Although the prognosis of systolic heart failure, also called heart failure with reduced ejection fraction, has improved with advances in therapy, the prognosis remains poor in patients who become refractory to such therapies. That cardiac transplantation improves the quality of life and survival of such patients has been established, but it is available to a very small number of patients. Thus, newer pharmacologic and nonpharmacologic therapies for patients with refractory systolic heart failure are being explored. Because chronic ischemic heart disease is the most common cause of systolic heart failure, potential exists for revascularization therapy. Although revascularization can be performed with low procedural mortality, improvement in left ventricular function, relief of symptoms, and long-term prognosis appear to be related to the presence and extent of viable ischemic hibernating myocardium. In conclusion, the detection of hibernating myocardium is highly desirable before revascularization treatment is undertaken.
Systolic heart failure (SHF), also termed heart failure with reduced ejection fraction, is 1 of the most common clinical subsets of chronic heart failure. During past 3 decades, there have been considerable advances in the management of SHF. With the implementation of such therapeutic interventions, a substantial improvement in the prognosis of patients with SHF has been observed. It has been reported that with modern pharmacotherapy, the annualized mortality rate has decreased from 18% to 21% to 8% to 12%. With the introduction of long-term resynchronization treatment and implantable cardioverter-defibrillators, the mortality of patients with stage C SHF has further decreased. However, the prognosis of patients who become refractory to these therapies remains very poor. Cardiac transplantation has been documented as an effective treatment for these end-stage (class D) patients with SHF. Cardiac transplantation, however, is available to a very small number of patients. Thus, newer pharmacologic and nonpharmacologic treatments, including revascularization, are being explored for treatment of patients with refractory heart failure. Because revascularization is likely to be of benefit when viable ischemic, hibernating myocardium is reperfused, it is logical to assess the presence and extent of hibernating myocardium. However, controversy exists on whether detection of hibernating myocardium is necessary before revascularization is undertaken. In this report, the potential mechanisms of hibernation and its detection and clinical relevance are briefly reviewed.
Myocardial Hibernation
Historical perspective
In 1978, in studies in experimental animals, Diamond et al first reported that “ischemic non infracted myocardium can exist in a state of hibernation.” However, Rahimtoola first demonstrated the importance of “hibernation” in patients with chronic ischemic heart disease and popularized the concept of hibernating myocardium.
Definition
Rahimtoola defined myocardial hibernation as a condition of chronic systolic and diastolic dysfunction in patients with obstructive coronary artery disease, which is reversible after revascularization. Myocardial stunning, a related but different pathophysiologic condition, is defined when there is a delayed recovery of myocardial function after reperfusion following ischemia caused by coronary artery occlusion.
Pathophysiology and mechanisms
Although the existence of myocardial hibernation has been documented, the pathophysiologic mechanisms still remain controversial. Rahimtoola’s proposed mechanism is “that there is a prolonged subacute or chronic stage of myocardial ischemia that is frequently not accompanied by pain and in which myocardial contractility and metabolism and ventricular function are reduced to match the reduced blood supply—perfusion—contraction matching.” There is residual contractile and metabolic function despite reduced perfusion in the hibernating myocardium. This proposed mechanism for “hibernation” has been subsequently termed the “smart heart hypothesis.” There is, however, considerable controversy about whether coronary blood flow at rest is reduced in the hibernating myocardial segments. In some studies, quantitative first-pass cardiovascular magnetic resonance perfusion imaging has reported a significant reduction of myocardial blood flow in the hibernating myocardium. However, other studies have demonstrated that myocardial perfusion at rest is similar before and after revascularization of the hibernating myocardial segments, suggesting that myocardial blood flow at rest is not reduced.
