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Pathophysiology of stunned or hibernating myocardium

Pathophysiology of stunned or hibernating myocardium
Literature review current through: Jan 2024.
This topic last updated: Apr 25, 2022.

INTRODUCTION — Left ventricular (LV) dysfunction, an important consequence of coronary artery disease, can result from myocardial ischemia or myocardial infarction [1,2]. In some patients, transient ischemia can lead to a period of persistent dysfunction after the restoration of flow while in others persistent, asymptomatic ischemia produces LV dysfunction that can mimic nonischemic causes of heart failure. The former phenomenon is referred to as myocardial stunning and the latter as hibernating myocardium.

The definitions and pathophysiology of myocardial stunning and hibernation will be reviewed here. The approach to diagnosis and therapy of hibernation, the clinical syndromes associated with stunned or hibernating myocardium, the role of nuclear imaging, dobutamine echocardiography, and cardiac magnetic resonance imaging to assess myocardial viability are discussed elsewhere. (See "Evaluation of hibernating myocardium" and "Clinical syndromes of stunned or hibernating myocardium" and "Assessment of myocardial viability by nuclear imaging in coronary heart disease" and "Dobutamine stress echocardiography in the evaluation of hibernating myocardium".)

DEFINITIONS — Hibernating myocardium must be distinguished from the stunned myocardium and from transient left ventricular (LV) dysfunction that is a result of ischemia induced by stress (eg, exercise, dobutamine). However, hibernating myocardium can coexist with both conditions.

Stunned myocardium — "Stunned myocardium" was the term initially used to describe a condition demonstrated in the laboratory in which total coronary artery occlusion lasting only 5 to 15 minutes (a period not associated with cell death) produced an abnormality in regional LV wall motion that persisted for hours or days following reperfusion [3-7]. Thus, the key elements of the stunned myocardium are:

Short-term, total, or near total reduction of coronary blood flow

Re-establishment of coronary blood flow

Subsequent LV dysfunction of limited duration

In the clinical setting, stunned myocardium may be superimposed on ischemia (including variant angina and during and after coronary revascularization), hibernation, or infarction when blood flow is re-established [8].

Hibernating myocardium — Hibernating myocardium is a state of persistently impaired myocardial and LV function at rest due to chronically reduced coronary blood flow that can be partially or completely restored to normal either by improving blood flow or by reducing oxygen demand [1,9-15]. The reduction in resting coronary blood flow in hibernating segments and the improvement following percutaneous coronary intervention and coronary artery bypass surgery have been directly demonstrated by cardiovascular magnetic resonance imaging [16].

Positron emission tomography (PET) has shown that regions with abnormal wall motion may still be metabolically active; these are the regions that can improve after revascularization [17]. Such regions are likely to be hypokinetic rather than akinetic or dyskinetic. In an autopsy series, 52 percent of myocardial segments that were hypokinetic had normal myocardium when examined histologically compared to only 7 percent of akinetic or dyskinetic segments [18].

Myocardial hibernation may be acute, subacute, or chronic, and can be superimposed upon stable or unstable angina and myocardial infarction (figure 1) [1]. Hibernating myocardium can be completely, or almost completely, restored to normal with therapy if the myocardial oxygen supply/demand relationship is favorably altered, either by improving blood flow and/or by reducing demand. On the other hand, if the hibernating myocardium is not treated in a timely manner, it may be associated with progressive cellular damage, recurrent myocardial ischemia, myocardial infarction, heart failure, and death [19].

The potential impact of hibernating myocardium was illustrated in a study of 112 cardiac transplant recipients [20]. Severe coronary disease was found in all patients with a pretransplant diagnosis of ischemic cardiomyopathy (57 percent of the total population); it was also present in nine of 38 patients with a pretransplant diagnosis of idiopathic dilated cardiomyopathy and in three of four with presumptive alcoholic cardiomyopathy. The presence of hibernating myocardium predicts an improvement in survival in patients undergoing revascularization; in contrast, in patients not receiving revascularization, the presence of viable myocardium is an independent predictor of mortality [21].

PATHOPHYSIOLOGY — A prerequisite for stunning and hibernation is a reduction in myocardial blood flow (figure 2). If contributions from collaterals, plaque morphology, and abnormal microvasculature are ignored, then a coronary stenosis of up to approximately 40 percent will not alter maximum blood flow, and coronary flow reserve will remain normal. Between 40 and 80 percent stenosis, resting myocardial blood flow will be normal, but maximum blood flow will be diminished; in this setting, episodes of increased oxygen demand may result in stunning. A stenosis greater than 80 percent is likely to be associated with a reduction in resting blood flow and could result in reduced contraction through perfusion-contraction matching. (See 'Myocardial adaption to ischemia' below.)

It is conceivable that, in the presence of a high grade stenosis, flow that was normal at rest may at times be reduced, and vice versa. If this is viewed in terms of perfusion-contraction matching, then myocardium that at one time point is by definition "stunned" may at another point in time be hypoperfused and therefore hibernating without any alteration in left ventricular (LV) systolic contraction or cardiac output (figure 2). There may also be transmural variations in myocardial blood flow. Thus, within one hypocontractile segment, it is possible that areas of dysfunction secondary to stunning and hypoperfusion may coexist and then interchange at another.

