(Circulation. 1997;95:1961-1971.)
© 1997 American Heart Association, Inc.
Articles |
Chronic Myocardial Hibernation in Humans
From Bedside to Bench
the Division of Cardiology, University of Louvain, Brussels (J.-L.J.V., C.D., J.A.M.); the Cardiovascular Center, Aalst (W.W., G.H.); the Janssen Research Foundation, Beerse (M.B.); and the Department of Cardiovascular Surgery, Katholieke Universiteit Leuven (W.F.), Belgium.
Correspondence to Jean-Louis Vanoverschelde, MD, Divisionof Cardiology, Cliniques Universitaires St Luc, Ave Hippocrate10 (2881), B-1200 Brussels, Belgium. E-mail vanoverschelde{at}card.ucl.ac.be
Key Words: myocardium • stunning, myocardial • blood flow • tomography • metabolism
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Introduction |
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 Top Introduction Perfusion-Contraction Matching...Structural Determinants of...Recruitable Inotropic Reserve in...References |
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Since the pioneering work of Tennant and Wiggers,1 it has been known that total ischemia leads to a prompt cessation of contraction and eventually results in the appearance of cell damage and irreversible myocardial necrosis. Accordingly, in the minds of many cardiologists, the discovery of an abnormal regional contraction in a patient with coronary artery disease has long been equated with the presence of irreversible myocardial necrosis. With the advent of recanalization therapy, however, evidence progressively accumulated that prolonged regional "ischemic" dysfunction did not always arise from irreversible tissue damage and, to some extent, could be reversed by restoration of blood flow.2 3 4 5 These observations have led to the speculation that chronically hypoperfused myocardium, which is often referred to as "hibernating,"2 3 4 5 6 could maintain viability by simply reducing its metabolic demand to match the decreased supply for as long as myocardial perfusion was inadequate. The chronic impairment of contractile function in this setting has been regarded as a protective mechanism by which the heart spontaneously downgrades its myocardial function, minimizes its energy requirements, and prevents the appearance of irreversible tissue damage.2 4 5 The concept of chronic hibernation thus consists of two parts: a unique clinical observation that bears important implications for the management of patients with chronic coronary artery disease2 3 4 5 6 and a pathophysiological hypothesis, yet to be demonstrated, implying that the chronic dysfunction is due to a chronic reduction of resting MBF.4 5 Other aspects that were not included in the original description, ie, the rapidity of mechanical recovery after successful revascularization7 and the response of dysfunctional myocardium to inotropic stimulation, are now also considered to be integral parts of this condition. The purpose of this discussion is to review some of the more recent advances to the understanding of the pathophysiology of chronic myocardial hibernation in humans. Emphasis will be placed on regional perfusion-contraction matching in both the experimental and the clinical settings, on the peculiar morphological changes that have been shown to occur in the hibernating myocardium, on the determinants of mechanical reversibility on restoration of adequate coronary patency, and on the presence of recruitable inotropic reserve.
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Perfusion-Contraction Matching in Myocardial Hibernation |
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TopIntroductionPerfusion-Contraction Matching...Structural Determinants of...Recruitable Inotropic Reserve in...References |
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The term "hibernation" was first used by Diamond et al6 in 1978 to describe the chronic wall motion abnormalities of patients with coronary artery disease but no previous myocardial infarction and their reversibility after revascularization, and it was subsequently popularized by Rahimtoola4 5 and Braunwald and Rutherford.2 In his 1989 description of the syndrome, Rahimtoola4 postulated that this peculiar condition resulted from the "relatively uncommon response to reduced MBF at rest whereby the heart downgrades its myocardial function to the extent that blood flow and function are once again in equilibrium, and as a result, neither myocardial necrosis nor ischemic symptoms are present." The definition of myocardial hibernation, as formulated by Rahimtoola, thus implies that (1) the heart can spontaneously adapt to chronic underperfusion (the "smart heart" hypothesis), (2) a new steady state between perfusion and contraction can be reached, and (3) this new equilibrium can be maintained for a prolonged period of time. This definition raises two important, albeit conceptually different, questions: the first is whether the heart can adapt to prolonged periods of underperfusion while avoiding necrosis; the second, and more clinically relevant, is whether chronic left ventricular ischemic dysfunction in humans represents such an adaptive response to a chronic reduction of resting MBF. To answer the first question necessitates development of animal models of sustained perfusion-contraction matching and demonstration that it can be perpetuated over the long term.8 To answer the second question requires simultaneous assessment of perfusion and contraction directly in patients with hibernating myocardium.
