional myocardium with normal perfusion (79) and, unless associated with metabolic deterioration, does not distinguish hibernating from stunned myocardium.
E. Morphology in Chronic Hibernation
Morphological alterations affect the cardiomyocytes and the interstitial space (Table 5). In 1981, before the phenomenon of hibernation was recognized, Flameng et al. (68) already described typical alterations in the morphology of myocardium from areas that were dysfunctional and recovered after surgical revascularization. Loss of cardiomyocytes and loss of contractile material within the remaining cardiomyocytes, increased number of glycogen deposits, and increased interstitial fibrosis were characteristic findings and have been confirmed in a number of studies since then (Fig. 15) (11, 12, 60, 61, 192, 199, 214). The sarcoplasmic reticulum was reduced (11, 68). Also, numerous small doughnutlike mitochondria were consistently observed (11, 60, 61). Loss of contact sites between the inner and outer mitochondrial membranes was taken to indicate reduced oxidative phosphorylation and mitochondrial creatine kinase activity (16). The contractile proteins myosin, the thin filament complex, titin, and
-actinin are reduced (60, 61, 192), and the distribution of titin within the cardiomyocytes is altered (11, 12). The cytoskeleton, consisting of desmin, tubulin, and associated proteins such as vinculin, is disorganized, and these proteins in part accumulate (60, 61). Decreased connexin43 content and reduced gap junction size may predispose to arrhythmias and contribute to impaired excitation-contraction coupling (105).
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The interstitial space is characterized by an increased amount of fibrosis (Fig. 16) (10, 61, 68, 192, 214). Cellular particles sequestered into the extracellular space form cellular debris, and the number of macrophages and fibroblasts is increased (60). Extracellular matrix and structural proteins, i.e., all collagens and fibronectin, are increased (10, 28, 60, 61).
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Borgers and co-workers emphasized the dedifferentiated phenotype of hibernating myocardium, since
-smooth muscle actin, cardiotin, and titin were found to be expressed in patterns resembling an embryonic phenotype (12, 29), and proposed contractile unloading as the underlying mechanism (28). Somewhat in contrast, J. Schaper and co-workers (60, 61, 192) recognized the adaptive nature of some morphological changes and their reversibility up to a certain degree but emphasized the degenerative nature of more severe cardiomyocyte alterations and increased fibrosis.
It is somewhat difficult to estimate how much of the dysfunctional, hibernating myocardium was morphologically altered, because all analyses are based on biopsies that are not necessarily representative for the entire hibernating region. In correlation to the degree of dysfunction, however, the amount of cardiomyocytes with degeneration and the extent of fibrosis were increased and affected >50% of the myocardium that was morphologically studied (29, 61, 68, 199). The severity of morphological alterations surprisingly did not correlate with the degree of hypoperfusion and wall motion abnormalities and also not with the functional outcome after surgical revascularization in one study (192). On the other hand, the extent of fibrosis (ranging from 10 to 70% of the biopsy specimen) was the major determinant of postoperative functional recovery in the study by Shivalkar et al. (199) and by Elsässer et al. (61). Importantly, in the recent study by Elsässer et al. (61), clear evidence of apoptosis was found in dysfunctional myocardium recovering after surgical revascularization, using both electron microscopy and in situ labeling with terminal deoxynucleotidyl transferase (61), similar to a recent experimental study with hibernating myocardium in pigs with chronic coronary artery stenosis (40). Therefore, these authors emphasized the progressive diminution of the chance for complete structural and functional recovery after restoration of blood flow and the need for early revascularization.
In conclusion, the morphology of hibernation is characterized by signs of atrophy, most notably of the contractile myofibrils, similar to skeletal muscle wasting with prolonged quiescence, degeneration, most notably in the interstitial space, and possibly dedifferentiation.
F. Diagnosis of Chronic Hibernation
In principle, residual viability in chronically dysfunctional myocardium of patients with coronary artery disease, which may reflect either hibernating or stunned myocardium or some combination thereof, can be assessed by scintigraphy using either thallium or technetium sestamibi, by PET measurements of perfusion (13NH3, H215O) and metabolism (18FDG, [11C]acetate), and by echocardiography with an inotropic challenge. The value of the respective diagnostic procedures can only be judged with respect to the prediction of recovery of regional contractile function and patients' prognosis (26, 53).
Thallium and technetium sestamibi accumulation are dependent on myocardial blood flow, but also on membrane integrity. A significant inverse relation between the amount of fibrosis and tracer uptake was found for both thallium (48) and technetium sestamibi (44, 128, 141). The reversibility of wall motion abnormalities is well predicted by thallium scintigraphy, in particular when used in a redistribution/reinjection protocol (54, 99, 158, 160, 212). The positive predictive value for contractile recovery in areas with thallium uptake was 69%, and the negative predictive value in areas without thallium uptake was 90% in a review of 13 studies involving 378 patients (26). In a pooled analysis of seven studies, thallium reinjection imaging had an average sensitivity of 86% and an average specificity of 47% for functional improvement after revascularization (19). Thallium rest-redistribution imaging in eight studies had an average sensitivity of 90% and an average specificity of 54% for functional improvement after revascularization (19). Technetium sestamibi scintigraphy had an average sensitivity of 81% and an average specificity of 60% in seven studies.
The reversibility of wall motion abnormalities is also well predicted by PET techniques (49, 87, 135, 199, 208), and a number of pertinent studies on PET measurements of myocardial perfusion and metabolism have been discussed above. The positive predictive value for contractile recovery in areas with a mismatch between 18FDG uptake and myocardial blood flow was 82%, and the negative predictive value in areas without mismatch was 83% in a review of six studies involving 146 patients (26). In a pooled analysis of 12 studies, FDG-PET imaging had an average sensitivity of 88% and an average specificity of 73% for functional improvement after revascularization (19).
Recruitment of inotropic reserve is a hallmark of short-term hibernation (38, 182). Such recruitment of inotropic reserve can be clinically monitored by dobutamine echocardiography. A positive, sometimes biphasic (2, 148, 173) response to dobutamine predicts functional recovery upon revascularization (15, 18, 87, 118, 148, 158, 160, 212). The positive predictive value for functional recovery in areas with a positive response to dobutamine echocardiography was 83%, and the negative predictive value was 81% in a review of 15 studies involving 402 patients (26). In a pooled analysis of 16 studies, low-dose dobutamine echocardiography had an average sensitivity of 84% and an average specificity of 81% for functional improvement after revascularization (19). Interestingly, lack of a positive response to low-dose dobutamine with a decrease in regional function at high-dose dobutamine also predicts a significant improvement of regional wall motion after percutaneous transluminal coronary angioplasty (2). However, dobutamine echocardiography, in particular when using a prolonged ramp protocol and when higher doses of dobutamine are required (2), is not without risks for the patient (165, 186).
Upon direct comparison, it appears that thallium scintigraphy and PET techniques identify more or less the same regions as viable or nonviable (15, 27). Also, thallium scintigraphy and dobutamine echocardiography yield largely concordant information on viability (158, 160, 212). Given the end point of contractile recovery, it is not surprising that dobutamine echocardiography appears to have greater specificity to predict functional recovery (19, 158, 160, 212), whereas thallium scintigraphy appears to have greater sensitivity (19, 160). Also, dobutamine echocardiography has a higher false-negative rate than PET (155).
It must be emphasized that the above diagnostic tests identify viable, dysfunctional myocardium in patients with coronary artery disease but do not distinguish chronic hibernation from cumulative stunning. Such a distinction requires flow measurements or the analysis of metabolism during inotropic stimulation. Only those dysfunctional areas with reduced myocardial blood flow at rest on quantitative PET flow measurements (see sect. IV B) or those with a positive response to dobutamine in combination with impaired aerobic metabolism (98) can unequivocally be identified as hibernating myocardium. The distinction between chronic hibernation and cumulative stunning may not be that important, however, clinically because revascularization is mandatory in any event. Definitely, patients with multivessel coronary disease and severe left ventricular dysfunction who have signs of maintained viability on thallium scintigraphy (156) or PET imaging of flow and glucose uptake (85) have better postoperative outcome and prognosis than those who have not.
G. Therapy of Chronic Hibernation
Currently, the therapy of chronically hibernating myocardium is reperfusion. Surgical revascularization of chronically dysfunctional myocardium in patients with coronary artery disease is long known to be capable of improving regional wall motion, left ventricular pump function, and clinical status (3, 36), and a review of the results of large randomized coronary bypass surgery trials actually led Rahimtoola to introduce the concept of hibernation (Fig. 17) (161, 162). Also, the presence of hibernating myocardium is associated with an adverse prognosis (52, 59, 121, 218), and its revascularization is associated with improved prognosis (52, 59, 84, 121, 156, 216). In patients with severe coronary artery disease and severe chronic ischemic cardiomyopathy, coronary revascularization is actually a reasonable alternative to cardiac transplantation, in particular given the shortage of donor hearts (57, 114, 125). The recovery of contractile function after coronary revascularization may be almost immediate and detected intraoperatively (209) or occur early after revascularization (2). However, it is important to realize that the improvement in both perfusion and contraction in an area with infarction may not always be immediate upon revascularization, but may require several months in a number of patients (75).
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V. CONCLUSIONS AND PERSPECTIVES |
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Clearly, the myocardium can adapt to prolonged moderate ischemia for several hours. Such short-term hibernation is entirely consistent with the concept of hibernation, and it is characterized by 1) sustained perfusion-contraction matching, 2) recovery of contractile function during reperfusion, and 3) lack of necrosis. In addition, 4) recovery of energy and substrate metabolism, and 5) the potential for recruitment of inotropic reserve at the expense of metabolic recovery have become characteristic features of short-term hibernation. Apart from reduced calcium responsiveness, the underlying mechanisms of short-term hibernation are currently unclear. Several studies demonstrated profound spatial heterogeneity of myocardial blood flow distribution during normal conditions (14, 50, 203), and it was hypothesized that small areas with low perfusion may also have low energy demand secondary to a state of "physiological hibernation" in the absence of ischemia (203). Although such perfusion inhomogeneities at the microvascular level are intriguing and thought provoking, their functional relevance is still questionable, since with integration of 1 g of myocardium or more, little inhomogeneity of blood flow measurements is left.
For future studies on short-term hibernation, experimental models with quiescent isolated cardiomyocytes are, almost by definition, inappropriate. The "lowest acceptable denominator" for the study of short-term hibernation is the isolated perfused heart (93). The limitations of this preparation include denervation, lack of extracardiac hormonal stimuli, buffer perfusion, and usually global rather than regional ischemia. A particular problem is that isolated hearts appear to exhibit no metabolic recovery during prolonged ischemia (202). Therefore, the mechanisms underlying short-term hibernation are probably best studied in acute, large-animal in situ models with regional ischemia, exhibiting all of the above criteria and permitting measurements of flow and mechanical function with good spatial resolution. Also, carefully focused studies in transgenic animals may help to identify the underlying mechanisms. It is expected that, with better understanding of the underlying mechanism(s) of short-term hibernation, the mechanism(s) can be pharmacologically recruited and exploited to convert the scenario of an acute impending infarction into a state of adaptation, and then to gain precious time for diagnostic and therapeutic procedures before the ischemic myocardium becomes necrotic.
Almost all of the existing studies on short-term hibernation over longer than a few hours duration can be criticized because of the limited observation periods and the lack of continuous monitoring of both regional myocardial blood flow and function, such that the history of the observed dysfunction is not known. Clearly, however, reduced blood flow at rest is observed in dysfunctional regions of conscious, chronically instrumented animals with chronic coronary stenosis, consistent with the original concept of Rahimtoola (162). Also, morphological alterations in such animal models with chronic coronary stenosis are remarkably similar to those found in patients with chronic hibernation. The existence of cumulative stunning secondary to repeated episodes of stress-induced ischemia in regions with normal blood flow at rest but reduced coronary reserve was proposed as an alternative mechanism underlying the observed regional contractile dysfunction in studies with chronic coronary stenosis. This possibility certainly exists, as do other more complex scenarios of flow and function in the setting of coronary stenosis (23), but has not been systematically investigated and, above all, does not exclude the existence of hibernation in other studies. To resolve such controversies, studies in conscious, chronically instrumented animals with a chronic coronary stenosis and continuous monitoring of flow and function with the stenosis and after its removal are required.