Relation between hibernation and stunning — The preceding observations suggest that the difference between hibernation and stunning may be one of degree: In hibernation, resting blood flow is low, whereas in stunning resting flow is normal but maximal blood flow is reduced (figure 1). There may, however, be considerable overlap between these phenomena (table 1). As an example, absolute myocardial blood flow may be normal or near normal in some hibernating segments [22-24]. However, coronary flow reserve, ie, the ratio of maximum to basal coronary flow, may be reduced within these segments, leading to the hypothesis that hibernation may result from repetitive stunning, secondary to repeated episodes of ischemia or from chronic stunning.

A number of studies provide support for the transition from repetitive stunning to hibernation [25-27]:

In a canine study, multiple coronary artery obstructions resulted in collateral dependent, noninfarcted, and reversibly dysfunctional myocardium, representing stunning; this early phase of episodic dysfunction was followed by persistent dysfunction in the presence of normal resting blood flow and was characterized at a later stage by persistent dysfunction and subendocardial hypoperfusion [25].

A temporal transition from chronic stunning to hibernation was seen in an animal study in which chronic stunning, with normal resting perfusion, was produced by a gradual increase in stenosis severity [26]. As coronary flow reserve, demonstrated by adenosine, decreased over two months, there was an increase in the uptake of the glucose analog, fluorine-18 labeled deoxyglucose (FDG), characteristic of hibernating myocardium. These data suggest that both coronary flow reserve and the length of time during which the heart is subjected to reversible ischemia are determinants of increased FDG uptake and the transition to hibernating myocardium.

Myocardial stunning and hibernation share other features that suggest that they are not completely separate phenomena (table 1). In both, there is a resting wall motion abnormality occurring as a result of coronary disease, which improves following the restoration of flow. In addition, contractility will respond to inotropes in both phenomena, which provides the rationale for dobutamine echocardiography in patients with suspected hibernating myocardium. (See "Dobutamine stress echocardiography in the evaluation of hibernating myocardium".)

Both phenomena are also associated with a switch from free fatty acids to glucose as the preferred substrate, which provides the rationale for the use of radionuclide myocardial perfusion imaging with FDG in these patients. (See "Assessment of myocardial viability by nuclear imaging in coronary heart disease".)

Myocardial adaption to ischemia — There is a relation between myocardial blood flow and systolic function, the so-called "flow function" relation [28,29]. As blood flow is reduced, there is a corresponding reduction in contractile performance ("perfusion-contraction matching"). There may no ischemic symptoms or necrosis when this occurs slowly since blood flow and function are once again in equilibrium [9,10].

Thus, the hibernating response of the heart, namely a reduction of function to cope with a reduced myocardial blood flow, could be considered an act of self-preservation (little blood, little work) and the heart could be considered to be a "smart heart." If, however, myocardial oxygen supply/demand balance is subsequently altered unfavorably, then symptoms and signs of ischemia and/or necrosis can occur. As an example, intermittent brief episodes of ischemia can have a cumulative effect, leading to myocardial necrosis [30].

If blood flow remains low, the myocardium may be able to reduce its metabolic requirements still further by undergoing a more chronic form of adaptation involving alterations in the morphology and protein content of the myocardium [23,31-34]. These changes, which have been well documented and can be quite profound, are viewed by some as an adaptation to substrate deprivation and by others as degeneration [31,33-35].

Dedifferentiation or embryonic regression is an active adaptive process to reduced flow, supporting the "smart heart" hypothesis.

Supporting the forced degeneration hypothesis are the observations that some myocytes show nucleolar condensations suggestive of apoptosis [36] and that cardiac myocyte apoptosis can be triggered by ischemia. (See 'Myocardial changes associated with hibernation' below.)

Whatever the cause, structural remodeling would be necessary to restore contractility. As a result, chronically impaired but viable myocardium may take weeks or months to recover once flow is restored [28].

Although not demonstrated in all studies, transient disturbances in contraction have been documented following exercise in patients with coronary artery disease, particularly when multivessel disease is present [37,38]. It seems likely that transient wall motion abnormalities will occur in areas of myocardium subtended by a coronary stenosis that have reduced coronary flow reserve even though the stenosis is not severe enough to diminish resting myocardial blood flow. In such patients, another period of ischemia may occur before the myocardium has had time to recover fully from the first episodes. Thus, repeated episodes of ischemia may result in an apparent chronic reduction in LV function [39].