Another proposed mechanism of hibernation is that there is repetitive stunning (the “repetitive stunning hypothesis”). Myocardial stunning is defined when there is delayed recovery of myocardial mechanical and metabolic function after reperfusion of the ischemic myocardium is established. The determinants of the time course of recovery of function are the duration of ischemia before reperfusion is established and the amount of baseline fibrosis. Clinical studies suggest that recovery of function occurs earlier in stunned myocardium than in hibernating myocardium. Experimental studies suggest that “stunning” is associated with upregulation of the antiapoptotic and other survival proteins and downregulation of antisurvival signaling pathways. According to the stunning hypothesis, the myocardium is subjected to repeated episodes of ischemia followed by reperfusion, which maintains myocardial viability and preserves metabolic and mechanical function. Myocardial ischemia occurs because of an imbalance between myocardial oxygen demand and oxygen supply. When there is increased oxygen demand, as during exercise, ischemia is precipitated because of limited coronary flow reserve because of coronary artery stenosis. With the cessation of increased demand, perfusion becomes adequate again, producing “myocardial stunning.” This repeated episodes of stunning produce sustained chronic reduction of myocardial contractile function. The myocardium, however, remains viable, and function recovers after reperfusion, as occurs in hibernating myocardial segments.
Irrespective of the initial mechanisms, it appears that in “hibernating” myocardium, the cell survival pathways are triggered, and there is activation of survival proteins and suppression of “cell death pathways.” The cellular, biochemical, and genetic changes in myocytes in hibernating myocardium have been investigated. Biopsy studies during coronary artery bypass grafting (CABG) have reported that the myocytes in the hibernating myocardial segments can be dedifferentiated with loss of myofilaments and glycogen accumulation. However, other studies have reported that there is no dedifferentiation of myocardial proteins, and also, there is virtually no myocardial necrosis in the hibernating tissue segments, also obtained during CABG. In these studies, apoptosis of myocytes was observed. Apoptotic loss of myocytes resulting in reduced numbers of functional myocytes is associated with hypertrophy of the remaining functional myocytes. Myocyte remodeling has been observed in experimental models of hibernating myocardium induced by coronary artery stenosis. In the hibernating myocardial segments, the myocytes are hypertrophied, and the action potential duration is prolonged. L-type Ca 2+ currents and Ca 2+ release are also decreased. In human hibernating myocardium, it has been reported that sarcoplasmic reticular Ca 2+ –adenosine triphosphatase activity is impaired because of reduced phosphorylation of phospholamban, contributing to reduced contractile function. The gene profile has been studied in human hibernating myocardium in tissue samples obtained during CABG. Upregulation of the inhibitor of apoptosis gene, cytoprotective heat-shock proteins, hypoxia-inducible factor–1a, vascular endothelial growth factor, and the stress-responsive glucose transporter gene has been reported. An upregulation of β-adrenergic receptor kinase–1, fas-activated serine/threonine kinase, and reduced expression of desmoplakin have been observed. Increased expression of B-type natriuretic peptide in human hibernating myocardium has been also reported.
An increase in α-adrenergic density and an increased ratio of α receptor to β receptor density in the hibernating myocardium in patients who undergo CABG has been documented. However, the cellular mechanism by which the altered adrenergic receptor activity induces hibernation and or stunning remains unclear.
Increased levels of tumor necrosis factor–α and inducible nitric oxide synthase have been detected in hibernating myocardial segments obtained during CABG and have been thought to be a contributing molecular mechanism for depressed contractile function. Levels of tumor necrosis factor–α and inducible nitric oxide synthase are much higher in irreversibly damaged myocardial segments compared to hibernating segments.
Hibernation and Stunning: Clinical Prevalence
In several clinical subsets of coronary artery disease, the phenomenon of myocardial stunning is observed. In patients with ST elevation myocardial infarctions, myocardial functional recovery is often delayed, even after successful reperfusion. In some studies, at 90 days after reperfusion, there was only 22% complete recovery and 36% partial recovery after successful recanalization of the infarct-related artery. Also, in stable angina, a stunning phenomenon occurs. Delayed recovery of left ventricular dysfunction after exercise or dobutamine stress is probably due to stunning of the myocardium.