Flow-Function Relations During Partial Coronary Occlusion
The tight coupling between coronary flow, myocardial oxygen consumption, and contractile performance of the heart is a fundamental principle of cardiac physiology. Because of the small extraction reserve of oxygen, decreases in coronary blood flow rapidly translate into decreases in contractile performance.1 Several studies have examined the relation between regional MBF (radioactive microspheres) and function (sonomicrometry) in both open-chest9 and conscious10 11 dogs undergoing graded reductions in coronary flow. These studies have demonstrated the existence of a close coupling between the supply of myocardial substrates, including O2, of which the measurement of regional perfusion provides a rough estimate,12 and myocardial energy demand, as reflected by the steady-state level of regional contraction. The proportional decrease in regional myocardial flow and function in this setting has been called "acute perfusion-contraction matching" and is typical of acute myocardial ischemia. Reperfusion after very short periods of low coronary flow (<10 minutes) usually results in rapid and complete restoration of cardiac performance. There is no necrosis, and myocardial ultrastructure is normal. More prolonged periods of coronary flow reduction, up to 15 to 20 minutes, do not usually cause tissue necrosis but, with reperfusion, are associated with a prolonged, albeit reversible, dysfunction that has been called myocardial stunning.13 Further increases in the duration of ischemia usually result in variable degrees of irreversible cell damage.14
Myocardial Hibernation as an Adaptive Response to Sustained Reduction of Resting MBF
The observation that under acute conditions myocardial contraction decreases to a level matched to the available blood supply has inclined investigators to examine whether sustained perfusion-contraction matching could be achieved without necrosis being induced. Studies in open-chest anesthetized animals undergoing 1 to 5 hours of partial coronary occlusion have shown that the heart can indeed adapt to a sustained reduction of resting MBF.15 16 17 18 19 20 Several investigators have reported on the successful development of sustained low-flow perfusion-contraction matching (also called short-term hibernation) in both dog15 and pig heart.16 17 18 19 20 Ischemia was produced by incomplete coronary occlusion leading to a 20% to 70% reduction of transmural MBF. Despite continuing low flow and dysfunction, intriguing phenomena were observed, including the spontaneous resolution of some of the metabolic markers of ischemia (mainly lactate production)15 16 and the regeneration of PCr back to nearly normal levels.17 18 19 20 Short-term hibernation is a fragile and unstable condition, however, because superimposition of a chronotropic or inotropic stress invariably results in increased lactate production, decreased PCr, and eventually myocardial necrosis.19 20
Although the above findings suggest that a precarious steady state between reduced oxygen supply and decreased oxygen demand can be achieved and maintained for some time under particular experimental conditions, few data are presently available to indicate that such a perfusion-contraction matching can persist for weeks or months in animals under long-term study. On the contrary, most investigators who have thus far succeeded in reproducing long-term (>1 week) but reversible regional left ventricular ischemic dysfunction in the experimental laboratory have ended up with models of perfusion-contraction mismatch. Canty and Klocke21 examined the temporal response of regional function after ameroid implantation in conscious dogs. In their model, regional contraction was found to decrease progressively during the course of ameroid occlusion. Yet, at the time of ameroid occlusion (2 to 4 weeks), the measurements of regional endocardial blood flow showed a dissociation between flow and function. Bolukoglu et al22 and Liedtke et al23 achieved sustained reduction in segmental shortening without necrosis in swine undergoing a 50% reduction of the left anterior descending coronary artery flow velocity for 7 days. In these experiments too, the decrease in segmental function was progressive over time and was not associated with reduced subendocardial blood flow by day 4. More recently, Shen and Vatner24 and Fallavollita et al25 in pigs as well as Gerber et al26 in dogs succeeded in producing regional contractile dysfunction over periods of 1, 3, and 6 months, respectively. In each of these studies, the severity of regional dysfunction was found to be out of proportion to the reduction in MBF, thus demonstrating perfusion-contraction mismatch. Although the above studies do not dismiss the possibility that chronic perfusion-contraction matching could exist in intact animals over prolonged periods of time, they nevertheless suggest that chronic underperfusion is not a necessary prerequisite to the development of chronic dysfunction in the presence of chronic coronary artery stenoses.
