Hibernating myocardium: A historical perspective

Summary Hibernating myocardium refers to the presence of persistent myocardial and left ventricular dysfunction at rest, associated with conditions of severely reduced coronary blood flow. This left ventricular dysfunction probably represents an adaptive mechanism preventing irreversible myocardial cell damage, since myocardial and left ventricular dysfunction in hibernating myocardium improve following the restoration of coronary blood flow. This review examines the evolution of the concept of hibernation from a clinical observation to the potential underlying mechanisms recently proposed.     

Hibernating myocardium: diagnosis and patient outcomes

Approximately 50% of the patients with chronic obstructive coronary artery disease resulting in chronic contractile dysfunction have hibernating myocardium and may benefit from revascularization. This pooled analysis describes the relative merits of dobutamine echocardiography, thallium-201 and technetium-99m scintigraphy, positron emission tomography, and magnetic resonance imaging, for the diagnosis of hibernating myocardium and prediction of patient outcomes.     

Hibernating myocardium: a hypometabolic state for energy conservation

Conclusions Moderately hypoperfused myocardium in animals initiates an active process that transiently reduces regional energy consumption below that required by the reduced flow. This eliminates most metabolic abnormalities of ischemia despite ongoing hypoperfusion. These interesting early metabolic adaptations help to confirm the concept of hibernating myocardium, a hypometabolic state for energy conservation. A similar metabolic response probably can occur in human myocardium. However, the complexities of coronary disease may make it difficult to demonstrate these metabolic adaptations in chronically hypofunctioning myocardium in humans.     

Hibernating myocardium: morphological correlates of inotropic stimulation and glucose uptake

BACKGROUND—In patients with postischaemic left ventricular dysfunction, segments recovering function after revascularisation (hibernating myocardium) may not respond during dobutamine echocardiography, despite preserved [¹⁸F] 2-fluoro-2-deoxy-D-glucose (FDG) uptake at positron emission tomography.
OBJECTIVE—To investigate whether this lack of response might reflect the degree of ultrastructural change in hibernating myocardium.
METHODS—Transmural biopsies were obtained from 22 dysfunctional segments in 22 patients during coronary artery bypass grafting and examined by light and electron microscopy. Wall motion scores and coronary vasodilator reserve were assessed before and after coronary artery bypass grafting (CABG).
RESULTS—Mean (SD) wall motion score improved in all segments following CABG (from 2.24 (0.4) to 1.55 (0.4); p < 0.0001), confirming hibernating myocardium. In these segments myocardial blood flow (positron emission tomography with H₂¹⁵O) before CABG was similar to that in normal volunteers (1.02 (0.24) v 1.02 (0.23) ml/min/g), while the coronary vasodilator reserve was blunted (1.26 (0.7) v 3.2 (1.6); p < 0.0001). Myocardial blood flow was unchanged after CABG, whereas coronary vasodilator reserve increased to 2.10 (0.90) (p < 0.0007). In hibernating myocardium myofibrillar loss, interstitial fibrosis, and glycogen-rich myocytes were more marked than in control donor hearts. On the basis of the response to dobutamine before CABG, two functional groups were identified: group A, segments with inotropic reserve (n = 15); group B, segments without inotropic reserve (n = 7). FDG uptake was similar in group A and group B (0.40 (0.1) v 0.44 (0.1) µmol/min/g). In group B there was more myofibrillar loss (26 (8)% v 11 (5)%; p = 0.0009) and glycogen-rich myocytes (28 (11)% v 17 (10)%; p = 0.02), whereas interstitial fibrosis, myocardial blood flow, and coronary vasodilator reserve were similar in the two groups. Myofibrillar loss was the only independent predictor of inotropic reserve (p = 0.01).
CONCLUSIONS—Hibernating myocardium is characterised by a reduced coronary vasodilator reserve which improves on revascularisation and shows a spectrum of ultrastructural changes that influence the response to dobutamine, while FDG uptake is invariably preserved.


Keywords: coronary artery disease; heart failure; myocardial viability; myocardial blood flow; positron emission tomography     

Hibernating myocardium associated with coronary artery dissection and vasospastic angina.

Hibernating myocardium is an uncommon clinical state involving persistently impaired myocardial function. A 61-year-old man was admitted because of vasospastic angina. Coronary angiography revealed coronary artery dissection in the midportion of the right coronary artery, and segmental vasoconstriction was evoked by acetylcholine. In this patient, hibernating myocardium in the dissected region was clearly demonstrated by dipyridamole thallium-201 imaging. This report describes the first documented case of hibernating myocardium associated with coronary artery dissection, and the usefulness of dipyridamole thallium-201 imaging in the assessment of this state. Coronary artery spasm might be relevant to the etiology of coronary artery dissection.     

Hibernating myocardium: Programmed cell survival or programmed cell death?

Evidence that programmed cell death contributes to cardiomyocyte loss is substantial for some cardiac pathologies such as myocardial infarction and a variety of cardiomyopathies. For others, such as chronic hibernating and stunned myocardium, its involvement is still debated. Recent studies have indicated that the heart remodels its structure in a rather stereotypical way when subjected to unfavourable conditions such as ischemia and pressure or volume overload. This stereotypical response is characterized by subcellular adaptations in cardiomyocytes whereby the cells switch from an adult (functional) to a fetal (survival) phenotype, a process akin to dedifferentiation. Structural hallmarks of dedifferentiation are reduction of contractile filaments, accumulation of glycogen in the cytosol, dispersion of nuclear heterochromatin, changes in mitochondrial shape and size, and loss of sarcoplasmic reticulum and T-tubules. The changes are accompanied by important alterations in the expression and distribution of structural proteins in these organelles. Today, there is only circumstantial evidence that cardiomyocyte dedifferentiation is an adaptive and reversible phenomenon instead of a degenerative event leading to apoptotic cell death. Indeed, some research groups consider the switch to a fetal phenotype to be a rescue reaction and therefore coined the name ‘programmed cell survival’, whereas others interpret this as an event on the ‘programmed cell death’ pathway. It is obvious that resolving this controversial issue is of direct clinical importance as far as prognosis and therapy are concerned.     

