Review
The Biology of Myocardial Hibernation

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Abstract

Patients with chronic coronary artery disease frequently have contractile dysfunction that recovers upon reperfusion. The concept of myocardial hibernation views the observed reduction in contractile function not as the result of an ongoing energetic deficit, but as an adaptive down-regulation that serves to maintain myocardial integrity and viability. In the experiment, sustained perfusion-contraction matching, recovery of energy and substrate metabolism during ongoing ischemia, the potential for recruitment of inotropic reserve, lack of necrosis, and therefore recovery of function upon reperfusion are established features of hibernation. Apart from reduced calcium responsiveness, the underlying mechanisms are still unclear. In patients, the importance of reduced baseline blood flow vs. that of superimposed repetitive stunning is somewhat controversial; however, in most studies blood flow is reduced, and the myocardium must be ischemic often enough to have persistent dysfunction. Morphologically, hibernating myocardium displays features of dedifferentiation, with loss of cardiomyocytes and myofibrils, and of degeneration, with increased interstitial fibrosis. Patients with hibernating myocardium must be identified and undergo revascularization. With a better understanding of the underlying mechanisms of hibernation, these adaptive responses to ischemia can potentially be recruited and reinforced pharmacologically to delay impending myocardial infarction.

Section snippets

Blood Flow in Myocardial Hibernation: Persistent Ischemia or Cumulative Stunning, or Both?

When he first proposed the concept of myocardial hibernation, Rahimtoola reasonably assumed that the observed reduced regional contractile function which recovered upon reperfusion must have reflected reduced resting blood flow Rahimtoola 1982, Rahimtoola 1985. A series of experimental studies with controlled coronary hypoperfusion identified features consistent with myocardial hibernation—perfusion-contraction matching Gallagher et al. 1984, Heusch et al. 1996, Ito 1995, Schulz et al. 1992,

Substrate and Energy Metabolism in Hibernating Myocardium

Most experimental studies with controlled coronary hypoperfusion over several hours report recovery of the initially perturbed substrate and energy metabolism during ongoing ischemia (Figure 2). Initial reductions in pH and lactate extraction recover over time Arai et al. 1991, Chen et al. 1996, Chen et al. 1997a, Eberli et al. 1991, Fedele et al. 1988, Heusch et al. 1996, Schaefer et al. 1992, Schulz et al. 1992. Likewise, initial reductions in creatine phosphate content Arai et al. 1991,

Morphology of Hibernating Myocardium

In contrast to metabolism where clinical studies still largely lag behind experimental research, studies on the morphology of hibernating myocardium have been led by clinical research that was only subsequently confirmed in the experimental animal. In biopsies from human hibernating myocardium, the loss of contractile function is associated with loss of cardiomyocytes and myofilaments, loss of sarcoplasmic reticulum and disorganization of the cytoskeleton. Numerous small, doughnut-like

Mechanism(s) of Myocardial Hibernation

The mechanism(s) responsible for the development of myocardial hibernation, in particular the biochemical signal that rapidly reduces contractile function in proportion to reduced blood flow, are largely unclear. Alterations in beta- adrenoceptor density and affinity (Schulz et al. 1993), adenosine, and activation of ATP-dependent K-channels have been excluded (Schulz et al. 1995). Calcium responsiveness in experimental myocardial hibernation is reduced, and this reduction is not related to

Conclusions and Perspectives

The existence and importance of hibernating myocardium is beyond doubt. Clearly, chronically dysfunctional myocardium in patients with coronary artery disease is frequently viable, amenable to reperfusion/revascularization, and its reperfusion is associated with improved prognosis (Di Carli et al. 1994, Eitzman et al. 1992, Gunning et al. 1997, Lee et al. 1994, Pagley et al. 1997, vom Dahl et al. 1996). The experimental counterpart is characterized by: 1) sustained perfusion-contraction

Acknowledgements

The authors' studies were supported by the Deutsche Forschungsgemeinschaft, the IFORES program of the Medical School of the University of Essen, the German Cardiac Society, and the Hans und Gerti Fischer Stiftung.

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