Perfusion-Contraction Matching in Patients With Hibernating Myocardium
Assessment of perfusion-contraction matching in patients with hibernating myocardium requires the ability to measure blood flow and function simultaneously.8 Direct assessment of resting MBF in patients is complicated by two factors: the difficulty of measuring MBF in absolute terms in the clinical setting and the known tissue heterogeneity of ischemically injured myocardium. The contention that flow is decreased in human hibernating myocardium is based on the results of clinical studies of the relative distribution of radiolabeled flow tracers such as 201Tl,27 28 29 82Rb,30 or 99mTc-MIBI.31 The interpretation of these scintigrams usually assumes that the segments with maximum tracer uptake have normal flow and that any region with an apparent reduction of tracer uptake is underperfused. Because perfusion scintigraphy provides only estimates of relative differences in tracer distribution, a seemingly decreased perfusion to a dysfunctional segment may result in part from an absolute increase in flow to the remote hyperfunctioning tissue.32 The accuracy of relative perfusion scintigraphy is further affected by the limited spatial resolution of the current SPECT devices. This results in significant underestimation of true regional activity concentrations, a phenomenon known as "partial volume effect," which describes how counts measured from a myocardial region with reduced wall thickness will always be lower than those measured from a region with a normal wall thickness.33 The partial volume effect is particularly relevant to the situation of the hibernating myocardium, because the sole loss of systolic wall thickening is expected to result in a 20% to 25% underestimation of regional counts.34 The degree of underestimation can be even larger in the presence of significant wall thinning. Taken together, these limitations make it difficult to determine whether a dysfunctional myocardial segment that exhibits reduced radiolabeled flow tracer uptake at rest with SPECT is truly underperfused or not. Recent refinements in myocardial perfusion imaging, and particularly the advent of PET, have greatly enhanced our ability to measure flow directly in patients with coronary artery disease.35 36 37 PET is a truly quantitative method. It has a much better spatial resolution than SPECT; it allows for accurate correction of photon attenuation and, to some extent, of partial volume effects; and finally, when mathematically and physiologically appropriate models are used to describe the biological behavior of the radiotracers in blood and myocardium, it allows for computation of quantitative estimates of regional myocardial perfusion. Several investigators have attempted to assess the level of resting MBF in patients with hibernating myocardium by PET. Initial studies in patients with previous myocardial infarction indicated that reversibly dysfunctional segments corresponded to areas with qualitatively reduced perfusion but preserved metabolism.38 39 40 However, quantitative studies using [13N]ammonia found that reversibly dysfunctional segments after revascularization had normal or only mildly reduced baseline flow compared with remote, normally contracting areas in the same patients, and myocardial segments with persistent dysfunction had even lower values.41 42
On the basis of these studies, one could inadvertently conclude that the hibernating myocardium is indeed characterized by a mildly reduced perfusion. Two important aspects must nonetheless be considered. First, the level of flow reduction in most studies is not sufficient to justify ischemic dysfunction.8 Second, many if not all of the above studies have included a variable proportion of patients with previous myocardial infarction, which greatly complicates the interpretation of the flow data. Flow estimates with PET are indeed critically dependent on the mass of tissue that actively participates in tracer exchange within the region of interest. In the presence of marked spatial tissue heterogeneity, such as occurs in previously infarcted myocardium, flow estimates represent the transmural average between several values from very low in microinfarcted areas to almost normal in the noninfarcted epicardial zones and thus may not reflect the actual level of flow seen in the viable part of the wall. One approach to circumvent this problem is to study carefully selected patients with hibernating myocardium in whom any evidence of previous myocardial infarction is lacking. Vanoverschelde et al32 studied 26 patients whose clinical and angiographic characteristics were quite similar to those initially described by Rahimtoola.4 All had symptomatic coronary artery disease, no previous myocardial infarction, and complete chronic occlusion of a major coronary artery. In patients with normal resting wall motion, no difference in MBF measured with [13N]ammonia and PET was found between normal and collateral-dependent myocardium. In patients with abnormal resting wall motion, MBF was higher in remote than in collateral-dependent segments (95±27 versus 77±25 mL·min-1·100 g-1, P<.001). Yet no difference was found among collateral-dependent segments from patients with and without wall motion abnormalities (77±25 versus 85±14 mL·min-1·100 g-1, P=NS) (Fig 1
). To corroborate their surprising results, the authors also investigated regional myocardial oxygen consumption using [11C]acetate and PET. In patients with normal resting wall motion, oxygen consumption was comparable between remote and collateralized segments. In patients with resting wall motion abnormalities, myocardial oxygen consumption was higher in remote than in collateral-dependent segments. It did not differ significantly, however, among collateral dependent segments of patients with and without regional wall motion abnormalities. Similar findings were also reported by Sambuceti et al.43 Another approach to circumvent the problems of tissue heterogeneity is to use [15O]H2O and PET to measure MBF.44 45 Quantification of MBF by use of [15O]H2O indeed allows us to incorporate into the kinetic model an estimate of the fraction of tissue in the region of interest that is exchanging the freely diffusible water.44 45 This approach provides values of flow per gram of perfusable tissue as opposed to per gram of region of interest. Because for any practical purposes, the exchange of water by scar tissue can be regarded as negligible, this technique thus measures flow predominantly in the nonnecrotic part of the wall. Using [15O]H2O, de Silva et al,46 Marinho et al,47 and Conversano et al48 found that 80% to 90% of hibernating segments exhibited baseline flow values that are within the range of resting flow values measured in normal regions.
