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Original Articles: Adult Cardiac

Invited Commentary

Cardiac Surgical Research, The Rayne Institute (King's College London), Guy's and St. Thomas' NHS Foundation Trust, St. Thomas' Hospital, London, SE1 7EH United Kingdom

(Email: david.chambers{at}kcl.ac.uk).

Mitochondria have been shown to have an ever increasing importance in determining the outcome of hearts subjected to ischemia-reperfusion. In particular, the role of the mitochondrial permeability transition pore (mPTP) appears fundamental to cardioprotection, with prolonged pore opening during reperfusion, inducing an injury that ultimately leads to cell death (by necrosis or apoptosis). This injury occurs by excessive calcium influx (through reverse Na/Ca exchange) that swamps the ATP-dependent efflux mechanisms. Consequently, agents that will inhibit mPTP opening should reduce ischemia-reperfusion injury and improve cardioprotection. One such agent, cyclosporine A (CsA) has been shown in many studies to be efficacious when used either before ischemia, during ischemia, or on reperfusion. However, CsA is not believed to directly inhibit the mPTP, and has been suggested to act through a calcineurin mechanism. The present study [1] indicates that calcineurin inhibition is not involved in the protective mechanism of CsA, since FK506 (a calcineurin inhibitor that is believed to be without effect on mPTP opening) was not protective. Furthermore, the authors suggest that CsA may induce protection by mPTP inhibition.

These findings are quite controversial. Despite the availability of a technique that allows direct measurement of inhibition of mPTP opening, this has not been demonstrated in this study; this would be important to confirm the CsA effects. In addition, the efficacy of FK506 has been shown to be dose-dependent; in this study, CsA and FK506 were administered in a 20 mL infusion for 1 hour at doses of 25 and 1 mg/kg, respectively. It would be interesting to know how these doses compared with concentrations used in some in vitro studies. For example, is it possible that the dose of FK506 used in this study was too low to induce the protection seen with higher concentrations? Another confounding factor between studies is the use of different animal species (usually rats or rabbits), and also whether the hearts are isolated and perfused with a relatively nonphysiologic crystalloid solution or whether the studies are conducted in vivo, as is the case with this study.

A disappointing aspect of the study was the timing of the administration of the agents under investigation. It was previously known that CsA was effective when given prior to induction of regional ischemia, but that there was some doubt as to its efficacy if given after the onset of ischemia or immediately prior to reperfusion. Although an in vivo rabbit preparation was used, it would have been more clinically relevant to explore later administration. This would have increased the relevance for patients undergoing percutaneous coronary intervention therapy, or even those undergoing cardiac surgery. Infusion of drugs for 1 hour prior to induction of a regional ischemia questions this relevance. Inclusion of a section for limitations to the study described in the discussion would also have been useful. So, this study, although it is of interest, does seem to raise more questions than it answers.

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1. Leshnower BG, Kanemoto S, Matsubara M, et al. Cyclosporine preserves mitochondrial morphology after myocardial ischemia/reperfusion independent of calcineurin inhibition Ann Thorac Surg 2008;86:1286-1292.[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 Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): David J. Chambers Permission Requests Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Chambers, D. J. Search for Related Content PubMed PubMed Citation Articles by Chambers, D. J. Related Collections Myocardial protection Related Article