Chronic hibernation in patients will always be a hypothetical condition, insofar as the natural history of the observed dysfunction is never known. The majority of quantitative data available, however, indicate reduced blood flow at rest in the dysfunctional region as compared with an intraindividual remote reference region, consistent with the original concept of hibernation. However, it must be acknowledged that reduced blood flow at rest does not exclude superimposed episodes of stress-induced ischemia, resulting in stunning. In most patients with chronic ischemic dysfunction, there will also be an admixture of some necrotic/fibrotic tissue.
Conceptually, it appears that the process of hibernation involves an initial biochemical signal inducing contractile quiescence and energetic recovery, followed by altered gene and protein expression and finally altered morphology, including apoptosis, to cope with reduced myocardial blood flow and maintain myocardial viability in the affected region. Clinically, the recognition of viability in chronic dysfunctional myocardium of patients with coronary artery disease and the selection for revascularization is of utmost importance. Given the presence of viable myocardium, the distinction between chronic hibernation and cumulative stunning may be of only academic value, since revascularization is mandatory in any event (131). Somewhat paradoxically, it appears that therapeutic approaches will aim at mimicking and reinforcing short-term hibernation, but at removing chronic hibernation. A better mechanistic understanding is therefore particularly important for short-term hibernation.
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ACKNOWLEDGEMENTS |
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I am grateful to my friends and colleagues Drs. Roberto Bolli, Roberto Ferrari, Kim Gallagher, David Hearse, Shahbudin Rahimtoola, John Ross, Jutta Schaper, Wolfgang Schaper, Jochen Schipke, and Rainer Schulz for critical comments and helpful suggestions. The secretarial help of Heike Bongartz is greatly appreciated.
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FOOTNOTES |
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I am also grateful to the German Research Foundation who supported my work with a number of grants throughout the years (He 1320/1-1 to 9-1).
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REFERENCES |
|---|
|
|
|---|
1.
ADAMS, J. N.,
M. NORTON,
R. J. TRENT,
P. MIKECZ,
S. WALTON,
AND N. EVANS.
Incidence of hibernating myocardium after acute myocardial infarction treated with thrombolysis.
Heart
75: 442-446, 1996.
2. AFRIDI, I., U. QURESHI, H. A. KOPELEN, W. L. WINTERS, AND W. A. ZOGHBI. Serial changes in response of hibernating myocardium to inotropic stimulation after revascularization: a dobutamine echocardiographic study. J. Am. Coll. Cardiol. 30: 1233-1240, 1997[Abstract].
3. AKINS, C. W., G. M. POHOST, R. W. DESANCTIS, AND P. C. BLOCK. Selection of angina-free patients with severe left ventricular dysfunction for myocardial revascularization. Am. J. Cardiol. 46: 695-700, 1980[Medline].
4. AMBROSIO, G., W. E. JACOBUS, C. A. BERGMANN, H. F. WEISMAN, AND L. C. BECKER. Preserved high energy phosphate metabolic reserve in globally stunned hearts despite reduction of basal ATP content and contractility. J. Mol. Cell. Cardiol. 19: 953-964, 1987[Medline].
5.
ARAI, A. E.,
S. E. GRAUER,
C. G. ANSELONE,
G. A. PANTELY,
AND J. D. BRISTOW.
Metabolic adaptation to a gradual reduction in myocardial blood flow.
Circulation
92: 244-252, 1995
6.
ARAI, A. E.,
G. A. PANTELY,
C. G. ANSELONE,
J. BRISTOW,
AND J. D. BRISTOW.
Active downregulation of myocardial energy requirements during prolonged moderate ischemia in swine.
Circ. Res.
69: 1458-1469, 1991
7.
ARAI, A. E.,
G. A. PANTELY,
W. J. THOMA,
C. G. ANSELONE,
AND J. D. BRISTOW.
Energy metabolism and contractile function after 15 beats of moderate myocardial ischemia.
Circ. Res.
70: 1137-1145, 1992
8. ARNOLD, J. M. O., E. BRAUNWALD, T. SANDOR, AND R. A. KLONER. Inotropic stimulation of reperfused myocardium with dopamine: effects on infarct size and myocardial function. J. Am. Coll. Cardiol. 6: 1036-1044, 1985.
9.
ASIMAKIS, G. K.,
K. INNERS-MCBRIDE,
G. MEDELLIN,
AND V. R. CONTI.
Ischemic preconditioning attenuates acidosis and postischemic dysfunction in isolated rat heart.
Am. J. Physiol.
263(Heart Circ. Physiol. 32): H887-H894, 1992
10. AUSMA, J., J. CLEUTJENS, F. THONE, W. FLAMENG, F. RAMAEKERS, AND M. BORGERS. Chronic hibernating myocardium: interstitial changes. Mol. Cell. Biochem. 147: 35-42, 1995[Medline].
11. AUSMA, J., D. FÜRST, F. THONÉ, B. SHIVALKAR, W. FLAMENG, K. WEBER, F. RAMAEKERS, AND M. BORGERS. Molecular changes of titin in left ventricular dysfunction as a result of chronic hibernation. J. Mol. Cell. Cardiol. 27: 1203-1212, 1995[Medline].
12. AUSMA, J., G. SCHAART, F. THONÉ, B. SHIVALKAR, W. FLAMENG, C. DEPRÉ, J.-L. VANOVERSCHELDE, F. RAMAEKERS, AND M. BORGERS. Chronic ischemic viable myocardium in man: aspects of dedifferentiation. Cardiovasc. Pathol. 4: 29-37, 1995.
13.
AUSMA, J.,
M. WIJFFELS,
F. THONÉ,
L. WOUTERS,
M. ALLESSIE,
AND M. BORGERS.
Structural changes of atrial myocardium due to sustained atrial fibrillation in the goat.
Circulation
96: 3157-3163, 1997
14.
AUSTIN, R. E.,
G. S. ALDEA,
D. L. COGGINS,
A. E. FLYNN,
AND J. I. E. HOFFMAN.
Profound spatial heterogeneity of coronary reserve. Discordance between patterns of resting and maximal myocardial blood flow.
Circ. Res.
67: 319-331, 1990
15. BAER, F. M., E. VOTH, H. J. DEUTSCH, C. A. SCHNEIDER, M. HORST, E. R. DE VIVIE, H. SCHICHA, E. ERDMANN, AND U. SECHTEM. Predictive value of low dose dobutamine transesophageal echocardiography and fluorine-18 fluorodeoxyglucose positron emission tomography for recovery of regional left ventricular function after successful revascularization. J. Am. Coll. Cardiol. 28: 60-69, 1996[Abstract].
16. BAKKER, A., F. THONE, M. BORGERS, AND W. JACOB. Contact sites between the inner and outer mitochondrial membranes in stunned versus hibernating myocardium. Cardiovasc. Pathol. 4: 195-202, 1995.
17.
BATTLER, A.,
V. F. FROELICHER,
K. P. GALLAGHER,
W. S. KEMPER,
AND J. ROSS.
JR. Dissociation between regional myocardial dysfunction and ECG changes during ischemia in the conscious dog.
Circulation
62: 735-744, 1980
18. BAX, J. J., J. H. CORNEL, F. C. VISSER, P. M. FIORETTI, A. VAN LINGEN, A. E. M. REIJS, E. BOERSMA, G. J. J. TEULE, AND C. A. VISSER. Prediction of recovery of myocardial dysfunction after revascularization. Comparison of fluorine-18 fluorodeoxyglucose/thallium-201 SPECT, thallium-201 stress-reinjection SPECT and dobutamine echocardiography. J. Am. Coll. Cardiol. 28: 558-564, 1996[Abstract].
19. BAX, J. J., W. WIJNS, J. H. CORNEL, F. C. VISSER, E. BOERSMA, AND P. M. FIORETTI. Accuracy of currently available techniques for prediction of functional recovery after revascularization in patients with left ventricular dysfunction due to chronic coronary artery disease: comparison of pooled data. J. Am. Coll. Cardiol. 30: 1451-1460, 1997[Abstract].
20.
BERMAN, M.,
A. J. FISCHMAN,
J. SOUTHERN,
E. CARTER,
F. MIRECKI,
W. STRAUSS,
A. NUNN,
AND H. GEWIRTZ.
Myocardial adaptation during and after sustained, demand-induced ischemia. Observations in closed-chest, domestic swine.
Circulation
94: 755-762, 1996
21.
BITTL, J. A.,
M. L. WEISFELDT,
AND W. E. JACOBUS.
Creatine kinase of heart mitochondria.
J. Biol. Chem.
260: 208-214, 1985
22. BOLLI, R. Mechanism of myocardial "stunning." Circulation 82: 723-738, 1990.
23.
BOLLI, R..
Myocardial "stunning" in man.
Circulation
86: 1671-1691, 1992
24.
BOLLING, S. F.,
N. L. TRAMONTINI,
K. S. KILGORE,
T.-P. SU,
P. R. OELTGEN,
AND H. H. HARLOW.
Use of "natural" hibernation induction triggers for myocardial protection.
Ann. Thorac. Surg.
64: 623-627, 1997
25.
BOLUKOGLU, H.,
A. J. LIEDTKE,
S. H. NELLIS,
A. M. EGGLESTON,
R. SUBRAMANIAN,
AND B. RENSTROM.
An animal model of chronic coronary stenosis resulting in hibernating myocardium.
Am. J. Physiol.
263(Heart Circ. Physiol. 32): H20-H29, 1992
26.
BONOW, R. O..
Identification of viable myocardium.
Circulation
94: 2674-2680, 1996
27.
BONOW, R. O.,
V. DILSIZIAN,
A. CUOCOLO,
AND S. L. BACHARACH.
Identification of viable myocardium in patients with chronic coronary artery disease and left ventricular dysfunction.
Circulation
83: 26-37, 1991
28. BORGERS, M., AND J. AUSMA. Structural aspects of the chronic hibernating myocardium in man. Basic Res. Cardiol. 90: 44-46, 1995[Medline].
29. BORGERS, M., F. THONÉ, L. WOUTERS, J. AUSMA, B. SHIVALKAR, AND W. FLAMENG. Structural correlates of regional myocardial dysfunction in patients with critical coronary artery stenosis: chronic hibernation? Cardiovasc. Pathol. 2: 237-245, 1993.
30. BRAUNWALD, E., AND J. D. RUTHERFORD. Reversible ischemic left ventricular dysfunction: evidence for the "hibernating myocardium." J. Am. Coll. Cardiol. 8: 1467-1470, 1986.
31. BRUNELLI, C., O. PARODI, G. SAMBUCETI, L. CORSIGLIA, P. SPALLAROSSA, G. M. ROSA, A. GIORGETTI, G. P. BEZANTE, N. NISTA, AND S. CAPONNETTO. Improvement of hibernation in the clinical setting. J. Mol. Cell. Cardiol. 18: 2415-2418, 1996.
32.
CAMICI, P. G.,
W. WIJNS,
M. BORGERS,
R. DE SILVA,
R. FERRARI,
J. KNUUTI,
A. A. LAMMERTSMA,
A. J. LIEDTKE,
G. PATERNOSTRO,
AND S. F. VATNER.
Pathophysiological mechanisms of chronic reversible left ventricular dysfunction due to coronary artery disease.
Circulation
96: 3205-3214, 1997
33.
CANTY, J. M..
Coronary pressure-function and steady-state pressure-flow relations during autoregulation in the unanesthetized dog.
Circ. Res.
63: 821-836, 1988
34.
CANTY, J. M.,
AND F. J. KLOCKE.
Reductions in regional myocardial function at rest in conscious dogs with chronically reduced regional coronary artery pressure.
Circ. Res.