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P<.05 vs collateral-dependent segments of patients with anterior wall dysfunction. Adapted with permission from Reference 28.
Repeated Stunning as a Plausible Mechanism for Chronic Myocardial Hibernation
If resting flow is not reduced, what can then be the trigger for the chronic reduction in mechanical function? Even if resting perfusion is nearly normal, perfusion reserve is highly abnormal in hibernating segments. Vanoverschelde et al32 investigated the regional flow reserve of collateral-dependent myocardium using dipyridamole as the hyperemic agent. They found a wide range of hyperemic transmural flow values, from a fourfold increase to a 20% decrease in basal flow. Importantly, the collateral flow reserve of the dysfunctional segments was markedly blunted and correlated with the severity of chronic regional wall motion abnormalities. Accordingly, these authors suggested that repetitive intermittent episodes of ischemia (either exercise-induced or related to primary reductions in coronary blood flow [plaque events, vasoconstriction, platelet aggregation]) followed by stunning could be the mechanism leading to chronic regional ischemic dysfunction. It is worth mentioning that Braunwald and Kloner49 had already proposed such a mechanism back in 1982. Although because of the study design, no single episode of stunning could be demonstrated in the study by Vanoverschelde et al,32 subsequent observations by Shen and Vatner24 have provided evidence that chronic dysfunction in collateral-dependent myocardium can result from repeated episodes of ischemia followed by a perpetuated state of chronic stunning. These authors examined the time course of regional dysfunction after ameroid implantation in chronically instrumented pigs and found that the onset of dysfunction was not associated with permanently reduced subendocardial blood flow but was always preceded by repeated episodes of acute dysfunction induced by transient increases in regional demand. Altogether, these data suggest that repetitive stunning is a plausible mechanism that can account for the sustained prolonged contractile dysfunction of the hibernating myocardium. Alternatively, chronic dysfunction could result from a chronic decrease in coronary perfusion pressure in the poststenotic bed.50 51 Coronary pressure has been shown to regulate contractile performance acutely, even in the absence of changes in coronary flow.52 Whether a decrease in coronary perfusion pressure can be involved in long-term regulation of contractile function in the hibernating myocardium is unknown and requires further investigation.
Chronic Reduction in MBF as a Consequence Rather Than the Cause of Chronic Hibernation
The fact that chronic contractile dysfunction in the presence of severe coronary artery disease most likely results from repeated episodes of ischemia followed by a state of chronic stunning does not exclude the possibility that MBF may eventually become reduced in the affected segments. Indeed, increasing evidence suggests that MBF progressively downgrades in response to reduced contractile function. Back in 1975, Heyndrickx et al13 already indicated that MBF measured 4 to 6 hours after reperfusion was often decreased by 20% to 25% in acutely stunned myocardium. Canty and Klocke21 made very similar observations in their dog model of chronic ameroid occlusion. In their experiments, subendocardial blood flow, which had remained normal up to the time of ameroid occlusion and peak contractile dysfunction, gradually decreased after ameroid occlusion. Interestingly, this occurred in the face of a progressive increase in coronary perfusion pressure and a slow normalization of regional contractile function. Recently, Berman et al53 studied the effects of sustained demand-induced ischemia in a pig model of short-term hibernation. They made the intriguing observation that, despite no changes in MBF during stress, transmural blood flow decreased after cessation of the stress and remained depressed for a prolonged period of time. Although it is possible that the above observations are related to some form of microvascular stunning, it is tempting to hypothesize that the progressive reduction in MBF seen under these conditions is somehow secondary to the reduction in resting contractile function and serves as a means to increase residual myocardial perfusion reserve.54
Structural and Metabolic Alterations in the Hibernating Myocardium
Although there is little doubt that myocardial stunning contributes in one way or another to the chronic dysfunction of the hibernating myocardium, not all the features of chronic myocardial hibernation can be ascribed to stunning. Since the early 1980s, it has been known that chronically dysfunctional myocardial segments exhibit distinct morphological changes that can be demonstrated by both the light and the electron microscope. Flameng et al55 56 were the first to report on the presence of such abnormalities. These authors conducted a series of studies on human myocardial biopsy samples harvested at the time of bypass surgery and provided evidence for specific alterations affecting both the cardiomyocytes and the extracellular matrix in chronically dysfunctional segments.32 55 56 57 58 59 One striking feature of the changes seen in cardiomyocytes was the loss of contractile material (Fig 2).58 In some cells, this was limited to the vicinity of the nucleus, whereas in others it was very extended, leaving only few or no sarcomeres at the cell periphery. Myofibrillar loss was not accompanied by major cell volume changes, which is clearly different from atrophic degeneration. The space previously occupied by the myofilaments was filled with an amorphous, strongly PAS-positive material typical of glycogen. Under the electron microscope, the