In chronic ischemic heart disease, the presence of hibernating myocardium has been documented. In 1 study, 59 of 81 hypokinetic or akinetic myocardial segments improved after revascularization, confirming “hibernation.” Hibernating myocardial segments are present in patients with acute coronary syndromes. The frequency of hibernating myocardium appears to be more common in unstable than in chronic stable angina (75% vs 28%), probably reflecting the duration and severity of ischemia. Hibernating myocardium is present in patients with left ventricular dysfunction with or without symptoms of congestive heart failure.
In patients with severe SHF due to ischemic cardiomyopathy (average left ventricular ejection fraction 32%) in an analysis of 24 viability studies in 3,088 patients, the prevalence of hibernating myocardium was 42%. Several studies have reported that approximately 10% of patients with ischemic SHF referred for cardiac transplantation had some viable ischemic myocardium. Another example of the presence of hibernating myocardium in chronic ischemic heart disease is the congenital heart disease “anomalous left coronary artery from the pulmonary artery.” Nearly complete recovery of left ventricular function occurs after appropriate corrective surgery.
Hibernation and Stunning: Clinical Prevalence
In several clinical subsets of coronary artery disease, the phenomenon of myocardial stunning is observed. In patients with ST elevation myocardial infarctions, myocardial functional recovery is often delayed, even after successful reperfusion. In some studies, at 90 days after reperfusion, there was only 22% complete recovery and 36% partial recovery after successful recanalization of the infarct-related artery. Also, in stable angina, a stunning phenomenon occurs. Delayed recovery of left ventricular dysfunction after exercise or dobutamine stress is probably due to stunning of the myocardium.
In chronic ischemic heart disease, the presence of hibernating myocardium has been documented. In 1 study, 59 of 81 hypokinetic or akinetic myocardial segments improved after revascularization, confirming “hibernation.” Hibernating myocardial segments are present in patients with acute coronary syndromes. The frequency of hibernating myocardium appears to be more common in unstable than in chronic stable angina (75% vs 28%), probably reflecting the duration and severity of ischemia. Hibernating myocardium is present in patients with left ventricular dysfunction with or without symptoms of congestive heart failure.
In patients with severe SHF due to ischemic cardiomyopathy (average left ventricular ejection fraction 32%) in an analysis of 24 viability studies in 3,088 patients, the prevalence of hibernating myocardium was 42%. Several studies have reported that approximately 10% of patients with ischemic SHF referred for cardiac transplantation had some viable ischemic myocardium. Another example of the presence of hibernating myocardium in chronic ischemic heart disease is the congenital heart disease “anomalous left coronary artery from the pulmonary artery.” Nearly complete recovery of left ventricular function occurs after appropriate corrective surgery.
Detection of Hibernating Myocardium: Rationale
It has been hypothesized that the detection of the presence and magnitude of hibernating ischemic myocardium is desirable before revascularization treatment is undertaken in patients with SHF. The rationale is that it is more likely that regional and global myocardial function will recover after revascularization of hibernating myocardium. When myocardium with predominantly scar tissue is revascularized, functional recovery and improvement in prognosis are unlikely to occur. In contrast, revascularization of predominantly ischemic viable myocardium will be associated with an improvement of function, with relief of symptoms and improved prognosis.
Techniques
Initially, contrast ventriculography, before and after nitroglycerin, or positive inotropic agents were used for the detection of viable ischemic myocardium. Nitroglycerin can reduce ischemia and improve the mechanical function of myocardial segments. The rationale for the use of positive inotropic agents is that mechanical function is likely to improve in response to inotropic stimulation if viable but hypofunctioning myocardium is present. Postextrasystolic potentiation and exercise can be used instead of positive inotropic agents for the detection of viable ischemic myocardium. Amrinone, a relatively cardiospecific phosphodiesterase inhibitor, has also been used instead of dobutamine to detect hibernating myocardium.