Ischemic preconditioning — Another phenomenon closely associated with stunning is ischemic preconditioning. This was originally defined as a brief period of ischemia protecting the myocardium from a subsequent, more prolonged period of ischemia [40]. Implicit in this definition is a defined period of reperfusion between the triggering (preconditioning) ischemia and the subsequent prolonged period of ischemia. However, the phenomenon can also be triggered if the onset of ischemia is gradual rather than sudden, so-called intra-ischemic preconditioning [41]. Studies suggest that remote ischemic preconditioning reduces perioperative myocardial injury in patients undergoing elective coronary artery bypass surgery and elective percutaneous coronary intervention (PCI) and reduces long-term mortality in patients with ST elevation myocardial infarction (STEMI) undergoing primary PCI [42,43]. One study found that remote ischemic preconditioning reduced the combined endpoint of cardiac mortality and hospitalization for heart failure in patients undergoing primary PCI for STEMI [44]. It appears that classic preconditioning resembles repetitive stunning, while intra-ischemic preconditioning resembles flow-function matching in hibernation. It is therefore possible that one of the mechanisms by which clinically hibernating myocardium survives the disturbance in myocardial blood flow is by being preconditioned. (See "Myocardial ischemic conditioning: Pathogenesis" and "Myocardial ischemic conditioning: Clinical implications".)

Coronary autoregulation — In humans, there are extensive autoregulatory processes that maintain coronary blood flow despite changes in mean coronary pressure. Over a wide range of coronary pressures, coronary blood flow remains normal, largely through variations in arterial tone. As coronary pressure falls, for example, vasodilatation occurs, maintaining flow. Once maximum vasodilatation is present, any further reduction in coronary pressure will result in a precipitous reduction in flow. This relation between pressure and flow is influenced by numerous factors, such as sympathetic tone, hypertrophy, tachycardia, LV end-diastolic pressure, viscosity, infarction, medial smooth muscle tone, and cyclical platelet aggregation.

Myocardial changes associated with hibernation — Studies in animals and humans suggest that, during long-term myocardial hypoperfusion, there is ongoing myocyte death through apoptosis [36,45,46]. There is also structural degeneration characterized by reduced protein and mRNA expression, disorganization of the contractile and cytoskeletal proteins, an increased amount of extracellular matrix proteins and reparative fibrosis, and a progressive reduction and disruption of connexin43 gap junctions that may contribute to the electromechanical dysfunction and to arrhythmogenicity [46,47].

These degenerative changes and deterioration in myocardial function are time-dependent. In a study of 32 patients, those with subacute hibernation (<50 days from onset of new or worsening symptoms) had a higher preoperative LV ejection fraction and better preserved wall motion than patients who had intermediate (>50 days) or chronic (>six months) ischemia [48]. Structural degeneration, based upon biopsy samples obtained at the time of bypass surgery, correlated with the duration of ischemia, while recovery of function after revascularization correlated inversely with the duration of ischemia, being most pronounced in those with subacute hibernation.

There are inconclusive data from animal models and human studies regarding the underlying mechanisms of reversible chronic LV dysfunction. Animal models have demonstrated that significant regional and global dysfunction can exist without extensive cell necrosis in the presence of a coronary stenosis as long as there is preserved resting perfusion [49,50]. How this occurs is not well understood but the following factors may contribute [51-53]:

Reduced myocardial high energy phosphates

Impaired calcium handling by the sarcoplasmic reticulum

Diminished sensitivity of myofibrils to calcium

A shift from aerobic or oxidative metabolism of free fatty acids to anaerobic metabolism

The underperfused myocardium retains its responsiveness to an inotropic challenge even though there is no change in regional blood flow; this observation suggests that the reduction in contractility is not entirely due to a decrease in energy stores [11,54]. As mentioned above, it is still uncertain if the chronic contractile dysfunction is due to persistent ischemia (representing true hibernation) or to repetitive episodes of ischemia and reperfusion (representing myocardial stunning) [23].

Altered adrenergic density — Alteration in the density of alpha and beta adrenergic receptors has been observed in various pathologic states associated with myocardial dysfunction, particularly heart failure. Alterations in adrenergic receptor density may also play a role in the depression of myocardial function and preserved contractile reserve seen in hibernation. In one histologic study of myocardial biopsies from patients with ischemic LV dysfunction who underwent bypass surgery, segments that were dysfunctional but viable, as determined by preoperative dobutamine echocardiography and radionuclide myocardial perfusion imaging, showed an increase in alpha receptor density, a decrease in beta receptor density, and an increase in the ratio of alpha to beta receptor density compared to normal segments [55]. Worsening of resting function, inotropic reserve, and recovery of function were all associated with a graded increase in alpha receptor density and a decrease in beta receptor density.

SUMMARY

Hibernating myocardium is a state of persistently impaired left ventricular myocardial function at rest due to chronically reduced coronary blood flow that can be partially or completely restored to normal either by improving blood flow or by reducing oxygen demand. (See 'Hibernating myocardium' above.)

"Stunned myocardium" was the term initially used to describe a condition demonstrated in the laboratory in which total coronary artery occlusion lasting only 5 to 15 minutes (a period not associated with cell death) produced an abnormality in regional left ventricular wall motion that persisted for hours or days following reperfusion. (See 'Stunned myocardium' above.)

A prerequisite for stunning and hibernation is a reduction in myocardial blood flow. (See 'Pathophysiology' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff thank Dr. David Shavelle for his past contributions to prior versions of this topic review.

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