61, Suppl. II: 107-116, 1987
35. CARLSON, E. B., M. J. COWLEY, T. C. WOLFGANG, AND G. W. VETROVEC. Acute changes in global and regional rest left ventricular function after coronary angioplasty: comparative results in stable and unstable angina. J. Am. Coll. Cardiol. 13: 1262-1269, 1989[Abstract].
36.
CHATTERJEE, K.,
H. J. C. SWAN,
W. W. PARMLEY,
H. SUSTAITA,
H. S. MARCUS,
AND J. MATLOFF.
Influence of direct myocardial revascularization on left ventricular asynergy and function in patients with coronary heart disease with and without previous myocardial infarction.
Circulation
47: 276-286, 1973
37.
CHEN, C.,
L. CHEN,
J. T. FALLON,
L. MA,
L. LI,
L. BOW,
D. KNIBBS,
R. MCKAY,
L. D. GILLAM,
AND D. D. WATERS.
Functional and structural alterations with 24-hour myocardial hibernation and recovery after reperfusion. A pig model of myocardial hibernation.
Circulation
94: 507-516, 1996
38.
CHEN, C.,
L. LI,
L. L. CHEN,
J. V. PREDA,
M. H. CHEN,
S. T. FALLON,
A. E. WEYMAN,
D. WATERS,
AND L. GILLAM.
Incremental doses of dobutamine induce a biphasic response in dysfunctional left ventricular regions subtending coronary stenoses.
Circulation
92: 756-766, 1995
39. CHEN, C., L. MA, W. DYCKMAN, F. SANTOS, T. LAI, L. D. GILLAM, AND D. D. WATERS. Left ventricular remodeling in myocardial hibernation. Circulation 96, Suppl. II: II-46-II-50, 1997.
40. CHEN, C., L. MA, D. R. LINFERT, T. LAI, J. T. FALLON, L. D. GILLAM, D. D. WATERS, AND G. J. TSONGALIS. Myocardial cell death and apoptosis in hibernating myocardium. J. Am. Coll. Cardiol. 30: 1407-1412, 1997[Abstract].
41.
CLARKE, K.,
J. A. O'CONNOR,
AND R. J. WILLIS.
Temporal relation between energy metabolism and myocardial function during ischemia and reperfusion.
Am. J. Physiol.
253(Heart Circ. Physiol. 22): H412-H421, 1987
42. CONVERSANO, A., J. F. WALSH, E. M. GELTMAN, J. E. PEREZ, S. R. BERGMANN, AND R. J. GROPLER. Delineation of myocardial stunning and hibernation by positron emission tomography in advanced coronary artery disease. Am. Heart J. 131: 440-450, 1996[Medline].
43.
CZERNIN, J.,
G. PORENTA,
R. BRUNKEN,
J. KRIVOKAPICH,
K. CHEN,
R. BENNETT,
A. HAGE,
C. FUNG,
J. TILLISCH,
M. E. PHELPS,
AND H. R. SCHELBERT.
Regional blood flow, oxidative metabolism, and glucose utilization in patients with recent myocardial infarction.
Circulation
88: 884-895, 1993
44.
DAKIK, H. A.,
J. F. HOWELL,
G. M. LAWRIE,
R. ESPADA,
D. G. WEILBAECHER,
Z.-X. HE,
J. J. MAHMARIAN,
AND M. S. VERANI.
Assessment of myocardial viability with 99mTC-sestamibi tomography before coronary bypass graft surgery. Correlation with histopathology and postoperative improvement in cardiac function.
Circulation
96: 2892-2898, 1997
45. DARMER, D., B. BARTLING, J. HOFFMANN, H. SCHUMANN, J. HOLTZ, R. SCHULZ, AND G. HEUSCH. Weitgehend konstante Expression von Apoptose-Genen im "short-term-hibernating" und "stunned" Myokard von Schweinen (Abstract). Z. Kardiol. 86, Suppl. 2: 102, 1997.
46.
DECKING, U. K. M.,
T. REFFELMANN,
J. SCHRADER,
AND H. KAMMERMEIER.
Hypoxia-induced activation of KATP channels limits energy depletion in the guinea pig heart.
Am. J. Physiol.
269(Heart Circ. Physiol. 38): H734-H742, 1995
47. DEINDL, E., E. NEUBAUER, A. ELSÄSSER, R. ZIMMERMANN, AND W. SCHAPER. Reduced contractile function characteristic of hibernating human heart is not mediated by phospholamban. Ann. NY Acad. Sci. 853: 270-272, 1998[Medline].
48.
DE MARIA, R.,
O. PARODI,
G. BAROLDI,
G. SAMBUCETI,
R. TESTA,
L. OLTRONA,
M. GRASSI,
M. PAROLINI,
M. BARBERIS,
R. SARA,
C. DE VITA,
AND A. PELLEGRINI.
Morphological bases for thallium-201 uptake in cardiac imaging and correlates with myocardial blood flow distribution.
Eur. Heart J.
17: 951-961, 1996
49.
DE SILVA, R.,
Y. YAMAMOTO,
C. G. RHODES,
H. IIDA,
P. NIHOYANNOPOULOS,
G. J. DAVIES,
A. A. LAMMERTSMA,
T. JONES,
AND A. MASERI.
Preoperative prediction of the outcome of coronary revascularization using positron emission tomography.
Circulation
86: 1738-1742, 1992
50. DEUSSEN, A., C. W. FLESCHE, T. LAUER, M. SONNTAG, AND J. SCHRADER. Spatial heterogeneity of blood flow in the dog heart. II. Temporal stability in response to adrenergic stimulation. Pflügers Arch. 432: 451-461, 1996[Medline].
51. DIAMOND, G. A., J. S. FORRESTER, P. L. DE LUZ, H. L. WYATT, AND H. J. C. SWAN. Postextrasystolic potentiation of ischemic myocardium by atrial stimulation. Am. Heart J. 95: 204-209, 1978[Medline].
52. DI CARLI, M. F., M. DAVIDSON, R. LITTLE, S. KHANNA, F. V. MODY, R. C. BRUNKEN, J. CZERNIN, S. ROKHSAR, L. W. STEVENSON, H. LAKS, R. HAWKINS, H. R. SCHELBERT, M. E. PHELPS, AND J. MADDAHI. Value of metabolic imaging with positron emission tomography for evaluating prognosis in patients with coronary artery disease and left ventricular dysfunction. Am. J. Cardiol. 73: 527-533, 1994[Medline].
53.
DILSIZIAN, V.,
AND R. O. BONOW.
Current diagnostic techniques of assessing myocardial viability in patients with hibernating and stunned myocardium.
Circulation
87: 1-20, 1993
54. DILSIZIAN, V., T. P. ROCCO, N. M. T. FREEDMAN, M. B. LEON, AND R. O. BONOW. Enhanced detection of ischemic but viable myocardium by the reinjection of thallium after stress-redistribution imaging. N. Engl. J. Med. 323: 141-146, 1990[Abstract].
55.
DOWNING, S. E.,
AND V. CHEN.
Myocardial hibernation in the ischemic neonatal heart.
Circ. Res.
66: 763-772, 1990
56.
DOWNING, S. E.,
AND V. CHEN.
Acute hibernation and reperfusion of the ischemic heart.
Circulation
85: 699-707, 1992
57. DREYFUS, G. D., D. DUBOC, A. BLASCO, F. VIGONI, C. DUBOIS, D. BRODATY, P. DE LENTDECKER, J. BACHET, B. GOUDOT, AND D. GUILMET. Myocardial viability assessments in ischemic cardiomyopathy: benefits of coronary revascularization. Ann. Thorac. Surg. 57: 1402-1408, 1994[Abstract].
58.
EBERLI, F. R.,
E. O. WEINBERG,
W. N. GRICE,
G. L. HOROWITZ,
AND C. S. APSTEIN.
Protective effect of increased glycolytic substrate against systolic and diastolic dysfunction and increased coronary resistance from prolonged global underperfusion and reperfusion in isolated rabbit hearts perfused with erythrocyte suspensions.
Circ. Res.
68: 466-481, 1991
59. EITZMAN, D., Z. AL-AOUAR, H. L. KANTER, AND J. VOM. DAHL, M. KIRSH, G. M. DEEB, AND M. SCHWAIGER. Clinical outcome of patients with advanced coronary artery disease after viability studies with positron emission tomography. J. Am. Coll. Cardiol. 20: 559-565, 1992[Abstract].
60. ELSÄSSER, A., AND J. SCHAPER. Hibernating myocardium: adaptation or degeneration? Basic Res. Cardiol. 90: 47-48, 1995.
61.
ELSÄSSER, A.,
M. SCHLEPPER,
W.-P. KLÖVEKORN,
W. CAI,
R. ZIMMERMANN,
K.-D. MÜLLER,
R. STRASSER,
S. KOSTIN,
C. GAGEL,
B. MÜNKEL,
W. SCHAPER,
AND J. SCHAPER.
Hibernating myocardium. An incomplete adaptation to ischemia.
Circulation
96: 2920-2931, 1997
62.
FALLAFOLLITA, J. A.,
B. J. PERRY,
AND J. M. CANTY.
18F-2-deoxyglucose deposition and regional flow in pigs with chronically dysfunctional myocardium. Evidence for transmural variations in chronic hibernating myocardium.
Circulation
95: 1900-1909, 1997
63.
FEDELE, F. A.,
H. GEWIRTZ,
R. J. CAPONE,
B. SHARAF,
AND A. S. MOST.
Metabolic response to prolonged reduction of myocardial blood flow distal to a severe coronary artery stenosis.
Circulation
78: 729-735, 1988
64. FERRARI, R., M. BONGRAZIO, A. CARGNONI, L. COMINI, E. PASINI, G. GAIA, AND O. VISIOLI. Heat shock protein changes in hibernation: a similarity with heart failure? J. Mol. Cell. Cardiol. 28: 2383-2395, 1996.
65.
FERRARI, R.,
A. CARGNONI,
P. BERNOCCHI,
E. PASINI,
S. CURELLO,
C. CECONI,
AND T. J. C. RUIGROK.
Metabolic adaptation during a sequence of no-flow and low-flow ischemia: a possible trigger for hibernation.
Circulation
94: 2587-2596, 1996
66. FERRARI, R., AND G. LA. CANNA, R. GIUBBINI, AND O. VISIOLI. Stunned and hibernating myocardium: possibility of intervention. J Cardiovasc. Pharmacol. 20, Suppl.: S5-S13, 1992.
67. FIGUEREDO, V. M., R. BRANDES, M. W. WEINER, B. M. MASSIE, AND S. A. CAMACHO. Cardiac contractile dysfunction during mild coronary flow reductions is due to an altered calcium-pressure relationship in rat hearts. J. Clin. Invest. 90: 1794-1802, 1992.
68. FLAMENG, W., R. SUY, F. SCHWARZ, M. BORGERS, J. PIESSENS, F. THONE, H. VAN ERMEN, AND H. DE GEEST. Ultrastructural correlates of left ventricular contraction abnormalities in patients with chronic ischemic heart disease: determinants of reversible segmental asynergy postrevascularization surgery. Am. Heart J. 102: 846-857, 1981[Medline].
69.
FLISS, H.,
AND D. GATTINGER.
Apoptosis in ischemic and reperfused rat myocardium.
Circ. Res.
79: 949-956, 1996
70. FRAGASSO, G., S. L. CHIERCHIA, G. LUCIGNANI, C. LANDONI, A. CONVERSANO, M. C. GILARDI, F. COLOMBO, C. ROSSETTI, AND F. FAZIO. Time dependence of residual tissue viability after myocardial infarction assessed by [18F]fluorodeoxyglucose and positron emission tomography. Am. J. Cardiol. 72: 131G-139G, 1993[Medline].
71. GALINANES, M., D. J. HEARSE, AND M. J. SHATTOCK. The role of the rate of vascular collapse in ischemia-induced acute contractile failure and decreased diastolic stiffness. J. Mol. Cell. Cardiol. 28: 519-529, 1996[Medline].
72.
GALLAGHER, K. P.,
M. MATSUZAKI,
J. A. KOZIOL,
W. S. KEMPER,
AND J. ROSS.