general organization pattern of the remaining peripherally located sarcomeres was well preserved. Mitochondria were small and scattered throughout the myolytic cytoplasm. Nuclei were tortuous and showed uniformly dispersed heterochromatin. Sarcoplasmic reticulum was virtually absent, as were T tubules. There were no signs of degeneration, such as cytoplasmic vacuolization, edema, mitochondrial swelling, membrane disruption, or lipid droplets, that would indicate acute ischemic damage or cellular atrophy. From a biochemical point of view, the tissue content of ATP, total adenine nucleotides, and PCr usually remained nearly normal.57 Mitochondrial function, as reflected by the ADP/ATP and PCr/ATP ratios, was also nearly intact,57 a finding consistent with subsequent observations that oxygen consumption (measured with [11C]acetate and PET) is well preserved in the hibernating myocardium.32 60 It is interesting to note that these critical observations were made and reported several years before the concept of chronic hibernation was put forward by Rahimtoola and that they have been ignored for more than a decade. It is only recently that the link between these structural alterations and myocardial hibernation has been established.32 58 Their presence is now considered a hallmark of the hibernating myocardium, as are the changes in myocardial glucose utilization that have subsequently been described.
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Several investigators have indeed reported that under fasting conditions, the hibernating myocardium was taking up glucose more avidly than remote normal myocardium,40 61 62 a feature that has been used to predict the reversibility of regional dysfunction after revascularization.40 The comparison of morphological data with the findings on metabolic imaging (which demonstrates increased rate of FDG transport and phosphorylation) has raised intriguing questions about the biochemical fate of exogenous glucose in "hibernating" cells.63 Although it was originally suggested that the increased glucose uptake in the hibernating myocardium resulted from stimulation of anaerobic metabolism by chronic ischemia,64 this explanation now appears unlikely in view of the normal or nearly normal levels of absolute MBF32 41 42 43 46 47 48 and oxygen consumption32 60 measured in these segments. It would also hardly explain the accumulation of glycogen, a quite unusual finding in the setting of ongoing ischemia, which would rather be expected to result in the opposite.65 Even if ongoing ischemia is not implicated, it remains possible that a change in the pattern of myocardial substrate utilization from fatty acid to glucose contributes to the metabolic alterations of the hibernating myocardium. In this regard, it is worth mentioning that Liedtke et al23 recently presented strong evidence that such a metabolic switch occurred in pigs with chronic coronary stenosis. Chronic activation of glycogen synthase by ischemia has also been proposed to account for the metabolic alterations seen in the hibernating myocardium. McNulty and Luba66 recently showed that transient ischemia induced a sustained activation of the glucose-6-phosphate–independent form of glycogen synthase, allowing for a rapid replenishment of the glycogen stores during reperfusion. Similar observations were also reported by Bolukoglu et al.67 Together, these data thus suggest that the alterations of glucose metabolism seen in experimental myocardial ischemia and hibernation could result from a concerted deregulation of glycolysis and glycogen synthesis. Further studies are nonetheless required to verify this hypothesis in the clinical setting. Finally, because the uptake of glucose by dysfunctional but metabolically active myocardium was shown to be relatively independent of the hormonal milieu and dietary conditions,61 62 some investigators have postulated that a change in the activity or in the expression of the two major cardiac glucose transporters, GLUT-1 and GLUT-4, could be involved in this phenomenon.68 So far, only two preliminary studies have attempted to measure the messenger RNA of these two glucose transporters by quantitative PCR in dysfunctional segments from patients with hibernating myocardium, and they produced conflicting results.68 69
Recent studies have suggested that the structural changes occurring in hibernating myocardium were the consequence of a dedifferentiation process. The hibernating cardiomyocytes indeed show many features of neonatal cardiomyocytes,70 including (1) depletion of contractile filaments, (2) presence of rough sarcoplasmic reticulum, (3) accumulation of glycogen, (4) occurrence of irregularly shaped nuclei with peculiar distribution of chromatin, (5) loss of organized sarcoplasmic reticulum, (6) lack of T tubules, and (7) vesiculization of the sarcolemma.58 Not all the characteristics of altered cardiomyocytes resemble those of embryonic cells, however. For instance, the remaining sarcomeres in the altered cells often retain their orderly arrangement at the cell periphery, whereas they are randomly distributed in embryonic cells. Also, the amount of glycogen seen in altered cardiomyocytes far exceeds that reported in the embryo. The hypothesis of dedifferentiation is further substantiated by immunohistological studies showing that hibernating cardiomyocytes reexpress contractile proteins that are specific to the fetal heart, such as 
-smooth muscle actin (Fig 3), while at the same time they exhibit the same organization of structural proteins, such as titin, as developing cardiomyocytes.59 In addition, cardiotin, a recently described high-molecular-weight protein absent in fetal cells, is also absent in the altered cells. These findings reinforce the thesis that hibernating cardiomyocytes undergo partial dedifferentiation.