Hibernating myocardium: chronically adapted to ischemia but vulnerable to sudden death

The inability to reproduce spontaneous ventricular fibrillation in an animal model of chronic coronary artery disease has limited advances in understanding mechanisms of sudden cardiac death (SCD). Swine with hibernating myocardium arising from a chronic left anterior descending coronary artery (LAD) occlusion have a high rate of SCD that parallels the poor clinical survival of medically treated patients with hibernating myocardium. Kaplan-Meier analysis (n=426) demonstrated a cumulative mortality of 49% after 5 months that was almost entirely attributable to spontaneous SCD. Using implantable loop recorders, ventricular fibrillation was documented as the arrhythmic mechanism of death in all animals (n=10) and was usually preceded by ventricular tachycardia (n=8). Physiological studies before SCD (n=7) demonstrated total LAD occlusion and collateral-dependent myocardium (n=5), excluding acute occlusion as a major trigger of arrhythmia. The physiological substrate of hibernating myocardium was present before SCD, with reductions in LAD perfusion (SCD 0.79+/-0.13 versus 0.80+/-0.08 mL/min per g) and wall thickening (SCD 28+/-3% versus 22+/-3%) that were similar to survivors (n=14). Triphenyltetrazolium chloride infarcts among animals with SCD were infrequent (4 of 32) and small, averaging 4.6% of LV mass. Histology (n=4) showed postmortem changes but no acute inflammation nor contraction band necrosis. These data support the notion that hibernating myocardium is a pathophysiological substrate at high risk of SCD. This is independent of changes in functional stenosis severity, acute myocardial necrosis, or fibrotic scar. Thus, regional adaptations that promote myocyte survival in the setting of chronic repetitive ischemia result in a substrate with enhanced vulnerability to lethal arrhythmias and SCD.     

Hibernating myocardium in patients with coronary artery disease: Identification and clinical importance

Summary The term hibernating myocardium describes a particular outcome of myocardial ischemia in which myocytes show a chronically depressed contractile ability but remain viable. Revascularization of hibernating tissue causes a recovery of mechanical function that correlates with long-term survival. Therefore it is important clinically to distinguish hibernating from infarcted myocardium, since asynergies due to hibernation will improve on reperfusion, whilst those due to infarct will not. One suggested technique to identify hibernating myocardium is to stimulate the myocytes acutely, but briefly, by administration of inotropic agents while monitoring contractile function by echocardiography. We report our experience on the use of low dosages of dobutamine. Myocardial viability was validated by measuring the recovery in contraction of the akinetic areas after coroanry artery bypass surgery by means of intraoperative epicardial echocardiography. The test has a sensitivity of 93% and a specificity of 78%. It is useful for identification of viable myocardium and also for quantification of intraoperative risk in individual patients. Limitations of this test are related to the presence of downregulation of beta receptors and to the impossibility of differentiating hibernating from stunned myocardium. Another useful technique of identifying hibernating myocardium is the use of radionuclear markers for viability. In our experience the two most important tests are (1) rest-redistribution imaging of thallium 201 (which has a high sensitivity of 93% but a low specificity of 44%) and (2) ^99mTe-Sestamibi imaging, which provides information on both perfusion and function with a single injection. This latter technique allows differentiation between stunning and hibernating on the basis of coronary flow, which is preserved in stunning and reduced in hibernation.     

Hibernating myocardium caused by isolated, radiation induced left main stem coronary artery stenosis

A 45 year old man presented with a five week history of worsening exertional dyspnoea and orthopnoea. He had also noted mild, bilateral ankle swelling. The patient had been diagnosed with stage III Hodgkin's lymphoma in 1968 at the age of 21. During the same year he underwent total nodal irradiation followed by chemotherapy in 1971. He had remained entirely asymptomatic over the course of the next 24 years with no evidence of relapse. Cardiac catheterisation undertaken soon after admission revealed a tight left main stem stenosis with a left dominant system. Left ventriculogram showed severe, global hypokinesia, and raised left ventricular end diastolic pressure (22 mm Hg). Urgent coronary artery bypass graft surgery was carried out. He made an uncomplicated recovery and his condition improved sufficiently to allow discharge eight days following the procedure. His heart failure slowly resolved and repeat transthoracic echocardiogram performed six months after surgery showed an unequivocal improvement in left ventricular function. Left ventricular ejection fraction continued to improve and increased from 23% at two months to 42% at two years. He currently remains entirely asymptomatic off all medication.

Keywords: left main stem stenosis;  radiation induced coronary artery disease;  hibernating myocardium     

冬眠心肌研究进展

冬眠心肌是由于冠状动脉血流减少所致的心肌及左室功能持续性损害,改善心肌灌注血流,可使心肌及左室功能异常达到部分或完全恢复。冬眠心肌存在于多种临床综合征中。冬眠心肌在血流动力学、能量物质代谢、形态和组织学特征方面均有自身的特点。临床上有多种无创性方法可用来检测冬眠心肌的存在,术前对心肌的缺血程度和范围进行准确的评估,是选择性地施行心肌血运重建术的主要依据。