JR. Regional myocardial perfusion and wall thickening during ischemia in conscious dogs.
Am. J. Physiol.
247(Heart Circ. Physiol. 16): H727-H738, 1984
73.
GALLAGHER, K. P.,
M. MATSUZAKI,
G. OSAKADA,
W. S. KEMPER,
AND J. ROSS.
JR. Effect of exercise on the relationship between myocardial blood flow and systolic wall thickening in dogs with acute coronary stenosis.
Circ. Res.
52: 716-729, 1983
74. GALLAGHER, K. P., G. OSAKADA, M. MATSUZAKI, M. MILLER, W. S. KEMPER, AND J. ROSS. JR. Nonuniformity of inner and outer systolic wall thickening in conscious dogs. Am. J. Physiol. 249(Heart Circ. Physiol. 18): H241-H248, 1985.
75.
GALLI, M.,
C. MARCASSA,
R. BOLLI,
P. GIANNUZZI,
P. L. TEMPORELLI,
A. IMPARATO,
P. L. S. ORREGO,
R. GIUBBINI,
A. GIORDANO,
AND L. TAVAZZI.
Spontaneous delayed recovery of perfusion and contraction after the first 5 weeks after anterior infarction. Evidence for the presence of hibernating myocardium in the infarcted area.
Circulation
90: 1386-1397, 1994
76. GAO, Z.-P., H. F. DOWNEY, W.-L. FAN, AND R. T. MALLET. Does interstitial adenosine mediate acute hibernation of guinea pig myocardium? Cardiovasc. Res. 29: 796-804, 1995.
77.
GARLID, K. D.,
P. PAUCEK,
V. YAROV-YAROVOY,
H. N. MURRAY,
R. B. DARBENZIO,
A. J. D'ALONZO,
N. J. LODGE,
M. A. SMITH,
AND G. J. GROVER.
Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels. Possible mechanism of cardioprotection.
Circ. Res.
81: 1072-1082, 1997
78.
GAYHEART, P. A.,
J. VINTEN-JOHANSEN,
W. E. JOHNSTON,
T. O. HESTER,
AND A. R. CORDELL.
Oxygen requirements of the dyskinetic myocardial segment.
Am. J. Physiol.
257(Heart Circ. Physiol. 26): H1184-H1191, 1989
79.
GERBER, B. L.,
J.-L. J. VANOVERSCHELDE,
A. BOL,
C. MICHEL,
D. LABAR,
W. WIJNS,
AND J. A. MELIN.
Myocardial blood flow, glucose uptake, and recruitment of inotropic reserve in chronic left ventricular ischemic dysfunction. Implications for the pathophysiology of chronic myocardial hibernation.
Circulation
94: 651-659, 1996
80.
GHALEH, B.,
Y.-T. SHEN,
AND S. F. VATNER.
Spatial heterogeneity of myocardial blood flow presages salvage versus necrosis with coronary artery reperfusion in conscious baboons.
Circulation
94: 2210-2215, 1996
81. GÖRGE, G., I. PAPAGEORGIOU, AND R. LERCH. Epinephrine-stimulated contractile and metabolic reserve in postischemic rat myocardium. Basic Res. Cardiol. 85: 595-605, 1990[Medline].
82. GOTTLIEB, R. A., K. O. BURLESON, R. A. KLONER, B. M. BARBIOR, AND R. L. ENGLER. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J. Clin. Invest. 94: 1621-1628, 1994.
83.
GRANDIN, C.,
W. WIJNS,
J. A. MELIN,
A. BOL,
A. R. ROBERT,
G. R. HEYNDRICKX,
C. MICHEL,
AND J.-L. J. VANOVERSCHELDE.
Delineation of myocardial viability with PET.
J. Nucl. Med.
36: 1543-1552, 1995
84. GUNNING, M. G., T. P. CHUA, D. HARRINGTON, C. J. KNIGHT, E. BURMAN, D. J. PENNELL, J. PEPPER, K. FOX, AND S. R. UNDERWOOD. Hibernating myocardium: clinical and functional response to revascularization. Eur. J. Cardio-thorac. Surg. 11: 1105-1112, 1997[Abstract].
85. HAAS, F., C. G. HAEHNEL, W. PICKER, S. NEKOLLA, S. MARTINOFF, H. MEISNER, AND M. SCHWAIGER. Preoperative viability assessment and peri- and postoperative risk in patients with advanced ischemic heart disease. J. Am. Coll. Cardiol. 30: 1693-1700, 1997[Abstract].
86.
HACKER, T. A.,
B. RENSTROM,
S. H. NELLIS,
AND A. J. LIEDTKE.
Effect of repetitive stunning on myocardial metabolism in pig hearts.
Am. J. Physiol.
273(Heart Circ. Physiol. 42): H1395-H1402, 1997
87.
HATA, T.,
R. NOHARA,
M. FUJITA,
R. HOSOKAWA,
L. LEE,
T. KUDO,
E. TADAMURA,
N. TAMAKI,
J. KONISHI,
AND S. SASAYAMA.
Noninvasive assessment of myocardial viability by positron emission tomography with 11C acetate in patients with old myocardial infarction. Usefulness of low-dose dobutamine infusion.
Circulation
94: 1834-1841, 1996
88. HEARSE, D. J.. Oxygen deprivation and early myocardial contractile failure: a reassessment of the possible role of adenosine triphosphate. Am. J. Cardiol. 44: 1115-1121, 1979[Medline].
89. HEARSE, D. J. Myocardial ischemia: can we agree on a definition for the 21st century? Cardiovasc. Res. 28: 1737-1744, 1994.
90.
HERRERO, P.,
A. STAUDENHERZ,
J. F. WALSH,
R. J. GROPLER,
AND S. R. BERGMAN.
Heterogeneity of myocardial perfusion provides the physiological basis of perfusable tissue index.
J. Nucl. Med.
36: 320-327, 1995
91. HEUSCH, G.. The relationship between regional blood flow and contractile function in normal, ischemic, and reperfused myocardium. Basic Res. Cardiol. 86: 197-218, 1991[Medline].
92. HEUSCH, G. Hibernation. Which are the underlying mechanisms? Dial Cardiovasc. Med. 2: 79-83, 1997.
93.
HEUSCH, G.,
R. FERRARI,
D. J. HEARSE,
T. J. C. RUIGROK,
AND R. SCHULZ.
"Myocardial hibernation": questions and controversies.
Cardiovasc. Res.
36: 301-309, 1997
94.
HEUSCH, G.,
J. ROSE,
A. SKYSCHALLY,
H. POST,
AND R. SCHULZ.
Calcium responsiveness in regional myocardial short-term hibernation and stunning in the in situ porcine heart: inotropic responses to postextrasystolic potentiation and intracoronary calcium.
Circulation
93: 1556-1566, 1996
95. HEUSCH, G., AND R. SCHULZ. Hibernating myocardium: a review. J. Mol. Cell. Cardiol. 28: 2359-2372, 1996[Medline].
96.
HEUSCH, G.,
AND R. SCHULZ.
Myocardial hibernation: adaptation to ischemia.
News Physiol. Sci.
11: 166-170, 1996.
97.
INDOLFI, C.,
B. D. GUTH,
T. MIURA,
S. MIYAZAKI,
R. SCHULZ,
AND J. ROSS.
JR. Mechanisms of improved ischemic regional dysfunction by bradycardia. Studies on UL-FS 49 in swine.
Circulation
80: 983-993, 1989
98. INDOLFI, C., F. PISCIONE, P. PERRONE-FILARDI, M. PRASTARO, E. DI LORENZO, L. SACCA, M. CONDORELLI, AND M. CHIARIELLO. Inotropic stimulation by dobutamine increases left ventricular regional function at the expense of metabolism in hibernating myocardium. Am. Heart J. 132: 542-549, 1996[Medline].
99. ISKANDRIAN, A. S., A.-H. HAKKI, S. A. KANE, I. P. GOEL, E. D. MUNDTH, A.-H. HAKKI, AND B. L. SEGAL. Rest redistribution thallium-201 myocardial scintigraphy to predict improvement in left ventricular function after coronary arterial bypass grafting. Am. J. Cardiol. 51: 1312-1316, 1983[Medline].
100.
ITO, B. R..
Gradual onset of myocardial ischemia results in reduced myocardial infarction. Association with reduced contractile function and metabolic downregulation.
Circulation
91: 2058-2070, 1995
101. JACOBUS, W. E., I. H. PORES, S. K. LUCAS, M. L. WEISFELDT, AND J. T. FLAHERTY. Intracellular acidosis and contractility in normal and ischemic hearts examined by 31P NMR. J. Mol. Cell. Cardiol. 14: 13-20, 1982.
102.
JANIER, M. F.,
J.-L. J. VANOVERSCHELDE,
AND S. R. BERGMANN.
Ischemic preconditioning stimulates anaerobic glycolysis in the isolated rabbit heart.
Am. J. Physiol.
267(Heart Circ. Physiol. 36): H1353-H1360, 1994
103. KAJSTURA, J., W. CHENG, K. REISS, W. A. CLARK, E. H. SONNENBLICK, S. KRAJEWSKI, J. C. REED, G. OLIVETTI, AND P. ANVERSA. Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Lab. Invest. 74: 86-107, 1996[Medline].
104. KAMMERMEIER, H., P. SCHMIDT, AND E. JÜNGLING. Free energy change of ATP-hydrolysis: a causal factor of early hypoxic failure of the myocardium? J. Mol. Cell. Cardiol. 14: 267-277, 1982.
105.
KAPRIELIAN, R. R.,
M. GUNNING,
E. DUPOND,
M. N. SHEPPARD,
S. M. ROTHERY,
R. UNDERWOOD,
D. J. PENNELL,
K. FOX,
J. PEPPER,
P. A. POOLE-WILSON,
AND N. J. SEVERS.
Downregulation of immunodetectable connexin43 and decreased gap junction size in the pathogenesis of chronic hibernation in the human left ventricle.
Circulation
97: 651-660, 1998
106. KELLER, A. M., P. J. CANNON, AND A. C. WOLNY. Effect of graded reductions of coronary pressure and flow on myocardial metabolism and performance: a model of "hibernating" myocardium. J. Am. Coll. Cardiol. 17: 1661-1670, 1991[Abstract].
107.
KENTISH, J. C..
The effects of inorganic phosphate and creatine phosphate on the force production in skinned muscle from rat ventricle.
J. Physiol. (Lond.)
370: 585-604, 1986
108.
KIDA, M.,
H. FUJIWARA,
M. ISHIDA,
C. KAWAI,
M. OHURA,
I. MIURA,
AND Y. YABUUCHI.
Ischemic preconditioning preserves creatine phosphate and intracellular pH.
Circulation
84: 2495-2503, 1991
109.
KITAKAZE, M.,
AND E. MARBAN.
Cellular mechanism of the modulation of contractile function by coronary perfusion pressure in ferret hearts.
J. Physiol. (Lond.)
414: 455-472, 1989
110.
KOJIMA, S.,
S. T. WU,
T. A. WATTERS,
W. W. PARMLEY,
AND J. WIKMAN-COFFELT.
Effects of perfusion pressure on intracellular calcium, energetics, and function in perfused rat hearts.
Am. J. Physiol.
264(Heart Circ. Physiol. 33): H183-H189, 1993
111.
KORETSUNE, Y.,
M. C. CORRETTI,
H. KUSUOKA,
AND E. MARBAN.
Mechanism of early ischemic contractile failure.
Circ. Res.
68: 255-262, 1991
112.
KRAUSE, S.,
AND M. L. HESS.
Characterization of cardiac sarcoplasmic reticulum dysfunction during short-term, normothermic, global ischemia.
Circ. Res.
55: 176-184, 1984
113.
KROLL, K.,
D. J. KINZIE,
AND L. A. GUSTAFSON.
Open-system kinetics of myocardial phosphoenergetics during coronary underperfusion.
Am. J. Physiol.
