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Ann Thorac Surg 2000;70:356-357
© 2000 The Society of Thoracic Surgeons
a Department of Surgery, University of Kentucky, Lexington, Kentucky, USA
Address reprint requests to Dr Mentzer, Department of Surgery, University of Kentucky, 800 Rose St, MN264, Lexington, KY 40536-0298
e-mail: mentzer{at}pop.uky.edu
It is well established experimentally that a brief interval of ischemic stress prior to a period of prolonged ischemia enhances the tolerance of the heart to the insult. This phenomenon, known by the term ischemic preconditioning (IPC), is not confined to the heart and is currently under intense investigation in other organs as well, eg, the brain, skeletal muscle, and the liver. In the heart, this increased tolerance is manifested as a reduction in ventricular arrhythmias and infarct size. Metabolically, it is associated with reduced rates of myocardial adenosine triphosphate (ATP) depletion and interstitial adenosine accumulation.
Despite the fact that classic IPC is one of the most potent methods for lessening infarct size, several aspects of the phenomenon limit direct clinical applicability. The timing of the conditioning event appears to be important, ie, the stimulus must be applied at least 3 minutes prior to the prolonged occlusion. Repeated episodes at short intervals do not enhance the degree of protection; the protection is short-lived and usually disappears within 2 to 3 hours. Ischemic preconditioning can be renewed, but tolerance develops within a short time. Finally, although a decrease in postoperative ventricular arrhythmias and a reduction in infarct size is desirable, a much more common and life-threatening problem after a cardiac surgical procedure is myocardial stunning. There is little convincing evidence that IPC in vivo reduces stunning.
With these observations in mind, one might ask why this phenomenon has generated so much interest among cardiovascular surgeons. The primary reason is the assumption that if we can understand the mechanisms underlying IPC, we might be able to develop new rational therapeutic strategies that will allow us to operate on the heart more safely, with or without cardiopulmonary bypass.
To this end, the findings in the articles by Gaudette [1] and associates and Saltman and colleagues [2] provide valuable insight into some of the intracellular processes involved in both IPC and pharmacologic preconditioning. Using well-established animal preparations and hypothesis-driven protocols, the two author groups clearly demonstrate that IPC protection involves the interactions of protein kinase C (PKC) pathways and ATP-sensitive channels and that a potassium-channel opener such as pinacidil can be an effective pharmacologic preconditioning agent.
As with many good studies, the findings raise additional questions, and the conclusions have to be interpreted in the context of the study design, the species studied, and the preparation used. For example, Saltman and co-workers studied the effects of pinacidil in isolated crystalloid-perfused rabbit hearts subjected either to regional ischemia or to IPC and pinacidil plus phenylephrine. Although these interventions reduced infarct size, the treatment failed to improve postischemic recovery of left ventricular function. This is consistent with reports by others that when rabbit hearts are subjected to 60 minutes of global ischemia, IPC has little effect on global functional recovery after ischemia despite a nearly threefold reduction in infarct size [3]. However, there are reports that hypoxic preconditioning of rabbit right ventricular papillary muscle improves developed force after hypoxia and that rabbit hypoxic-preconditioned myocytes exhibit enhanced velocity of shortening after cardioplegic arrest. These differences emphasize the need for investigators to take into account species-dependent and preparation-dependent variables when interpreting the data.
With respect to the PKC and KATP channel study by Gaudette and coauthors, it is important to note that although the KATP channel has been proposed to be an important effector of cardiac protection, it is becoming increasingly clear that the mitochondrial KATP channels may play a more important role than the sarcolemmal KATP channels. Regardless of intracellular location, it is still unknown how activation of the channel confers protection.
Likewise, even though PKC has been implicated as an important mediator of IPC, the signaling pathways still need to be determined. Efforts to elucidate its targets are confounded by the fact that PKC has multiple isoforms, some of which are Ca2+ independent and many of which have not been characterized. Nevertheless, as nicely demonstrated by Gaudette and colleagues, increasing evidence suggests that PKC signaling pathways and KATP channel activation are linked. A recent report by Hoek and associates [4] indicates that in chick cardiomyocytes, this linkage results in the attenuation of oxidant generation at the time of reoxygenation. In the same study, pinacidil was as effective as preconditioning in attenuating the reoxygenation burst of reactive oxygen species. Thus, it is possible that the protective effects of IPC and pharmacologic preconditioning are mediated in part by PKC, not only during ischemia but also during the first few minutes of reperfusion. However, the use of various agonists and antagonists to elucidate the pathways and effectors in such studies tends to produce inconclusive results. Although many of these agents are purportedly selective, they may have different effects at different doses in different species. Finally, using a phorbol ester to activate PKC or chelerythine to inhibit PKC is not the same as measuring activity directly.
With respect to IPC, pharmacologic preconditioning, and clinical applicability, it is important to keep in mind short-term and long-term goals. In the short term, understanding the signaling pathways and effectors that result in a reduction in infarct size will undoubtedly lead to the development of new potent therapeutic agents that will make cardiac operations safer in high-risk patients. As noted earlier, however, low cardiac output and death after coronary artery bypass grafting is more often related to myocardial stunning than to myocardial infarction [5]. Likewise, low cardiac output or myocardial infarction is not a problem frequently encountered after minimally invasive direct coronary artery bypass procedures. Thus, before we extrapolate our experimental findings to the clinical arena, it is important that we recognize where they are most relevant and then tailor the therapy to meet specific needs, ie, reduce stunning and/or infarction. In the long term, if by understanding the mechanisms underlying IPC and pharmacologic preconditioning we can develop strategies that will prevent both stunning and infarction, we may be able to safely perform more complex surgical procedures in sicker patients.
The authors are to be commended for their diligent work and valuable contributions to an exciting area that is important to cardiac surgeons, cardiologists, and scientists.
References
This article has been cited by other articles:
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  S. J. Canyon and G. P. Dobson Pretreatment with an adenosine A1 receptor agonist and lidocaine: A possible alternative to myocardial ischemic preconditioning J. Thorac. Cardiovasc. Surg., August 1, 2005; 130(2): 371 - 377. [Abstract] [Full Text] [PDF]
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