Noninvasive tests should be considered before invasive tests are performed. Conventional electrocardiography frequently provides information about the extent of myocardial damage in patients with coronary artery disease. The presence of widespread “Q waves” and/or loss of R waves usually indicates extensive myocytes loss, fibrosis, and irreversible myocardial damage. However, positron emission tomographic studies have documented that the presence of Q waves correlates poorly with the detection of viable ischemic myocardium.
Several other noninvasive techniques are available for detection of hibernating myocardium ( Table 1 ).
| Dobutamine echocardiography |
| Thallium-201 stress imaging |
| Technetium-labeled agents for nuclear myocardial imaging |
| F-18-fluorodeoxyglucose positron emission tomography |
| Magnetic resonance angiography |
| Magnetic resonance angiography with contrast delayed enhancement |
| Contrast echocardiography |
| Strain rate echocardiography with or without dobutamine |
| Magnetic resonance spectroscopy |
| Metabolic imaging with β-methyl-iodophenyl pentadecanoic acid |
| Molecular imaging |
Dobutamine echocardiography, thallium-201 myocardial perfusion imaging, the use of technetium-99m labeled agents, F-18-fluorodeoxyglucose positron emission tomography, magnetic resonance imaging, contrast echocardiography, strain rate analysis by dobutamine echocardiography, molecular imaging, and fatty acid imaging have been used for the diagnosis of the presence of chronically ischemic viable myocardium.
The available techniques of determination of the presence and extent of viable ischemic myocardium and sensitivity, specificity, and predictive values have been assessed in patients with SHF with a wide range of ejection fractions. Most of these studies were not prospective or randomized. The numbers of patients in these studies were also relatively small. Thus, it is difficult to estimate the potential impact of these studies in clinical practice. Nevertheless, the results of these studies, which are listed in Table 2 , may have some practical application.
| Modality | Sensitivity | Specificity | Positive Predictive Value | Negative Predictive Value |
|---|---|---|---|---|
| Dobutamine stress echocardiography | 80% | 78% | 75% | 83% |
| Thallium-201 stress imaging | 87% | 54% | 67% | 79% |
| Single photon-emission computed tomography | 83% | 65% | 74% | 76% |
| F-18-fluorodeoxyglucose positron emission tomography | 92% | 63% | 74% | 87% |
| Magnetic resonance imaging | ||||
| Wall thickness | 95% | 41% | 56% | 92% |
| Dobutamine echocardiography | 74% | 82% | 78% | 78% |
| Contrast enhancement | 84% | 63% | 72% | 78% |
In clinical practice, dobutamine stress echocardiography is most frequently used, because it is widely availability and easy of perform and interpret the results. At many institutions, F-18-fluorodeoxyglucose positron emission tomography is used for detection of the presence and extent of hibernating myocardium. Cardiac magnetic resonance imaging with delayed contrast enhancement is being increasingly used to assess the magnitude and distribution of fibrosis ( Figure 1 ). The magnitude of fibrosis correlates with functional, hemodynamic, and short- and long-term improvements in prognosis of patients with stage C SHF who undergo revascularization treatment. Even in patients with nonischemic dilated cardiomyopathy, midwall fibrosis is associated with increased all-cause mortality, cardiac hospitalization, and increased risk for sudden cardiac death and ventricular tachycardia. NOGA electroanatomic endocardial mapping has been used to distinguish between fibrosis and viable myocardium. Very low endocardial unipolar voltages indicate fibrosis, whereas the presence of viable myocardium is associated with larger voltages. However, electroanatomic endocardial mapping is an invasive technique and rarely required in clinical practice. Metabolic single photon-emission computed tomographic imaging with β-methyl-iodophenyl pentadecanoic acid has been used to assess the presence of ischemic myocardium. Beta-methyl-iodophenyl pentadecanoic acid is a fatty acid analogue. Fatty acid metabolism is suppressed during ischemia, such as during exercise, and there is delayed recovery of metabolic function after reperfusion (metabolic stunning, ischemic memory). However, the role of these newer techniques for detecting hibernating myocardium in clinical practice has not been established.