272(Heart Circ. Physiol. 41): H2563-H2576, 1997
114. KRON, I. L., T. L. FLANAGAN, L. H. BLACKBOURNE, R. A. SCHROEDER, AND S. P. NOLAN. Coronary revascularisation rather than cardiac transplantation for chronic ischemic cardiomyopathy. Ann. Surg. 210: 348-352, 1989[Medline].
115. KÜBLER, W., AND A. M. KATZ. Mechanism of early "pump" failure of the ischemic heart: possible role of adenosine triphosphate depletion and inorganic phosphate accumulation. Am. J. Cardiol. 40: 467-471, 1977[Medline].
116. KUDEJ, R. K., B. GHALEH, N. SATO, S. P. BISHOP, AND S. F. VATNER. Perfusion-contraction matching with coronary stenosis induces necrosis rather than hibernating myocardium in conscious pigs (Abstract). Circulation 94, Suppl. I: I-186, 1996.
117.
KUSUOKA, H.,
M. L. WEISFELDT,
J. L. ZWEIER,
W. E. JACOBUS,
AND E. MARBAN.
Mechanism of early contractile failure during hypoxia in intact ferret heart: evidence for modulation of maximal Ca2+-activated force by inorganic phosphate.
Circ. Res.
59: 270-282, 1986
118. LA CANNA, G., O. ALFIERI, R. GIUBBINI, M. GARGANO, R. FERRARI, AND O. VISIOLI. Echocardiography during infusion of dobutamine for identification of reversible dysfunction in patients with chronic coronary artery disease. J. Am. Coll. Cardiol. 23: 617-626, 1994.
119.
LEE, H. H.,
V. G. DÁVILA-ROMÁN,
P. A. LUDBROOK,
M. COURTOIS,
J. F. WALSH,
D. A. DELANO,
P. J. RUBIN,
AND R. J. GROPLER.
Dependency of contractile reserve on myocardial blood flow. Implications for the assessment of myocardial viability with dobutamine stress echocardiography.
Circulation
96: 2884-2891, 1997
120.
LEE, J. D.,
T. TAJIMI,
B. D. GUTH,
R. SEITELBERGER,
M. MILLER,
AND J. ROSS.
JR. Exercise-induced regional dysfunction with subcritical coronary stenosis.
Circulation
73: 596-605, 1986
121.
LEE, K. S.,
T. H. MARWICK,
S. A. COOK,
R. T. GO,
J. S. FIX,
K. B. JAMES,
S. K. SAPP,
W. J. MACINTYRE,
AND J. D. THOMAS.
Prognosis of patients with left ventricular dysfunction, with and without viable myocardium after myocardial infarction. Relative efficacy of medical therapy and revascularization.
Circulation
90: 2687-2694, 1994
122. LIEDTKE, A. J., B. RENSTROM, S. H. NELLIS, J. L. HALL, AND W. C. STANLEY. Mechanical and metabolic functions in pig hearts after 4 days of chronic coronary stenosis. J. Am. Coll. Cardiol. 26: 815-828, 1995[Abstract].
123.
LIEDTKE, A. J.,
B. RENSTROM,
S. H. NELLIS,
AND R. SUBRAMANIAN.
Myocardial function and metabolism in pig hearts after relief from chronic partial coronary stenosis.
Am. J. Physiol.
267(Heart Circ. Physiol. 36): H1312-H1319, 1994
124. LIU, Y., T. SATO, B. O'ROURKE, AND E. MARBAN. Mitochondrial ATP-dependent potassium channels. Novel effectors of cardioprotection? Circulation 97: 2463-2469, 1998.
125. LOUIE, H. W., H. LAKS, E. MILGALTER, AND D. C. DRINKWATER. JR., M. A. HAMILTON, R. C. BRUNKEN, AND L. W. STEVENSON. Ischemic cardiomyopathy criteria for coronary revascularization and cardiac transplantation. Circulation 84, Suppl. III: III-290-III-295, 1991.
126. LÜSS, H., G. BOKNIK, G. HEUSCH, F. U. MÜLLER, J. NEUMANN, W. SCHMITZ, AND R. SCHULZ. Expression of calcium regulatory proteins in short-term hibernation and stunning in the in situ porcine heart. Cardiovasc. Res. 37: 606-617, 1998[Medline].
127.
MA, L.,
L. CHEN,
L. GILLAM,
D. D. WATERS,
AND C. CHEN.
Nitroglycerin enhances the ability of dobutamine stress echocardiography to detect hibernating myocardium.
Circulation
96: 3992-4001, 1997
128. MAES, A., M. BORGERS, W. FLAMENG, J. L. NUYTS, F. VAN DE WERF, J. J. AUSMA, P. SERGEANT, AND L. A. MORTELMANS. Assessment of myocardial viability in chronic coronary artery disease using technetium-99m sestamibi SPECT. Correlation with histologic and positron emission tomographic studies and functional follow-up. J. Am. Coll. Cardiol. 29: 62-68, 1997[Abstract].
129.
MARBAN, E..
Myocardial stunning and hibernation. The physiology behind the colloquialisms.
Circulation
83: 681-688, 1991
130.
MARBAN, E.,
M. KITAKAZE,
V. P. CHACKO,
AND M. M. PIKE.
Ca2+ transients in perfused hearts revealed by gated 19F NMR spectroscopy.
Circ. Res.
63: 673-678, 1988
131. MARBER, M.. Viewpoint: stunning and long-term perfusion-contraction matching are clinically indistinguishable components of clinical hibernation and separation, even if practical, is unlikely to matter. Basic Res. Cardiol. 92, Suppl. 2: 26-29, 1997.
132.
MARBER, M. S.,
D. S. LATCHMAN,
J. M. WALKER,
AND D. M. YELLON.
Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction.
Circulation
88: 1264-1272, 1993
133.
MARINHO, N. V. S.,
B. E. KEOGH,
D. C. COSTA,
A. A. LAMMERSTMA,
P. J. ELL,
AND P. G. CAMICI.
Pathophysiology of chronic left ventricular dysfunction. New insights from the measurement of absolute myocardial blood flow and glucose utilization.
Circulation
93: 737-744, 1996
134.
MARTIN, C.,
R. SCHULZ,
J. ROSE,
AND G. HEUSCH.
Inorganic phosphate content and free energy change of ATP hydrolysis in regional short-term hibernating myocardium.
Cardiovasc. Res.
39: 318-326, 1998
135.
MARWICK, T. H.,
W. J. MACINTYRE,
A. LAFONT,
J. J. NEMEC,
AND E. E. SALCEDO.
Metabolic response of hibernating and infarcted myocardium to revascularization. A follow-up study of regional perfusion, function, and metabolism.
Circulation
85: 1347-1353, 1992
136. MARZULLO, P., O. PARODI, G. SAMBUCETI, A. GIORGETTI, E. PICANO, A. GIMELLI, P. SALVADORI, AND A. L'ABBATE. Residual coronary reserve identifies segmental viability in patients with wall motion abnormalities. J. Am. Coll. Cardiol. 26: 342-350, 1995[Abstract].
137.
MATSUZAKI, M.,
K. P. GALLAGHER,
W. S. KEMPER,
F. WHITE,
AND J. ROSS.
JR. Sustained regional dysfunction produced by prolonged coronary stenosis: gradual recovery after reperfusion.
Circulation
68: 170-182, 1983
138.
MÄKI, M.,
M. LUOTOLAHTI,
P. NUUTILA,
H. IIDA,
L.-M. VOIPIO-PULIKKI,
U. RUOTSALAINEN,
M. HAAPARANTA,
O. SOLIN,
J. HARTIALA,
R. HÄRKÖNEN,
AND J. KNUUTI.
Glucose uptake in the chronically dysfunctional but viable myocardium.
Circulation
93: 1658-1666, 1996
139. MÄKI, M. T., M. T. HAAPARANTA, M. S. LUOTOLAHTI, P. NUUTILA, L.-M. VOIPIO-PULKKI, J. R. BERGMAN, O. H. SOLIN, AND J. M. KNUUTI. Fatty acid uptake is preserved in chronically dysfunctional but viable myocardium. Am. J. Physiol. 273(Heart Circ. Physiol. 42): H2473-H2480, 1997[Medline].
140.
MCFALLS, E. O.,
D. BALDWIN,
B. PALMER,
D. MARX,
D. JAIMES,
AND H. B. WARD.
Regional glucose uptake within hypoperfused swine myocardium as measured by positron emission tomography.
Am. J. Physiol.
272(Heart Circ. Physiol. 41): H343-H349, 1997
141.
MEDRANO, R.,
R. W. LOWRY,
J. B. YOUNG,
D. G. WEILBAECHER,
L. H. MICHAEL,
I. AFRIDI,
Z. X. HE,
J. J. MAHMARIAN,
AND M. S. VERANI.
Assessment of myocardial viability with 99mTc sestamibi in patients undergoing cardiac transplantation. A scintigraphic/pathological study.
Circulation
94: 1010-1017, 1996
142.
MILLS, I.,
J. T. FALLON,
D. WRENN,
H. SASKEN,
W. GRAY,
J. BIER,
D. LEVINE,
S. BERMAN,
M. GILSON,
AND H. GEWIRTZ.
Adaptive responses of coronary circulation and myocardium to chronic reduction in perfusion pressure and flow.
Am. J. Physiol.
266(Heart Circ. Physiol. 35): H447-H457, 1994
143.
MIYAMAE, M.,
S. A. CAMACHO,
W. D. ROONEY,
G. MODIN,
H.-Z. ZHOU,
M. W. WEINER,
AND V. M. FIGUEREDO.
Inorganic phosphate and coronary perfusion pressure mediate contractile dysfunction during mild ischemia.
Am. J. Physiol.
273(Heart Circ. Physiol. 42): H566-H572, 1997
144.
MONTALESCOT, G.,
M. FARAGGI,
G. DROBINSKI,
O. MESSIAN,
J. EVANS,
Y. GROSGOGEAT,
AND D. THOMAS.
Myocardial viability in patients with Q wave myocardial infarction and no residual ischemia.
Circulation
86: 47-55, 1992
145. MUDGE, G. H.. JR., R. M. MILLS, JR., H. TAEGTMEYER, R. GORLIN, AND M. LESCH. Alterations of myocardial amino acid metabolism in chronic ischemic heart disease. J. Clin. Invest. 58: 1185-1192, 1976.
146.
MURRY, C. E.,
R. B. JENNINGS,
AND K. A. REIMER.
Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium.
Circulation
74: 1124-1136, 1986
147.
MURRY, C. E.,
V. J. RICHARD,
K. A. REIMER,
AND R. B. JENNINGS.
Ischemic preconditioning slows energy metabolism and delays ultrastructural damage during a sustained ischemic episode.
Circ. Res.
66: 913-931, 1990
148. NAGUEH, S. F., P. VADUGANATHAN, N. ALI, A. BLAUSTEIN, M. S. VERANI, AND W. L. WINTERS. JR., AND W. A. ZOGHBI. Identification of hibernating myocardium: comparative accuracy of myocardial contrast echocardiography, rest-redistribution thallium-201 tomography and dobutamine echocardiography. J. Am. Coll. Cardiol. 29: 985-993, 1997[Abstract].
149. NEILL, W. A., J. S. INGWALL, E. ANDREWS, M. A. GOPAL, K. KLEIN, M. KRAMER, J. M. OXENDINE, Z. H. PIOTROWSKI, AND I. REIS. Stabilization of a derangement in adenosine triphosphate metabolism during sustained, partial ischemia in the dog heart. J. Am. Coll. Cardiol. 8: 894-900, 1986[Abstract].
150. NOMA, A.. ATP-regulated K+ channels in cardiac muscle. Nature 305: 147-148, 1983[Medline].
151.
OFFSTAD, J.,
K. A. KIRKEBOEN,
A. ILEBEKK,
AND S. E. DOWNING.
ATP gated potassium channels in acute myocardial hibernation and reperfusion.
Cardiovasc. Res.
28: 872-880, 1994
152.
OFFSTAD, J.,
K. A. KIRKEBOEN,
K. LANDE,
AND A. ILEBEKK.
Cardiac adaptation to one hour of mild regional low flow ischemia in the pig.
