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Ann Thorac Surg 1997;64:1874-1876
© 1997 The Society of Thoracic Surgeons
Department of Surgery, Montreal Heart Institute, 5000 Bélanger St E Montreal, Pq H1t 1c8 Canada
Department of Cardiovascular Surgery, Hôpital Lariboisière, 2, rue Ambroise Pare, Paris 75010, France
To the Editor:
We read with interest the report by Kaukoranta and co-workers [1] concerning the role of ischemic preconditioning before normothermic retrograde cardioplegia and wish to praise the elegance and thoroughness of their study. They have found that ischemic preconditioning before normothermic retrograde blood cardioplegia administered in nearly continuous fashion did not lead to clinical benefits and was associated with lower adenosine triphosphate levels at the end of the cross-clamping period and with a trend toward an increase in creatine kinase-MB and troponin T production. We [2] have reported a similar randomized study of 20 patients with comparable clinical characteristics using the same type of myocardial protection and equally found no clinical benefit from ischemic preconditioning in this setting and similar trends of increased myocardial ischemia with preconditioning as reflected by a higher transmyocardial lactate gradient and creatine kinase-MB levels. This led us to recommend caution with use of ischemic preconditioning in this setting and to turn to pharmacologic agents for duplicating the effect of preconditioning [2].
We would like to offer possible explanations for the positive results obtained in prior human studies. Ischemic preconditioning reduces infarct size after regional ischemia in animal preparations across a wide variety of species, but its effect on arrhythmias and on preservation of function after global ischemia is less consistent [3]. Paradoxically, this fact may account for the observation that preconditioning, at least of the ischemic type, is not as readily suited for use in clinical cardiac surgery as one would expect because, in most cases, postbypass pump failure is caused by reversible contractile dysfunction (stunning), not a discrete myocardial infarct [4]. Whether preconditioning can alleviate stunning independently of the reduction of infarct size can only be addressed by studies assessing concomitantly function and infarct size [3]. Those who have adhered to this design conclusively demonstrated that preconditioning improves postischemic function only by reducing infarct size, not by reducing stunning of reversibly injured myocardium. Importantly, this conclusion applies both to regionally ischemic preparations that have been preconditioned by a transient coronary artery occlusion and to models of global ischemia in which preconditioning has been induced by a transient period of aortic cross-clamping [5].
It is noteworthy that recent studies from the first group to report a metabolic benefit of preconditioning in clinical cardiac surgery, performed in the setting of normothermic ventricular fibrillation, failed to show any benefit when the preconditioning was induced at lower temperatures [6, 7]. Ischemic preconditioning may be an interesting adjunct to myocardial protection when cardioprotection is suboptimal such as in long cross-clamp times, inadequate delivery of cardioplegia, or situations when the heart is submitted to ischemic arrest rather than aerobic arrest [8]. Ischemic preconditioning has been found to confer equal but no additive benefit to hypothermia outside the situations mentioned above [9].
Thus, we conclude that the benefits confered by ischemic preconditioning before continuous normothermic blood cardioplegia, which results in aerobic cardioplegic arrest in most cases, are minimal and ischemic preconditioning may even be detrimental. It is important to remember that numerous confounding factors may skew the preconditioning effect and should be controlled for in both experimental and clinical studies. These include the use of opioid agonists, volatile anesthetics, 
-adrenergic agonists, aprotinin, and cardiopulmonary bypass itself, all of which may have preconditioning effects.
Again, we wish to command Dr Kaukoranta's group for their rigorous study, which helps define the role of ischemic preconditioning in clinical cardiac surgery.
References
Department of Internal Medicine, Oulu University Hospital, Kajaanintie 50, 90220 Oulu, Finland
To the Editor:
We thank Drs Perrault and Menasché for their valuable comments concerning our article published recently in The Annals. We are, of course, aware of their interesting results published elsewhere somewhat earlier [1]. Our study and the study by Dr Menasché's group were probably initiated and conducted at the same time without the groups knowing of each other's efforts. The results of these two studies are surprisingly similar, and in our opinion prove that ischemic preconditioning does not offer any additional benefits over conventional retrograde continuous warm blood cardioplegia during coronary bypass operations. On the contrary, myocardial injury seems to be more prominent if the heart is exposed to preceding ischemia (although for only 3 to 5 minutes) before cardiac arrest.
Doctor Yellon's group has reported that ischemic preconditioning reduces troponin T release in patients undergoing coronary artery bypass grafting with the technique of intermittent ischemic arrest with fibrillation for the distal vein to coronary artery anastomosis, and the heart reperfused and beating for the proximal vein-to-aorta anastomosis [2]. Adenosine triphosphate contents of myocardial biopsy specimens remained similar in the control and preconditioned groups, however, this being somewhat surprising in light of the results of the previous study from the same group reporting that ischemic preconditioning is able to preserve myocardial adenosine triphosphate [3]. We and others have shown in animal models that ischemic preconditioning is associated with sparing of tissue high-energy phosphates [4–6]. Studying of the changes in myocardial energy metabolism in human myocardium is difficult, and taking serial biopsy specimens from very localized areas of the myocardium is probably not the best way to approach the problem [7], and this may be the reason for the varying results obtained by Dr Yellon's group [2, 3]. We have proposed that sparing of the high-energy phosphates in preconditioned rat hearts may be due to transient inhibition of the F1F0-adenosine triphosphatase [4], and it is interesting that this mechanism seems to be operative also in human hearts subjected to 5 minutes of global ischemia by aortic cross-clamping but not during cardioplegia (unpublished).
We agree with Drs Perrault and Menasché that preconditioning probably does not alleviate stunning of the myocardium postoperatively, and that the preconditioning effects against stunning and myocyte necrosis have to be distinguished. In accordance with this we have recently found in rat hearts that preconditioning does not affect formation of free oxygen radicals or initial increase in intracellular Ca2+ during reperfusion (unpublished), the two mechanisms considered the most important in the pathogenesis of stunning [8].
It is difficult to study ischemic preconditioning in humans, and there are some potential artefacts involved, at least when coronary angioplasty is used as a model [9]. Although there is increasing evidence that ischemic preconditioning also occurs in humans, the issue is far from settled. At the moment there is no evidence that ischemic preconditioning offers any benefits over conventional modes of cardioplegia, and its use cannot be recommended. We agree with Drs Perrault and Menasché that more studies are needed in humans to resolve the mechanisms of preconditioning, because this may enable us to recruit endogenous protection by pharmacologic means in conjunction with bypass grafting. Adenosine has been shown to possess cardioprotective effects in humans [10], and it could be worthwhile to study whether administration of adenosine could precondition human heart during coronary bypass operations.
References
This article has been cited by other articles:
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  L. Wan-Jun Ischemic preconditioning in children undergoing open heart operation. Ann. Thorac. Surg., December 1, 1998; 66(6): 2163 - 2164. [Full Text] [PDF]
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