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The molecular events or series of events that lead to the hibernating phenotype remain poorly understood and are at best sketchy. Because myocardial ischemia plays a central role in myocardial hibernation, ischemic preconditioning could participate in its development. Ischemic preconditioning is a recently described condition in which ischemically compromised myocardium downgrades its energy requirements and becomes more tolerant to ischemia (ie, develops less ischemic injury) because it has been primed or preconditioned by a preceding transient episode of ischemia followed by reperfusion.71 72 Although the exact mechanisms underlying ischemic preconditioning are still unknown, there is increasing evidence that changes in myocardial gene expression may be involved. Indeed, transient periods of ischemia followed by reperfusion have recently been shown to induce the expression of several transcription factors73 and to result in the upregulation of various cytoplasmic proteins (such as the heat shock proteins)74 and growth factors (such as IGF-1 and IGF-2).75 76 Although this remains speculative, ischemia-induced changes in myocardial gene expression could be the basis of both ischemic preconditioning and hibernation. Apart from ischemia and preconditioning, other factors could also contribute to the hibernating phenotype. In chronically fibrillating atria from the goat77 but also from humans,78 the atrial myocytes progressively develop structural abnormalities that are quite similar to those observed in hibernating ventricular myocytes. This suggests that myocardial ischemia is neither necessary nor mandatory to induce the hibernating phenotype. Since ischemia not only results in metabolic abnormalities but also provokes dramatic mechanical disturbances (loss of contractile activity, systolic bulging, and stretch), part of the phenotypic changes seen in the hibernating myocardium could be mediated by the mechanical as opposed to biochemical consequences of ischemia.
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Structural Determinants of Mechanical Reversibility |
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Morphological studies of human hibernating myocardium have shown that successful hibernation involves more than the simple adaptation of the heart to chronic coronary stenosis and results in complex structural changes at both the cardiomyocyte and extracellular matrix levels. Obviously, these structural changes are unlikely to be immediately reversible on coronary revascularization. Thus, although restoration of adequate coronary patency may improve and sometimes normalize ventricular function over the long term, time may be required before function recovers back to normal, and the pace at which the functional improvement occurs after revascularization is likely to be influenced by the extent and severity of the underlying structural alterations. Surprisingly, the time course of recovery of contractile performance after revascularization has received little attention, and the results of the few clinical studies that have addressed this issue have been varied, going from an early7 79 80 to a late81 82 recovery of function after revascularization. Although these studies suggest that the recovery of function after revascularization is variable, which would be consistent with the heterogeneous nature of the underlying disease process, it remains possible that the discordant results obtained reflect the lack of uniformity in patient selection in the extent and quality of revascularization and in the timing of reexamination. To overcome this problem, we83 recently studied the time course of recovery of left ventricular function after revascularization in patients with chronic left ventricular ischemic dysfunction who had undergone successful coronary revascularization and who manifested significant increases in left ventricular function 6 months after revascularization. In these patients, we serially measured regional and global left ventricular function at 10 days, 2 months, and 6 months after revascularization and found that the reversal of left ventricular dysfunction was a slow and progressive phenomenon that followed a monoexponential time course, with a time constant of 23 days. Intriguingly, the rate of functional recovery in individual patients was quite variable and appeared to be linked to the severity of cardiomyocyte alteration and remodeling. When dysfunctional myocardium displayed little or no structural alterations, significant recovery could be noted as early as 10 days after revascularization, and complete recovery was usually achieved within the first 2 months. In contrast, when the structural changes were severe and extensive, the recovery of regional contraction was usually quite delayed, and the extent of recovery at 6 months remained incomplete. These findings suggest that the structural abnormalities seen in the hibernating myocardium do indeed directly contribute to mechanical dysfunction and are responsible for the delayed return of contractile performance after revascularization. These observations are in agreement with recent data by Shivalkar et al,84 who demonstrated that only patients with no or minimal structural abnormalities invariably show early recovery of mechanical function after revascularization. Both of these studies have important clinical implications, because they demonstrate that in many patients, full recovery of function will not occur and should therefore not be expected before 4 to 6 months after revascularization.