Cardiovasc. Res.
27: 2248-2253, 1993
153.
OPIE, L. H..
Cardiac metabolism: emergence, decline, and resurgence.
Cardiovasc. Res.
26: 721-733, 1992
154.
PAGANI, M.,
S. F. VATNER,
H. BAIG,
AND E. BRAUNWALD.
Initial myocardial adjustment to brief periods of ischemia and reperfusion in the conscious dog.
Circ. Res.
43: 83-91, 1978
155.
PAGANO, D.,
R. S. BONSER,
J. N. TOWNEND,
F. ORDOUBADI,
R. LORENZONI,
AND P. G. CAMICI.
Predictive value of dobutamine echocardiography and positron emission tomography in identifying hibernating myocardium in patients with postischaemic heart failure.
Heart.
79: 281-288, 1998.
156.
PAGLEY, P. R.,
G. A. BELLER,
D. D. WATSON,
L. W. GIMPLE,
AND M. RAGOSTA.
Improved outcome after coronary bypass surgery in patients with ischemic cardiomyopathy and residual myocardial viability.
Circulation
96: 793-800, 1997
157.
PANTELY, G. A.,
S. A. MALONE,
W. S. RHEN,
C. G. ANSELONE,
A. ARAI,
J. BRISTOW,
AND J. D. BRISTOW.
Regeneration of myocardial phosphocreatine in pigs despite continued moderate ischemia.
Circ. Res.
67: 1481-1493, 1990
158.
PERRONE-FILARDI, P.,
L. PACE,
M. PRASTARO,
F. SQUAME,
S. BETOCCHI,
A. SORICELLI,
F. PISCIONE,
C. INDOLFI,
T. CRISCI,
M. SALVATORE,
AND M. CHIARIELLO.
Assessment of myocardial viability in patients with chronic coronary artery disease. Rest-4-hour-24-hour 201 TI tomography versus dobutamine echocardiography.
Circulation
94: 2712-2719, 1996
159. PRZYKLENK, K., B. BAUER, AND R. A. KLONER. Reperfusion of hibernating myocardium: contractile function, high-energy phosphate content, and myocyte injury after 3 hours of sublethal ischemia and 3 hours of reperfusion in the canine model. Am. Heart J. 123: 575-588, 1992[Medline].
160.
QURESHI, U.,
S. F. NAGUEH,
I. AFRIDI,
P. VADUGANATHAN,
A. BLAUSTEIN,
M. S. VERANI,
AND W. L. WINTERS.
JR., AND W. A. ZOGHBI. Dobutamine echocardiography and quantitative rest-redistribution 201TI tomography in myocardial hibernation. Relation of contractile reserve to 201TI uptake and comparative prediction of recovery of function.
Circulation
95: 626-635, 1997
161.
RAHIMTOOLA, S. H..
Coronary bypass surgery for chronic angina
1981.
Circulation
65: 225-241, 1982
162. RAHIMTOOLA, S. H.. A perspective on the three large multicenter randomized clinical trials of coronary bypass surgery for chronic stable angina. Circulation 72, Suppl. V: V-123-V-135, 1985.
163. RAHIMTOOLA, S. H.. The hibernating myocardium. Am. Heart J. 117: 211-221, 1989[Medline].
164. RAHIMTOOLA, S. H.. Hibernating myocardium. A brief article. Basic Res. Cardiol. 90: 38-40, 1995[Medline].
165.
RAHIMTOOLA, S. H..
Hibernating myocardium has reduced blood flow at rest that increases with low-dose dobutamine.
Circulation
94: 3055-3061, 1996
166. RAHIMTOOLA, S. H. Importance of diagnosing hibernating myocardium: how and in whom? J. Am. Coll. Cardiol. 30: 1701-1706, 1997.
167.
REIN, A. J. J. T.,
S. D. COLAN,
I. A. PARNESS,
AND S. P. SANDERS.
Regional and global left ventricular function in infants with anomalous origin of the left coronary artery from the pulmonary trunk: preoperative and postoperative assessment.
Circulation
75: 115-123, 1987
168.
ROSE, J.,
R. SCHULZ,
C. MARTIN,
AND G. HEUSCH.
Post-ejection wall thickening as a marker of successful short term hibernation.
Cardiovasc. Res.
27: 1306-1311, 1993
169.
ROSS, J..
JR. Myocardial perfusion-contraction matching. Implications for coronary heart disease and hibernation.
Circulation
83: 1076-1083, 1991
170. ROZANSKI, A., D. BERMAN, R. GRAY, G. DIAMOND, M. RAYMOND, J. PRAUSE, J. MADDAHI, H. J. C. SWAN, AND J. MATLOFF. Preoperative prediction of reversible myocardial asynergy by postexercise radionuclide ventriculography. N. Engl. J. Med. 307: 212-216, 1982[Abstract].
171. RÜEGG, J. C., M. SCHÄDLER, G. J. STEIGER, AND G. MÜLLER. Effect of inorganic phosphate on the contractile mechanism. Pflügers Arch. 325: 359-364, 1971[Medline].
172. SAMBUCETI, G., O. PARODI, P. MARZULLO, A. GIORGETTI, L. FUSANI, G. PUCCINI, P. SALVADORI, AND A. L'ABBATE. Regional myocardial blood flow in stable angina pectoris associated with isolated significant narrowing of either the left anterior descending or left circumflex coronary artery. Am. J. Cardiol. 72: 990-994, 1993[Medline].
173. SAWADA, S., G. ELSNER, D. S. SEGAR, M. O'SHAUGHNESSY, S. KHOURI, J. FOLTZ, P. D. V. BOURDILLON, J. R. BATES, N. FINEBERG, T. RYAN, G. D. HUTCHINS, AND H. FEIGENBAUM. Evaluation of patterns of perfusion and metabolism in dobutamine-responsive myocardium. J. Am. Coll. Cardiol. 29: 55-61, 1997[Abstract].
174.
SCHAEFER, S.,
L. J. CARR,
U. KREUTZER,
AND T. JUE.
Myocardial adaptation during acute hibernation: mechanisms of phosphocreatine recovery.
Cardiovasc. Res.
27: 2044-2051, 1993
175. SCHAEFER, S., E. PRUSSEL, AND L. J. CARR. Requirement of glycolytic substrate for metabolic recovery during moderate low flow ischemia. J. Mol. Cell. Cardiol. 27: 2167-2176, 1995[Medline].
176. SCHAEFER, S., G. G. SCHWARTZ, S. STEINMAN, J. GARCIA, S. D. TROCHA, M. W. WEINER, AND B. M. MASSIE. Effects of regional myocardial lidocaine infusion on high energy phosphates. J. Mol. Cell. Cardiol. 26: 1601-1611, 1994[Medline].
177.
SCHAEFER, S.,
G. G. SCHWARTZ,
J. A. WISNESKI,
S. D. TROCHA,
I. CHRISTOPH,
S. K. STEINMAN,
J. GARCIA,
B. M. MASSIE,
AND M. W. WEINER.
Response of high-energy phosphates and lactate during prolonged regional ischemia in vivo.
Circulation
85: 342-349, 1992
178. SCHÄFER, S., C. LINDER, AND G. HEUSCH. Xamoterol recruits an inotropic reserve in the acutely failing, reperfused canine myocardium without detrimental effects on its subsequent recovery. Naunyn-Schmiedebergs Arch. Pharmacol. 342: 206-213, 1990[Medline].
179. SCHAPER, J. Myocardial ultrastructure in ischemia. In: Pathophysiology and Rational Pharmacotherapy of Myocardial Ischemia, edited by G. Heusch. Darmstadt, Germany: Steinkopff, 1990, p. 11-36.
180. SCHIPKE, J. D., Y. HARASAWA, D. BURKHOFF, V. P. CHACKO, K. SAGAWA, AND W. E. JACOBUS. Decreased LV function secondary to decreased coronary arterial pressure (CAP) is not due to reduced high-energy phosphate content (Abstract). FASEB J. 3: A259, 1989.
181. SCHMIDT-OTT, S. C., C. BLETZ, C. VAHL, W. SAGGAU, S. HAGL, AND J. C. RÜEGG. Inorganic phosphate inhibits contractility and ATPase activity in skinned fibers from human myocardium. Basic Res. Cardiol. 85: 358-366, 1990[Medline].
182.
SCHULZ, R.,
B. D. GUTH,
K. PIEPER,
C. MARTIN,
AND G. HEUSCH.
Recruitment of an inotropic reserve in moderately ischemic myocardium at the expense of metabolic recovery: a model of short-term hibernation.
Circ. Res.
70: 1282-1295, 1992
183.
SCHULZ, R.,
C. KAPPELER,
H. H. COENEN,
A. BOCKISCH,
AND G. HEUSCH.
Positron emission tomography analysis of [1-11C]acetate kinetics in short-term hibernating myocardium.
Circulation
97: 1009-1016, 1998
184.
SCHULZ, R.,
H. POST,
S. SAKKA,
D. R. WALLBRIDGE,
AND G. HEUSCH.
Intraischemic preconditioning. Increased tolerance to sustained low-flow ischemia by a brief episode of no-flow ischemia without intermittent reperfusion.
Circ. Res.
76: 942-950, 1995
185.
SCHULZ, R.,
J. ROSE,
AND G. HEUSCH.
Involvement of activation of ATP-dependent potassium channels in ischemic preconditioning in swine.
Am. J. Physiol.
267(Heart Circ. Physiol. 36): H1341-H1352, 1994
186.
SCHULZ, R.,
J. ROSE,
C. MARTIN,
O. E. BRODDE,
AND G. HEUSCH.
Development of short-term myocardial hibernation: its limitation by the severity of ischemia and inotropic stimulation.
Circulation
88: 684-695, 1993
187. SCHULZ, R., J. ROSE, H. POST, AND G. HEUSCH. Involvement of endogenous adenosine in ischaemic preconditioning in swine. Pflügers Arch. 430: 273-282, 1995[Medline].
188.
SCHULZ, R.,
J. ROSE,
H. POST,
AND G. HEUSCH.
Regional short-term hibernation in swine does not involve endogenous adenosine or KATP channels.
Am. J. Physiol.
268(Heart Circ. Physiol. 37): H2294-H3201, 1995
189. SCHULZ, R., J. ROSE, C. VAHLHAUS, H. POST, U. BACKENKÖHLER, AND G. HEUSCH. No maintenance of perfusion-contraction matching during 24 hours sustained moderate myocardial ischemia in pigs (Abstract). FASEB J. 11: A432, 1997.
190. SCHWAIGER, M., H. R. SCHELBERT, D. ELLISON, H. HANSEN, L. YEATMAN, J. VINTEN-JOHANSEN, C. SELIN, J. BARRIO, AND M. E. PHELPS. Sustained regional abnormalities in cardiac metabolism after transient ischemia in the chronic dog model. J. Am. Coll. Cardiol. 6: 336-347, 1985[Abstract].
191. SCHWAIGER, M., H. R. SCHELBERT, R. KEEN, J. VINTEN-JOHANSEN, H. HANSEN, C. SELIN, J. BARRIO, S.-C. HUANG, AND M. E. PHELPS. Retention and clearance of C-11 palmitic acid in ischemic and reperfused canine myocardium. J. Am. Coll. Cardiol. 6: 311-320, 1985[Abstract].
192. SCHWARZ, E. R., J. SCHAPER, AND J. VOM. DAHL, C. ALTEHOEFER, B. GROHMAN, F. SCHOENDUBE, F. H. SHEEHAN, R. UEBIS, U. BUELL, B. J. MESSMER, W. SCHAPER, AND P. HANRATH. Myocyte degeneration and cell death in hibernating human myocardium. J. Am. Coll. Cardiol. 27: 1577-1585, 1996[Abstract].
193.
SHAH, A. M.,
A. MEBAZZA,
Z.-K. YANG,
G. CUDA,
E. B. LANKFORD,
C. B. PEPPER,
J. R. SELLERS,
J. L. ROBOTHAM,
AND E. G. LAKATTA.
