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Ann Thorac Surg 1999;67:1630
© 1999 The Society of Thoracic Surgeons

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Invited Commentaries

^a Division of Cardiac Surgery, Department of Surgery, University of Leicester, The Glenfield Hospital, Groby Rd, Leicester LE3 9QP, United Kingdom

Invited commentary

The study by Kirsch and associates investigated whether the potassium channel opener cromakalim is cardioprotective in a rabbit model of brain death. In their study, hearts were explanted 90 minutes after the induction of brain death and then they were subjected to a prolonged period of hypothermic storage followed by 60 minutes of reperfusion in a crystalloid perfused isolated heart preparation. They used a bolus injection of a single dose of cromakalim as a substitute for ischemic preconditioning and showed that this has no significant protective effect in the presence or absence of brain death. Ischemic preconditioning is readily applied experimentally but may be cumbersome and difficult to use in clinical conditions, and the search for agents that can substitute ischemic preconditioning (pharmacological preconditioning) is justified. However, a number of important aspects regarding the experimental design affecting the interpretation of the results of this study are discussed below.

Pharmacological preconditioning as a substitute for ischemic preconditioning

It is now well recognized that to achieve protection by ischemic preconditioning at least 3 to 5 minutes of ischemia should be applied and that shorter periods might not be as protective or protective at all. Previous experimental and human studies investigating the efficacy of pharmacologic preconditioning as a substitute for ischemic preconditioning used agents administered for periods comparable to ischemic preconditioning protocols, typically ranging from 3 to 10 minutes. The study by Kirsch and associates used cromakalim as a bolus injection, which is a short duration stimulus compared with the longer stimulus required to obtain protection by ischemic preconditioning. Therefore, the question of whether cromakalim, a potassium adenosine triphosphate (K_ATP) channel opener, can be used as a substitute for ischemic preconditioning is not answered by their study. However, there is evidence in the literature that K_ATP channel blockers abolish the protection induced by ischemic preconditioning and that K_ATP channel openers are as protective as ischemic preconditioning, suggesting that K_ATP channels are end-effectors of ischemic preconditioning.

Cautious interpretation of studies in which the protective efficacy of an intervention is investigated in the presence of other protective measures

My laboratory [1, 2] and other investigators [3] have shown that ischemic preconditioning has no additional protective effect to that of cardioplegia when both are used in combination. In their study, Kirsch and associates used the St. Thomas’ Hospital cardioplegic solution in all groups to arrest the hearts and thereafter for their storage, which might explain why any potential beneficial effect of cromakalim was missed.

The importance of control groups

The investigators did not show protective effect of cromakalim in hearts from animals without brain death, which contradicts their own previous study. A possible explanation for this may be that hearts from animals without brain death had little injury during the storage period and exhibited good recovery. If this were the case, then one would not expect to see a beneficial effect of any protective intervention. Clearly, proper aerobic controls are required to answer this question.

Does brain death precondition the heart?

Kirsch and associates expressed concern that the increase in catecholamines on induction of brain death could precondition the heart. This is an interesting hypothesis, but because this possibility is unknown and is not investigated in their study, it confounds the results with cromakalim.

The initial aim of the Kirsch and associates—to study a clinically relevant model of brain death—is commendable. Certainly, the study of protective interventions in complex biologic systems is desirable before clinical use is considered. However, the difficulties of these experimental models should be recognized and properly addressed in order to obtain meaningful data.

References

1. Galiñanes M., Argano V., Hearse D.J. Can ischemic preconditioning ensure optimal myocardial protection when delivery of cardioplegia is impaired?. Circulation 1995;92(Suppl II):II389-II394.
2. Kolocassides K.G., Galiñanes M., Hearse D.J. Ischemic preconditioning, cardioplegia or both? Differing approaches to myocardial and vascular protection. J Mol Cell Cardiol 1996;28:623-634.[Medline]
3. Perrault L.P., Menasché P., Bel A., et al. Ischemic preconditioning in cardiac surgery: a word of caution. J Thorac Cardiovasc Surg 1996;112:1378-1386.[Abstract/Free Full Text]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Manuel Galiñanes Permission Requests Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Galiñanes, M. Search for Related Content PubMed Articles by Galiñanes, M. Related Collections Related Article