Heart and Metabolism

Number 20, 2003
Hibernation preconditioning
Hibernating myocardium:
a clinical point of view

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A. Berger, W. Wijns
Cardiovascular Center, OLV Ziekenhuis, 9300 Aalst, Belgium
Correspondence: Dr A. Berger, Cardiovascular Center, OLV Ziekenhuis, 9300 Aalst, Belgium. Tel: +32 53724439, fax: +32 53724185

Abstract

Hibernating myocardium is a term used to described the state in which regional myocardial segments appear to be dead but can be awakened and return to normal conditions. The dramatic improvement in left ventricular function in patients with ischemic heart disease after CABG, demonstrated by Rahimtoola in retrospective studies, was postulated to be due to this pathophysiologic process. The ischemic heart downgrades its energy expenditure with a decrease in ventricular function and blood flow to a level of equilibrium which can be restored by revascularization. The prevalence of hibernating myocardium evaluated by PET or SPECT imaging was identified 60% of patients with depressed left ventricular function. Clinical presentation ranged from acute coronary syndrome to severe left ventricular dysfunction or anomalous left coronary artery from the pulmonary artery (ALCAPA syndrome). Diagnostic testing is recommended in patients with ischemic cardiomyopathy who are being considered for heart transplantation or who have coronary heart disease with left ventricular dysfunction whether asymptomatic or mildly symptomatic. In other situations, diagnostic testing should be individualized. Revascularization either by CABG or by percutaneous intervention achieves an improvement of 20% to 60% in left ventricular function. In patients with chronic heart failure due to coronary artery disease, a better outcome was achieved in revascularized patients with hibernating myocardium than in those treated medically. In the absence of viability, mortality was similar in patients who did or did not undergo revascularization. In conclusion, hibernating myocardium is a frequent cause of left ventricular dysfunction due to ischemic heart disease. The return of normal function after revascularization is clearly linked to a better outcome and emphasizes the need for a correct clinical and diagnostic approach. - Heart Metab. 2003;20:12–18.

Keywords: Hibernating myocardium, viable myocardium, left ventricular dysfunction, ischemic cardiomyopathy, prevalence, clinical presentation, diagnostic testing, revascularization outcomes

Introduction
Many mammals in north-temperate regions solve the problem of winter scarcity of food and low temperature by entering a prolonged and controlled state of dormancy called hibernation. During this state, the animal appears to be dead because the heart rate, body temperature, and movements slow down. Its metabolism is also greatly reduced. In the ground squirrel (gopher) for example, the respiratory rate drops from its usual 200 per minute to 4 to 5 per minute, and the heart rate from 150 to 5. In spring, it emerges from hibernation after recovery of normal metabolism.

Latin hibernatus, past participle of hibernare – to pass the winter, from hibernus – of winter
(Latin hiems, Greek cheima winter)

The term “hibernation” is used by cardiologists to describe a state where regional myocardial segments appear to be dead, due to decreased local contractile activity, but which can be awakened with reperfusion therapy. Indeed, a large proportion of patients with left ventricular dysfunction have viable myocardium that can recover its normal function with adequate revascularization.
The first step in the description of hibernating myocardium was taken in the early 70s [1,2], and over the next decade the concept was further explored [3,4]. In more recent years Braunwald and Rutherford [5], who emphasised the need for early recognition and treatment of the entity, have popularized the topic (Table I).

Table I. Historical milestones.

To date, the concept has evolved into three different pathophysiological responses to ischemia. Preconditioning is the ability to better tolerate a new insult after prior episodes of brief ischemia. Stunning, first described by Heyndrickx et al [6] in conscious ischemic dogs, is a general term defining the transient mechanical postischemic dysfunction that persists despite the return of normal perfusion. Hibernating myocardium is a left ventricular dysfunction due to chronic coronary artery disease, which responds positively to inotropic stress and predicts the recovery of resting function after revascularization [7]. The term “viable myocardium” includes stunning, hibernation, and normal heart tissue.
A number of studies have focused on the controversial issue related to the level of residual resting myocardial blood flow. If hibernation was a state of chronic ischemia, one would expect the reduction of the flow to be matched to the decreased contraction [9]. Although residual flow in the dysfunctioning area is reduced, compared with regions with normal contractile function, the decrease in function is out of proportion to the flow reduction, which is why hibernation is seen as a state of adaptation to chronic ischemia [10]. Fallavollita and colleagues [11] have shown that hibernating myocardium retains its ability to increase oxygen consumption in order to face superimposed acute ischemia.