Inhibition of myocardial crossbridge cycling by hypoxic endothelial cells. A potential mechanism for matching oxygen supply and demand.
Circ. Res.
80: 688-698, 1997
194. SHEN, Y.-T., R. K. KUDEJ, S. P. BISHOP, AND S. F. VATNER. Inotropic reserve and histological appearance of hibernating myocardium in conscious pigs with ameroid-induced coronary stenosis. Basic Res. Cardiol. 91: 479-485, 1996[Medline].
195.
SHEN, Y.-T.,
AND S. F. VATNER.
Mechanism of impaired myocardial function during progressive coronary stenosis in conscious pigs. Hibernation versus stunning.
Circ. Res.
76: 479-488, 1995
196.
SHEN, Y.-T.,
AND S. F. VATNER.
Differences in myocardial stunning following coronary artery occlusion in conscious dogs, pigs, and baboons.
Am. J. Physiol.
270(Heart Circ. Physiol. 39): H1312-H1322, 1996
197. SHERMAN, A. J., K. R. HARRIS, S. HEDJBELI, Y. YAROSHENKO, D. SCHAFER, S. SHROFF, J. SUNG, AND F. J. KLOCKE. Proportional reversible decreases in systolic function and myocardial oxygen consumption after modest reduction in coronary flow: hibernation versus stunning. J. Am. Coll. Cardiol. 29: 1623-1631, 1997[Abstract].
198. SHIVALKAR, B., M. BORGERS, W. DAENEN, M. GEWILLIG, AND W. FLAMENG. ALCAPA syndrome: an example of chronic myocardial hypoperfusion? J. Am. Coll. Cardiol. 23: 772-778, 1994.
199.
SHIVALKAR, B.,
A. MAES,
M. BORGERS,
J. AUSMA,
I. SCHEYS,
J. NUYTS,
L. MORTELMANS,
AND W. FLAMENG.
Only hibernating myocardium invariably shows early recovery after coronary revascularization.
Circulation
94: 308-315, 1996
200.
SILVERMAN, H. S.,
S. WEI,
M. C. P. HAIGNEY,
AND C. J. OCAMPO.
Myocyte adaptation to chronic hypoxia and development of tolerance to subsequent acute severe hypoxia.
Circ. Res.
80: 699-707, 1997
201.
SKOPICKI, H. A.,
S. A. ABRAHAM,
N. J. WEISSMAN,
A. K. MUKERJEE,
N. M. ALPERT,
A. J. FISCHMAN,
M. H. PICARD,
AND H. GEWIRTZ.
Factors influencing regional myocardial contractile response to inotropic stimulation. Analysis in humans with stable ischemic heart disease.
Circulation
94: 643-650, 1996
202. SOMMERSCHILD, H. T., J. OFFSTAD, F. GRUND, A. ILEBEKK, AND K. A. KIRKEBOEN. Characterization of metabolic responses to low-flow ischemia in intact pig hearts and isolated blood perfused neonatal pig hearts. Basic Res. Cardiol. 93: 38-49, 1998[Medline].
203. SONNTAG, M., A. DEUSSEN, J. SCHULTZ, R. LONCAR, W. HORT, AND J. SCHRADER. Spatial heterogeneity of blood flow in the dog heart. I. Glucose uptake, free adenosine and oxidative/glycolytic enzyme activity. Pflügers Arch. 532: 439-450, 1996.
204.
SUN, K. T.,
J. CZERNIN,
J. KRIVOKAPICH,
Y.-K. LAU,
M. BÖTTCHER,
G. MAURER,
M. E. PHELPS,
AND H. R. SCHELBERT.
Effects of dobutamine stimulation on myocardial blood flow, glucose metabolism, and wall motion in normal and dysfunctional myocardium.
Circulation
94: 3146-3154, 1996
205. TAMAKI, N., Y. YONEKURA, K. YAMASHITA, H. SAJI, Y. MAGATA, M. SENDA, Y. KONISHI, K. HIRATA, T. BAN, AND J. KONISHI. Positron emission tomography using fluorine-18 deoxyglucose in evaluation of coronary artery bypass grafting. Am. J. Cardiol. 64: 860-865, 1989[Medline].
206.
THEROUX, P.,
D. FRANKLIN,
AND J. ROSS.
JR., AND W. S. KEMPER. Regional myocardial function during acute coronary artery occlusion and its modification by pharmacological agents in the dog.
Circ. Res.
35: 896-908, 1974
207.
THEROUX, P.,
AND J. ROSS.
JR., D. FRANKLIN, W. S. KEMPER, AND S. SASAYAMA. Regional myocardial function in the conscious dog during acute coronary occlusion and responses to morphine, propranolol, nitroglycerin, and lidocaine.
Circulation
53: 302-314, 1976
208. TILLISCH, J., R. BRUNKEN, R. MARSHALL, M. SCHWAIGER, M. MANDELKERN, M. PHELPS, AND H. SCHELBERT. Reversibility of cardiac wall-motion abnormalities predicted by positron emission tomography. N. Engl. J. Med. 314: 884-888, 1986[Abstract].
209. TOPOL, E. J., J. L. WEISS, P. A. GUZMAN, S. DORSEY-LIMA, T. J. J. BLANCK, L. S. HUMPHREY, W. A. BAUMGARTNER, J. T. FLAHERTY, AND B. A. REITZ. Immediate improvement of dysfunctional myocardial segments after coronary revascularization: detection by intraoperative transesophageal echocardiography. J. Am. Coll. Cardiol. 4: 1123-1134, 1984[Abstract].
210. TORRE, M. A., E. PICANO, G. PARODI, R. SICARI, F. VEGLIA, A. GIORGETTI, P. MARZULLO, AND O. PARODI. Flow-function relation in patients with chronic coronary artery disease and reduced regional function. A positron emission tomographic and two-dimensional echocardiographic study with coronary vasodilator stress. J. Am. Coll. Cardiol. 30: 65-70, 1997[Abstract].
211. VAN BINSBERGEN, X. A., J. G. VAN EMOUS, R. FERRARI, C. J. A. VAN ECHTELD, AND T. J. C. RUIGROK. Metabolic and functional consequences of successive no-flow and sustained low-flow ischaemia: a 31P MRS study in rat hearts. J. Mol. Cell. Cardiol. 28: 2373-2381, 1996[Medline].
212. VANOVERSCHELDE, J.-L. J., A.-M. D'HONDT, T. MARWICK, B. L. GERBER, M. DE KOCK, R. DION, W. WIJNS, AND J. A. MELIN. Head-to-head comparison of exercise-redistribution-reinjection thallium single-photon emission computed tomography and low dose dobutamine echocardiography for prediction of reversibility of chronic left ventricular ischemic dysfunction. J. Am. Coll. Cardiol. 28: 432-442, 1996[Abstract].
213.
VANOVERSCHELDE, J.-L. J.,
W. WIJNS,
M. BORGERS,
G. R. HEYNDRICKX,
C. DEPRÉ,
W. FLAMENG,
AND J. A. MELIN.
Chronic myocardial hibernation in humans. From bedside to bench.
Circulation
95: 1961-1971, 1997
214.
VANOVERSCHELDE, J.-L. J.,
W. WIJNS,
C. DEPRÉ,
B. ESSAMRI,
G. R. HEYNDRICKX,
M. BORGERS,
A. BOL,
AND J. A. MELIN.
Mechanisms of chronic regional postischemic dysfunction in humans. New insights from the study of noninfarcted collateral-dependent myocardium.
Circulation
87: 1513-1523, 1993
215.
VATNER, S. F..
Correlation between acute reductions in myocardial blood flow and function in conscious dogs.
Circ. Res.
47: 201-207, 1980
216. VOM DAHL, J., C. ALTEHOEFER, P. BÜCHIN, F. H. SHEEHAN, E. R. SCHWARZ, K.-C. KOCH, G. SCHULZ, R. UEBIS, F. SCHÖNDUBE, U. BÜLL, AND P. HANRATH. Impact of myocardial viability and coronary revascularization on clinical outcome and prognosis: an observational study in 161 patients with coronary artery disease. Z. Kardiol. 85: 868-881, 1996.
217.
WEINTRAUB, W. S.,
S. HATTORI,
J. B. AGARWAL,
M. M. BODENHEIMER,
V. S. BANKA,
AND R. H. HELFANT.
The relationship between myocardial blood flow and contraction by myocardial layer in the canine left ventricle during ischemia.
Circ. Res.
48: 430-438, 1981
218. WILLIAMS, M. J., J. ODABASHIAN, M. S. LAUER, J. D. THOMAS, AND T. H. MARWICK. Prognostic value of dobutamine echocardiography in patients with left ventricular dysfunction. J. Am. Coll. Cardiol. 27: 132-139, 1996[Abstract].
219.
WOLFE, C. L.,
R. E. SIEVERS,
F. L. J. VISSEREN,
AND T. J. DONNELLY.
Loss of myocardial protection after preconditioning correlates with the time course of glycogen recovery within the preconditioned segment.
Circulation
87: 881-892, 1993
220.
WOLPERS, H. G.,
W. BURCHERT,
J. VAN DEN HOFF,
R. WEINHARDT,
G.-J. MEYER,
AND P. R. LICHTLEN.
Assessment of myocardial viability by use of 11C-acetate and positron emission tomography. Threshold criteria of reversible dysfunction.
Circulation
95: 1417-1424, 1997
221. YELLON, D. M., D. S. LATCHMAN, AND M. S. MARBER. Stress proteins, an endogenous route to myocardial protection: fact or fiction? Cardiovasc. Res. 27: 158-161, 1993.
222.
ZHANG, J.,
Y. ISHIBASHI,
Y. ZHANG,
M. H. J. EIJGELSHOVEN,
D. J. DUNCKER,
H. MERKLE,
R. J. BACHE,
K. UGURBIL,
AND A. H. L. FROM.
Myocardial bioenergetics during acute hibernation.
Am. J. Physiol.