The extent to which the structural abnormalities contribute to the extent of mechanical recovery after revascularization was recently addressed by Depré et al.63 These authors studied 24 nondiabetic patients with ischemic anterior wall dysfunction and correlated the amplitude and extent of mechanical recovery 6 months after successful revascularization with the results of a detailed morphometric analysis of dysfunctional myocardium biopsied at the time of bypass surgery. They found that myocardium that improved function after surgery showed significantly less transmural (24±13% versus 49±20%) and subendocardial (20±13% versus 53±27%) tissue fibrosis but contained significantly more metabolically active cardiomyocytes than myocardium with persistent postoperative dysfunction. This included a larger proportion of hibernating cardiomyocytes (35±14% versus 21±15%). The threshold amount of tissue fibrosis that best differentiated myocardium with from that without postoperative functional improvement was 35%. In addition, the authors observed significant correlations between the severity of tissue fibrosis and both the amplitude of mechanical recovery (r=.66) and the extent to which mechanical function recovered by 6 months after revascularization (r=.74).
Despite their obvious pathophysiological interest, none of the above studies permit identification of the mechanisms underlying the recovery of mechanical function after revascularization. Although the results suggest that structural reversibility could be involved, it remains possible that the structural changes are actually fixed and irreversible and that recovery of wall contraction is related to the effects of compensatory mechanisms, for instance hypertrophy, involving the few remaining normal cardiomyocytes. In this regard, it has recently been suggested that apoptosis, the genetically programmed cell death, could be involved in the pathogenesis of chronic myocardial hibernation.85 Although direct histological demonstration of apoptotic cell death in the hibernating myocardium has never been made conclusively, indirect markers of apoptosis, such as DNA fragmentation, have recently been found in some of the more severely affected hibernating cardiac myocytes. If these observations were to be confirmed, we will probably have to change the way we currently think about myocardial hibernation, ie, as a successful adaptive mechanism by which the myocardium preserves its integrity despite repeated ischemic insults. Although this is speculative, it would explain why, in some patients with severe structural changes, functional recovery remains modest and in the end largely incomplete.
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Recruitable Inotropic Reserve in Chronic Myocardial Hibernation |
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Recruitable Inotropic Reserve in Experimental Models of Regional Ischemic Dysfunction
It was previously shown in experimental myocardial stunning that reversibly injured myocardium retained the ability to temporarily improve function on stimulation with catecholamines or calcium, whereas infarcted myocardium usually remained unchanged.86 87 Short-term hibernating myocardium has also been shown to display recruitable inotropic reserve on stimulation with catecholamines. Schulz et al19 20 studied the impact of prolonged infusion of dobutamine, a synthetic catecholamine, on regional mechanical and metabolic function in open-chest anesthetized swine undergoing partial occlusion of the left anterior descending coronary artery. During occlusion, dobutamine infusion resulted in a transient improvement of regional mechanical function, which was rapidly followed by further functional deterioration, increased lactate production, decreased PCr levels, and eventually myocardial necrosis. Chen et al88 studied the effects of incremental doses of dobutamine (from 2.5 to 25 µg·kg-1·min-1) on regional mechanical function in pigs with a left anterior descending coronary artery stenosis and anterior wall dysfunction. They demonstrated sustained improvements in mechanical function at dobutamine doses of 2.5 to 10 (4.5±2.2) µg·kg-1·min-1 but deterioration with higher doses. More recently, Gerber et al26 examined the contractile response to low-dose dobutamine (2.5±1.0 µg·kg-1·min-1) of chronically (6 months) dysfunctional noninfarcted collateral-dependent canine myocardium. In their study too, dobutamine resulted in an improved mechanical function that persisted for at least 30 minutes. Similar findings were also reported by Sklenar et al89 and by Mertes et al.90 This diverging contractile response in dysfunctional but viable and infarcted myocardium thus provides a basis for distinguishing between reversible and irreversible tissue injury in patients with coronary artery disease and left ventricular ischemic dysfunction.
