PRECONDITIONING VERSUS BRAIN DEATH IN CLINICAL TRANSPLANTATION

Acute Brain Death Abolishes the Cardioprotective Effects of Ischemic Preconditioning in the Rabbit. Transplantation 2000; 69: 2013.Kirsch M, Farhat F, Garnier J-P, and Loisance D. Ischemic preconditioning was first described by Murry, Jennings, and Reimer in 1986 (1); it refers to the endogenous ability of the heart to protect itself from subsequent ischemia after an initial brief “stimulus.” Although originally described in a canine model of regional ischemia, the preconditioning effect has been reproduced in several animal models of regional and global ischemia and, in addition, has been observed in human tissue (23). Defining the mechanisms of the preconditioning effect may allow for a powerful, targeted intervention against an anticipated period of myocardial ischemia. Clearly, agents that induce the preconditioning response may assist the preservation of hearts for transplantation. Many candidate compounds have been put forward as the “trigger” for the preconditioning effect, such as adenosine, bradykinin, α-adrenergic agonists, protein kinase C (PKC) and potassium channel openers (4). There is increasing evidence that a combination of these agents can act synergistically to augment the preconditioning effect. Kirsch and colleagues have addressed an important reservation regarding the potential clinical applicability of preconditioning. They postulated that the many physiologic changes that occur as a result of brain death may attenuate the protective effect of ischemic preconditioning. The authors found that acutely increasing intracranial pressure prevented the infarct-limiting effects of ischemic preconditioning in an in-vivo model of regional myocardial ischemia. In control, non-brain-dead rabbits, preconditioning resulted in an impressive reduction in infarct size from 50% to 16% of myocardium at risk. When the experiments were repeated in animals that were subjected to brain death 90 min before the preconditioning stimulus, there was no difference in infarct size. The authors claim that the results of their study compromises the clinical potential of preconditioning for cardiac transplantation. The physiologic effects of brain death on myocardial performance have been well described (5). The most striking hormonal change is a dramatic increase in circulating catecholamines. In contrast to the chronic elevation of systemic catecholamines observed in congestive heart failure, brain death is associated with a transient increase in catecholamines, with a subsequent fall to subnormal levels. In a canine model of acute brain death similar to that used by Kirsch, Bittner and colleagues demonstrated a significant elevation of serum dopamine, epinephrine, and norepinephrine for at least 30 min (6). Despite this transient increase in catecholamines, myocardial dysfunction occurred within 4 hr in all animals. Yeh and colleagues implicated an imbalance between α- and β- adrenergic receptor activation as a potential mechanism of myocardial dysfunction after brain death (5). Because α-adrenergic stimulation is only one potential mechanism for the preconditioning effect, it is conceivable that the protective effects may be reproduced even after brain death by using alternative pathways. What are the effects of adenosine, potassium channel openers or PKC agonists in this model? In clinical practice, organ donors often receive substantial inotropic support to counteract the physiologic effects of brain death. A more clinically relevant study design would include the support of systemic hemodynamics after induced brain death. In Kirsch’s study, the mean arterial pressure of their animals dropped to approximately 30 mmHg in the brain dead groups, for 60–90 min. Surprisingly, infarct size was not larger in these two groups compared with that in the non-brain dead controls. It would be useful to repeat these experiments in the presence of hemodynamic support with exogenous inotropes. Isolated cardiomyocyte studies in our laboratory and others have demonstrated that a prolonged “ischemic stimulus” can attenuate the observed protective effects of preconditioning (2). It is conceivable that the hypotension created after balloon inflation in the brain dead group exacerbated the ischemic stimulus, leading to a loss of protection. Ischemic preconditioning remains as the most powerful endogenous protection against prolonged myocardial ischemia. In clinical situations of anticipated ischemia, such as cardiac transplantation, pharmacologic preconditioning may prove to be an important adjunct to myocardial preservation. Studies such as the one reported by Kirsch and colleagues are important to delineate the clinical limits of ischemic preconditioning. Although brain death may indeed abolish the infarct-limiting effects of classic, ischemic preconditioning, more investigation is required to determine whether targeted pharmacologic stimulation can effectively preserve the ischemic myocardium and prevent primary graft dysfunction.

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