273(Heart Circ. Physiol. 42): H1452-H1463, 1997
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J J Bax, D Poldermans, and E E van der Wall Evaluation of hibernating myocardium Heart, November 1, 2004; 90(11): 1239 - 1240. [Full Text] [PDF] |
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C. Depre, S.-J. Kim, A. S. John, Y. Huang, O. E. Rimoldi, J. R. Pepper, G. D. Dreyfus, V. Gaussin, D. J. Pennell, D. E. Vatner, et al. Program of Cell Survival Underlying Human and Experimental Hibernating Myocardium Circ. Res., August 20, 2004; 95(4): 433 - 440. [Abstract] [Full Text] [PDF] |
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S. Sun, M. H. Weil, W. Tang, T. Kamohara, and K. Klouche {delta}-Opioid receptor agonist reduces severity of postresuscitation myocardial dysfunction Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H969 - H974. [Abstract] [Full Text] [PDF] |
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A. Elsasser, A. M. Vogt, H. Nef, S. Kostin, H. Mollmann, W. Skwara, C. Bode, C. Hamm, and J. Schaper Human hibernating myocardium is jeopardized by apoptotic and autophagic cell death J. Am. Coll. Cardiol., June 16, 2004; 43(12): 2191 - 2199. [Abstract] [Full Text] [PDF] |
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C. Michiels Physiological and Pathological Responses to Hypoxia Am. J. Pathol., June 1, 2004; 164(6): 1875 - 1882. [Abstract] [Full Text] [PDF] |
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S.R. Underwood, J. J Bax, J. v. Dahl, M. Y Henein, A. C van Rossum, E. R Schwarz, J.-L. Vanoverschelde, E. E.v. d. Wall, and W. Wijns Imaging techniques for the assessment of myocardial hibernation: Report of a Study Group of the European Society of Cardiology Eur. Heart J., May 2, 2004; 25(10): 815 - 836. [Abstract] [Full Text] [PDF] |
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N. J. Severs, S. R. Coppen, E. Dupont, H.-I Yeh, Y.-S. Ko, and T. Matsushita Gap junction alterations in human cardiac disease Cardiovasc Res, May 1, 2004; 62(2): 368 - 377. [Abstract] [Full Text] [PDF] |
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G. Heusch and K. R. Sipido Myocardial Hibernation: A Double-Edged Sword Circ. Res., April 30, 2004; 94(8): 1005 - 1007. [Full Text] [PDF] |
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L. Lee, J. Horowitz, and M. Frenneaux Metabolic manipulation in ischaemic heart disease, a novel approach to treatment Eur. Heart J., April 2, 2004; 25(8): 634 - 641. [Abstract] [Full Text] [PDF] |
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V. Bito, F. R. Heinzel, F. Weidemann, C. Dommke, J. van der Velden, E. Verbeken, P. Claus, B. Bijnens, I. De Scheerder, G. J.M. Stienen, et al. Cellular Mechanisms of Contractile Dysfunction in Hibernating Myocardium Circ. Res., April 2, 2004; 94(6): 794 - 801. [Abstract] [Full Text] [PDF] |
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D. A Gorog, M. Tanno, X. Cao, M. Bellahcene, R. Bassi, A. M.N Kabir, K. Dighe, R. A Quinlan, and M. S Marber Inhibition of p38 MAPK activity fails to attenuate contractile dysfunction in a mouse model of low-flow ischemia Cardiovasc Res, January 1, 2004; 61(1): 123 - 131. [Abstract] [Full Text] [PDF] |
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M. Nahrendorf, K.-H. Hiller, A. Greiser, S. Kohler, T. Neuberger, K. Hu, C. Waller, M. Albrecht, S. Neubauer, A. Haase, et al. Chronic coronary artery stenosis induces impaired function of remote myocardium: MRI and spectroscopy study in rat Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2712 - H2721. [Abstract] [Full Text] [PDF] |
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G. G. Neri Serneri, M. Boddi, P. A. Modesti, I. Cecioni, M. Coppo, M. L. Papa, T. Toscano, A. Marullo, and M. Chiavarelli Immunomediated and Ischemia-Independent Inflammation of Coronary Microvessels in Unstable Angina Circ. Res., June 27, 2003; 92(12): 1359 - 1366. [Abstract] [Full Text] [PDF] |
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R. Southworth and P. B. Garlick Dobutamine responsiveness, PET mismatch, and lack of necrosis in low-flow ischemia: is this hibernation in the isolated rat heart? Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H316 - H324. [Abstract] [Full Text] [PDF] |
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E. o. Cosar and C. J. O'Connor Hibernation, Stunning, and Preconditioning: Historical Perspective, Current Concepts, Clinical Applications, and Future Implications Seminars in Cardiothoracic and Vascular Anesthesia, June 1, 2003; 7(2): 115 - 140. [Abstract] [PDF] |
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R. S. Ronson, J. D. Puskas, V. H. Thourani, D. A. Velez, B. L. Bufkin, J. Glass, R. A. Guyton, and J. Vinten-Johansen Controlled intermittent asystole cardiac therapy induced by pharmacologically potentiated vagus nerve stimulation in normal and hibernating myocardium Ann. Thorac. Surg., June 1, 2003; 75(6): 1929 - 1936. [Abstract] [Full Text] [PDF] |
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O. Dewald, N. G. Frangogiannis, M. Zoerlein, G. D. Duerr, C. Klemm, P. Knuefermann, G. Taffet, L. H. Michael, J. D. Crapo, A. Welz, et al. Development of murine ischemic cardiomyopathy is associated with a transient inflammatory reaction and depends on reactive oxygen species PNAS, March 4, 2003; 100(5): 2700 - 2705. [Abstract] [Full Text] [PDF] |
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P. G Camici and O. E Rimoldi Myocardial blood flow in patients with hibernating myocardium Cardiovasc Res, February 1, 2003; 57(2): 302 - 311. [Abstract] [Full Text] [PDF] |
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J. A. Fallavollita, B. J. Malm, and J. M. Canty Jr Hibernating Myocardium Retains Metabolic and Contractile Reserve Despite Regional Reductions in Flow, Function, and Oxygen Consumption at Rest Circ. Res., January 10, 2003; 92(1): 48 - 55. [Abstract] [Full Text] [PDF] |
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G. Heusch and R. Schulz Hibernating Myocardium: New Answers, Still More Questions! Circ. Res., November 15, 2002; 91(10): 863 - 865. [Full Text] [PDF] |
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S. A. Thomas, J. A. Fallavollita, G. Suzuki, M. Borgers, and J. M. Canty Jr Dissociation of Regional Adaptations to Ischemia and Global Myolysis in an Accelerated Swine Model of Chronic Hibernating Myocardium Circ. Res., November 15, 2002; 91(10): 970 - 977. [Abstract] [Full Text] [PDF] |
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J. A. Fallavollita, M. Logue, and J. M. Canty Jr. Coronary patency and its relation to contractile reserve in hibernating myocardium Cardiovasc Res, July 1, 2002; 55(1): 131 - 140. [Abstract] [Full Text] [PDF] |
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N. G. Frangogiannis, S. Shimoni, S. Chang, G. Ren, O. Dewald, C. Gersch, K. Shan, C. Aggeli, M. Reardon, G. V. Letsou, et al. Active interstitial remodeling: an important process in the hibernating human myocardium J. Am. Coll. Cardiol., May 1, 2002; 39(9): 1468 - 1474. [Abstract] [Full Text] [PDF] |
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A. Elsasser, K.-D. Muller, W. Skwara, C. Bode, W. Kubler, and A. M. Vogt Severe energy deprivation of human hibernating myocardium as possible common pathomechanism of contractile dysfunction, structural degeneration and cell death J. Am. Coll. Cardiol., April 3, 2002; 39(7): 1189 - 1198. [Abstract] [Full Text] [PDF] |
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K. Hamano, T.-S. Li, T. Kobayashi, K. Hirata, M. Yano, M. Kohno, and M. Matsuzaki Therapeutic angiogenesis induced by local autologous bone marrow cell implantation Ann. Thorac. Surg., April 1, 2002; 73(4): 1210 - 1215. [Abstract] [Full Text] [PDF] |
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N. G. Frangogiannis, S. Shimoni, S. M. Chang, G. Ren, K. Shan, C. Aggeli, M. J. Reardon, G. V. Letsou, R. Espada, M. Ramchandani, et al. Evidence for an Active Inflammatory Process in the Hibernating Human Myocardium Am. J. Pathol., April 1, 2002; 160(4): 1425 - 1433. [Abstract] [Full Text] [PDF] |
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R. G. Boutilier Mechanisms of cell survival in hypoxia and hypothermia J. Exp. Biol., March 11, 2002; 204(18): 3171 - 3181. [Abstract] [Full Text] [PDF] |
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L. A. Nikolaidis, T. Hentosz, A. Doverspike, R. Huerbin, C. Stolarski, Y.-T. Shen, and R. P. Shannon Mechanisms whereby rapid RV pacing causes LV dysfunction: perfusion-contraction matching and NO Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2270 - H2281. [Abstract] [Full Text] [PDF] |
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R. Schulz, H. Post, T. Neumann, P. Gres, H. Luss, and G. Heusch Progressive loss of perfusion-contraction matching during sustained moderate ischemia in pigs Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H1945 - H1953. [Abstract] [Full Text] [PDF] |
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R. Schulz, P. Gres, and G. Heusch Role of endogenous opioids in ischemic preconditioning but not in short-term hibernation in pigs Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2175 - H2181. [Abstract] [Full Text] [PDF] |
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F. J. Giordano, H.-P. Gerber, S.-P. Williams, N. VanBruggen, S. Bunting, P. Ruiz-Lozano, Y. Gu, A. K. Nath, Y. Huang, R. Hickey, et al. A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function PNAS, April 25, 2001; (2001) 91415198. [Abstract] [Full Text] |
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P. G. Camici and D. P. Dutka Repetitive stunning, hibernation, and heart failure: contribution of PET to establishing a link Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H929 - H936. [Full Text] [PDF] |
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K. Przyklenk and R. A. Kloner Sildenafil citrate (Viagra) does not exacerbate myocardial ischemia in canine models of coronary artery stenosis J. Am. Coll. Cardiol., January 1, 2001; 37(1): 286 - 292. [Abstract] [Full Text] [PDF] |
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T. Stumpe and J. Schrader Short-term hibernation in adult cardiomyocytes is PO2 dependent and Ca2+ mediated Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H42 - H50. [Abstract] [Full Text] [PDF] |
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A. Tawakol, H. A. Skopicki, S. A. Abraham, N. M. Alpert, A. J. Fischman, M. H. Picard, and H. Gewirtz Evidence of reduced resting blood flow in viable myocardial regions with chronic asynergy J. Am. Coll. Cardiol., December 1, 2000; 36(7): 2146 - 2153. [Abstract] [Full Text] [PDF] |
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R Schulz and G Heusch Hibernating myocardium Heart, December 1, 2000; 84(6): 587 - 594. [Full Text] |
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H. Dorge, T. Neumann, M. Behrends, A. Skyschally, R. Schulz, C. Kasper, R. Erbel, and G. Heusch Perfusion-contraction mismatch with coronary microvascular obstruction: role of inflammation Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2587 - H2592. [Abstract] [Full Text] [PDF] |
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U. Schwanke, A. Deussen, G. Heusch, and J. D. Schipke Heterogeneity of local myocardial flow and oxidative metabolism Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H1029 - H1035. [Abstract] [Full Text] [PDF] |
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R. Schulz, J. Rose, H. Post, A. Skyschally, and G. Heusch Less afterload sensitivity in short-term hibernating than in acutely ischemic and stunned myocardium Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H1106 - H1110. [Abstract] [Full Text] [PDF] |
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G. Heusch, H. Post, M. C. Michel, M. Kelm, and R. Schulz Endogenous Nitric Oxide and Myocardial Adaptation to Ischemia Circ. Res., July 21, 2000; 87(2): 146 - 152. [Abstract] [Full Text] [PDF] |
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R. Erbel and G. Heusch Coronary microembolization J. Am. Coll. Cardiol., July 1, 2000; 36(1): 22 - 24. [Full Text] [PDF] |
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A. J. Sherman, F. J. Klocke, R. S. Decker, M. L. Decker, K. A. Kozlowski, K. R. Harris, S. Hedjbeli, Y. Yaroshenko, S. Nakamura, M. A. Parker, et al. Myofibrillar disruption in hypocontractile myocardium showing perfusion-contraction matches and mismatches Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1320 - H1334. [Abstract] [Full Text] [PDF] |
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J.W.T Fiolet and A Baartscheer Cellular calcium homeostasis during ischemia; a thermodynamic approach Cardiovasc Res, January 1, 2000; 45(1): 100 - 106. [Full Text] [PDF] |
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J. M. Canty Jr. and J. A. Fallavollita Resting myocardial flow in hibernating myocardium: validating animal models of human pathophysiology Am J Physiol Heart Circ Physiol, July 1, 1999; 277(1): H417 - H422. [Full Text] [PDF] |
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K. W. Saupe, F. R. Eberli, J. S. Ingwall, and C. S. Apstein Hypoperfusion-induced contractile failure does not require changes in cardiac energetics Am J Physiol Heart Circ Physiol, May 1, 1999; 276(5): H1715 - H1723. [Abstract] [Full Text] [PDF] |
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F. J. Giordano, H.-P. Gerber, S.-P. Williams, N. VanBruggen, S. Bunting, P. Ruiz-Lozano, Y. Gu, A. K. Nath, Y. Huang, R. Hickey, et al. A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function PNAS, May 8, 2001; 98(10): 5780 - 5785. [Abstract] [Full Text] [PDF] |
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J. A. Fallavollita and J. M. Canty Jr. Ischemic cardiomyopathy in pigs with two-vessel occlusion and viable, chronically dysfunctional myocardium Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1370 - H1379. [Abstract] [Full Text] [PDF] |
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E. Barnes, D. P. Dutka, M. Khan, P. G. Camici, and R. J. Hall Effect of repeated episodes of reversible myocardial ischemia on myocardial blood flow and function in humans Am J Physiol Heart Circ Physiol, May 1, 2002; 282(5): H1603 - H1608. [Abstract] [Full Text] [PDF] |
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