Recruitable Inotropic Reserve in Patients With Left Ventricular Ischemic Dysfunction
Earlier investigators attempting to predict the reversibility of left ventricular ischemic dysfunction after revascularization on the basis of inotropic reserve used the response of global ejection fraction to an inotropic stimulus (epinephrine or postextrasystolic potentiation) at the time of cardiac catheterization as an index of myocardial viability.91 92 93 94 95 Nesto et al95 were among the first to use this approach. They showed that patients with an ejection fraction <35% who demonstrated a >10% increase in ejection fraction during inotropic stimulation improved global left ventricular function after revascularization. These patients also had better long-term survival than comparable patients lacking contractile reserve whether treated medically or surgically. Recent advances in noninvasive functional imaging, particularly in digitized echocardiography, and the use of standardized dobutamine infusion protocols have allowed application of these concepts on a large scale to patients with left ventricular dysfunction.96
The potential value of dobutamine echocardiography was first tested in patients with recent myocardial infarction. Piérard et al97 were the first to use low-dose dobutamine echocardiography to identify reversible dysfunction after reperfused acute myocardial infarction. They compared dobutamine echocardiography and PET for identification of viable myocardium in 17 patients treated with thrombolytic therapy for a first acute anterior myocardial infarction and found both techniques to be concordant in 79% of the dysfunctional segments. These results were subsequently confirmed by several other groups.96 More recently, investigators evaluated whether assessment of inotropic reserve could also be useful in patients with chronic left ventricular ischemic dysfunction, ie, chronic myocardial hibernation. In contrast to the early postinfarction myocardium, in which stunning is probably predominant, chronic myocardial hibernation is associated with both the loss of contractile material and a severe limitation of residual coronary flow reserve,32 two factors that may profoundly affect its ability to respond to an inotropic stimulus. Yet there is increasing evidence to indicate that chronically hibernating myocardium can display recruitable inotropic reserve on stimulation with low doses of dobutamine.80 98 99 100 101 102 103 It should be noted, however, that not every segment with hibernating myocardium improves functionally with dobutamine. In a recent study, Gerber et al42 showed that 
25% of the hibernating segments exhibited no response whatsoever to dobutamine stimulation. Interestingly, none of the flow and metabolic parameters analyzed in this particular study allowed distinction between hibernating segments with and without a positive response to dobutamine. It is therefore possible that mechanisms not evaluated in their study, such as the severity of the underlying cardiomyocyte alterations (particularly the loss of myofilament and contractile material),32 the extent of impairment of myocardial perfusion reserve,32 and the ß-receptor density and affinity, contributed to their observation.
Conclusions
The recent refinements in myocardial perfusion imaging and the results of morphological studies of biopsy specimens from human hibernating myocardium have shed a new light on our understanding of chronic myocardial hibernation. The pathophysiology of this peculiar condition now appears to be much more complex than previously anticipated. It most likely involves a combination of repetitive postischemic dysfunction, which is perpetuated because of renewed episodes of ischemia, and ischemia/reperfusion–induced changes in cell phenotype, which eventually culminate in the dramatic morphological alterations that have been described. In the end, however, this adaptation may not be as successful as initially anticipated. Evidence is indeed accumulating that the hibernating myocardium represents an unstable and precarious condition that requires if not urgent, then at least rapid revascularization. Failure to revascularize hibernating segments has been associated with an increased rate of adverse events and a poor prognosis.104 105 106 Much is still to be learned about the pathophysiology of myocardial hibernation and particularly how the hibernating phenotype develops. Future progress in this field will require the development of relevant animal models of chronic hibernation and a better understanding of how ischemia, reperfusion, and their various metabolic and mechanical consequences eventually interfere with myocardial gene expression. Identification of the various steps leading to the final picture is mandatory to develop new and better therapeutic strategies and to hasten functional recovery after revascularization.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by grants 3-4522-89, 3-4523-94, and 3-4540-95 from the Fonds National de la Recherche Scientifique et Médicale and by Action de Recherche Concertée grant 91/96-146.
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References |
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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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R. Schulz, C. Kappeler, H. Coenen, A. Bockisch, and G. Heusch Positron Emission Tomography Analysis of [1-11C]Acetate Kinetics in Short-term Hibernating Myocardium Circulation, March 17, 1998; 97(10): 1009 - 1016. [Abstract] [Full Text] [PDF]
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J. E. Udelson Steps Forward in the Assessment of Myocardial Viability in Left Ventricular Dysfunction Circulation, March 10, 1998; 97(9): 833 - 838. [Full Text] [PDF]
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H. A. Dakik, 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, November 4, 1997; 96(9): 2892 - 2898. [Abstract] [Full Text]
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