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Ann Thorac Surg 2001;72:563-564
© 2001 The Society of Thoracic Surgeons
a Department of Surgery, University of Kentucky, College of Medicine, Chandler Medical Center, 800 Rose St, Room MN 276, Lexington, KY 40536-0298, USA
e-mail: rlasley{at}pop.uky.edu
The study by Stadler and colleagues addresses several timely aspects of myocardial ischemia-reperfusion injury and its amelioration by exogenous and endogenous agents. The cardioprotective effects of adenosine and ischemic preconditioning have been reported by numerous laboratories, but this is one of the few studies to combine these two interventions. The observation that adenosine enhanced ischemic preconditioning provided a greater degree of infarct reduction than either therapy alone suggests that these two interventions may exert their beneficial effects by different mechanisms. This hypothesis is supported by the report that ischemic preconditioning, but not adenosine preconditioning, reduces the accumulation of interstitial purines during prolonged ischemia [1]. Differences between adenosine cardioprotection and ischemic preconditioning may also explain why adenosine A1 receptor antagonism generally blocks the beneficial effects of preischemic adenosine treatment, but does not block ischemic preconditioning.
Another aspect of this study that addresses a more controversial matter is the role or relevance of apoptosis in myocardial ischemia-reperfusion injury. Apoptosis was detected by DNA fragmentation (with the TUNEL assay) and DNA laddering, however DNA damage presumably represents the final stages of apoptotic cell death at which point the damage is irreversible. In addition it is not clear whether the tissue samples collected for these assays were obtained from TTC-negative or TTC-positive tissue. These limitations may explain the authors’ puzzling TUNEL findings. There was a time-dependent increase in infarct size in all of the groups, and the three treated groups exhibited increases in TUNEL positive nuclei with increasing duration of ischemia. However in the control group the nearly 100% increase in infarct size between 30 and 60 minutes ischemia was associated with little, if any, increase in the number of TUNEL positive nuclei. Furthermore, the adenosine treatment, which decreased infarct size by 40% after 60 minutes ischemia, exhibited the greatest increase in TUNEL positive nuclei. In contrast ischemic preconditioning, which reduced infarct size to the same extent as adenosine, significantly reduced TUNEL staining. Although the authors attributed this discrepancy to the high dose of adenosine, this appears to be unlikely since adenosine was only administered as a bolus (at a concentration of 
670 µg/kg) and its hemodynamic effects persisted for only one minute. A more likely explanation may be the lack of sensitivity and specificity of TUNEL and DNA laddering for detecting apoptosis. These results indicate that if apoptosis is truly a unique form of programmed cell death that differs from oncosis (or necrosis), then more specific techniques that detect cells in intact myocardium earlier in the apoptotic program are needed.
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