“Hibernation myocardium can be described by the clinical situation, ie, impaired left ventricular function at rest that is reversible by revascularization.”
— S.H. Rahimtoola [8]

The question then arises whether hibernation still represents a state of ischemia. As emphasized by Hearse [12], this depends on the definition used. From a physiological point of view, considering the limited coronary blood flow and reduced function, the hibernating heart should be seen as ischemic. On the other hand, biochemical ischemia is defined as a condition in which the coronary blood flow is inadequate to permit the maintenance of steady-state metabolism, while hibernating segments seem to have reached a state of equilibrium that can be maintained for some time (months). Currently, hibernation is considered to be a response to ischemia and therefore should be regarded as an expression of chronic ischemic heart disease, as shown in Figure 1.

Figure 1. Diagram showing the different entities of ischemic heart disease.

The purpose of this review is to discuss the clinical importance of the entity. Following this brief introduction, the clinical presentation, detection, and treatment of myocardial hibernation will be reviewed.

Epidemiology
Despite the advances in medical treatment, ischemic heart disease remains the leading cause of heart failure and is associated with high mortality, morbidity, and frequent hospital admissions for failure, angina, or recurrent ischemia [13, 14]. Dysfunctional but viable myocardium has the potential for functional recovery after revascularization. However, due to the balance between the benefit and risks of bypass surgery, only a subset of patients with a severely depressed ejection fraction will ultimately benefit. Data from the available studies show that between 20% and 60% of patients with ischemic cardiomyopathy will show functional improvement after revascularization [15, 16]. Bax et al [17] showed that 43% of patients with ischemic cardiomyopathy have viable segments (using PET and glucose metabolism imaging). In other studies using SPECT, the incidence of hibernating myocardium ranged from 50% to 61% of all dysfunctioning segments [18–20].

Clinical presentation
Hibernating myocardium has been documented in three clinical entities [21, 22]:
— acute coronary syndromes (unstable angina and reperfused acute myocardial infarction);
— severe chronic left ventricular dysfunction (ejection fraction below 35%);
— anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) [23, 24].
Numerous data demonstrate the benefit of revascularization in acute forms of ischemic heart disease. Because these patients need to be revascularized anyway, few studies have been performed in that setting. Following infarction, 70% to 80% of patients will present with hibernating tissue [25, 26].
In the chronic situation, the hibernating myocardium is characterized by ventricular dysfunction; therefore its main clinical feature is not angina but dyspnea due to the decrease in contractility and elevated diastolic left ventricular pressure. Angina is not always associated with the clinical presentation, thus viable myocardium should be sought even in angina-free patients. When present, chest pain reflects the impaired coronary flow reserve which can be superimposed on resting hibernation [27]. Diastolic gallop sounds (B3) or mitral insufficiency are frequently part of the clinical presentation due either to restricted motion of the mitral valve or consecutive to dilatation of the mitral annulus. Secondary tricuspid insufficiency due to postcapillary pulmonary hypertension should also be identified. Nakano et al [28] showed that ST-segment analysis of the resting electrocardiogram can help to detect viable myocardium after infarction, while the presence of Q-waves does not necessarily imply the absence of residual viability.
The rationale for viability screening is that the presence or absence of myocardial hibernation enables better risk stratification of patients in whom revascularization is being contemplated (Table II).

Tabel II. Indications for viability testing in patients with suspected hibernating myocardium.

Patients with suspected ischemic heart disease and severely depressed left ventricular function should be tested in order to select the best therapy among heart transplantation, revascularization, or resynchronization [8]. Patients with known coronary artery disease and severely depressed ventricular function (left ventricular function <35%) suitable for CABG should also be investigated. It is especially important to screen this group preoperatively in view of the high morbidity associated with cardiac surgery in this setting. In the Coronary Artery Surgery Study, surgical mortality was three times greater at 5 years in patients with impaired left ventricular contraction [29]. When a substantial amount of hibernating myocardium is present, the benefit of cardiac surgery outweighs its risk [17]. Even in patients with three-vessel disease and left ventricular dysfunction who have stable or unstable angina, identification and quantification of the hibernating myocardium could be of some benefit. The assessment of viability allows better stratification of the risks and benefits of the possible treatment strategies [30, 31]. The detection of viable myocardium is usually not needed following acute coronary syndromes, in patients with normal resting left ventricular function, or with coronary arteries that are not suitable for revascularization.

Detection
Identification of hibernating myocardium is key for stratifying patients in whom ventricular dysfunction is likely to improve after revascularization. Thus, techniques with high sensitivity are required in order not to miss patients who could benefit from the strategy. The available techniques are those assessing cellular integrity (structural viability), and stress echocardiography based on investigation of the contractile reserve of the myocardium (functional viability). The first group consists of PET with 18F-fluorodeoxyglucose and 11C-acetate, and SPECT with thallium and 99mTc sestamibi perfusion tracers.
Pooled analysis of 37 studies evaluating the relative merits of the most frequently used techniques showed that both echocardiography-based and nuclear approaches are effective [32]. A recent meta-analysis of 77 studies [33] confirmed that low-dose dobutamine echocardiography has the highest predictive value for predicting recovery of regional contraction. Overall, functional testing appears to have better specificity compared with structural testing (which is slightly more sensitive).

Outcome and treatment
It is generally accepted that patients with coronary stenoses and chronic ischemic cardiomyopathy will benefit from revascularization [3, 4, 34]. Most of the improvement is due to the recovery of dysfunctionally viable myocardium [35, 36]. The time course of the recovery is variable. It has been postulated that the recovery period might represent the time needed to regenerate and repair structural cell damage [22, 37]. Therefore, the more severe the dysfunction, the longer it takes to recover. Immediate recovery might indicate stunning, and slow recovery (months to years) is due to repeated stunning with cumulative dysfunction or chronic hibernation [38].

Functional improvement after CABG and percutaneous intervention
To date, there are no prospective randomized studies which demonstrate the benefit of revascularization. Although such trials are presently ongoing, we can rely in the meantime on numerous retrospective and observational studies. Most of these used either CABG or percutaneous intervention, depending on anatomical suitability for either technique [36].

Improvement in global versus regional left ventricular dysfunction
Bax et al [17] and others [15, 16, 33] have demonstrated the quantitative relation between the number of viable segments at preoperative screening and the magnitude of postoperative improvement in global function. Four to five segments (out of 19) or 25% to 30% of left ventricular myocardium must be viable in order to sustain a 5% increase in absolute ejection fraction units [35, 39–42].

Outcome after revascularization versus medical treatment
One study has shown the benefit of carvedilol versus placebo (double-blind randomized trial) in patients with chronic heart failure and residual viability [43]. This effect was not compared with revascularization. However, it was shown repeatedly that patients with viable myocardium who do not undergo revascularization have a worse prognosis than patients without residual viability [38, 44–50]. A meta-analysis of 1029 patients with ischemic cardiomyopathy showed better prognosis after revascularization than with medical treatment. Incidence of death, nonfatal infarction, unstable angina, and the need for cardiac transplantation was 8% versus 27% in patients with and without viability, respectively [47]. In the absence of viability, mortality was similar in those who did or did not undergo revascularization.

Symptomatic improvement
Few studies have indicated improved symptoms of heart failure and increased exercise tolerance in revascularized patients shown to have residual viability preoperatively [27, 51, 52]. No data are available comparing the relative merit of revascularization with resynchronization therapy, a new therapy recently shown to improve both symptoms and prognosis (COMPANION trial). Likewise, it is not known whether the results of resynchronization therapy are affected by the presence of residual viability.

Conclusion
Many patients with left ventricular dysfunction have viable myocardium that can recover with adequate revascularization. Hibernating myocardium describes a state where regional myocardial segments appear to be dead, due to decreased local contractile activity, but in which they can be awakened with reperfusion therapy. Between 20% and 60% of patients with ischemic cardiomyopathy will show left ventricular hibernation with functional improvement after revascularization.
Hibernating myocardium has been documented in acute coronary syndromes, severe chronic left ventricular dysfunction, and in ALCAPA syndrome. In those situations, viability screening is important because the presence of myocardial hibernation enables better risk stratification prior to coronary revascularization. This approach may certainly be advised in patients with suspected coronary artery disease or ischemic cardiomyopathy who are being considered for heart transplantation. In patients with ischemic heart disease and severe left ventricular dysfunction, quantification of hibernating myocardium will enable risk stratification and evaluation of the benefits of the different treatment strategies.
Overall, functional testing appears to have better specificity compared with structural testing. Dobutamine echocardiography is widely available and has a very high predictive value for the recovery of regional contraction.
Even in the absence of large randomized studies, there is quite a body of accurate data from large observational investigations which demonstrate the benefit of revascularization in patients with hibernating myocardium in terms of regional and global left ventricular recovery as well as improvement in the patient’s functional status.

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REFERENCES

52. Eitzman D, al-Aouar Z, Kanter HL, vom Dahl J, Kirsh M, Deeb GM, Schwaiger M.
Clinical outcome of patients with advanced coronary artery disease after viability studies with positron emission tomography.
J Am Coll Cardiol. 1992 Sep;20(3):559-65.
PMID: 1512333 [PubMed - indexed for MEDLINE]

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Number 20, 2003Hibernation preconditioning Hibernating myocardium: a clinical point of view

Number 20, 2003Hibernation preconditioning

Number 20, 2003
Hibernation preconditioning
Hibernating myocardium:
a clinical point of view

Number 20, 2003
Hibernation preconditioning