Does cool reperfusion limit myocardial infarction injury?

The investigator team is to be congratulated for successfully surmounting a formidable implementation challenge. Within 30 minutes, they were able to rapidly cool patient body temperatures to an average less than the target temperature of 35°C without allowing the induction of cooling to interfere with or prolong the door-to-balloon time for percutaneous coronary intervention. To put this 30-minute speed of cooling into perspective, a 2010 investigation of human hypothermia from Australia reported a nearly 8-hour time interval to achieve temperatures 34°C in patients with cardiac arrest.2 The Götberg pilot study goes on to describe a 38% reduction in infarct size and 43% reduction in peak troponin T release for the patients who received cooling before coronary reperfusion versus controls who received standard reperfusion within the same time period. The study raises an important clinical question that we must address: Is cool reperfusion the best reperfusion? An even more crucial scientific question lies just beneath the surface of these data: Does reperfusion injury exist in humans, and if so, does it have any relevance in terms of long-term function or tissue injury? Reperfusion injury remains controversial since its first description in the 1970s when it was observed that reoxygenation of the ischemic perfused isolated heart resulted in a large release of cardiac injury enzymes along with structural cellular damage seen extensively during reperfusion but only very minimally during the preceding ischemia.3,4 The notion of reperfusion injury suggested that some portion of cell death was caused by the conditions of reperfusion, not simply by the conditions or injury produced by the period of ischemia alone.5,6 The critical experiment to prove the existence of reperfusion injury was to demonstrate that long-term cell death or infarct size could be reduced by a therapy delivered after the ischemia. Much animal data seemed to support the existence of reperfusion injury, but nearly all the human trials of cardioprotection have failed to support the idea that any therapy could significantly alter cell death or infarct size after the ischemia had occurred.7 There are a few important exceptions to this general failure, but thus far in routine cardiovascular practice, there are no widespread therapies to treat or prevent reperfusion injury. The failure of cardioprotection after reperfusion in clinical trials has been interpreted by many as evidence that reperfusion injury is quite negligible or does not exist.7,8 Moreover, our current paradigm for the treatment of acute myocardial infarction is founded on this assumption, and early reperfusion has become the primary goal for the treatment of ischemic cardiac syndromes.9 Could this simple pilot study with 20 patients significantly alter our view of the treatment of ischemia? If these results are confirmed in a larger trial, the answer is yes. This study has the potential to change our fundamental understanding of the mechanisms of cell death following ischemia and how it should be treated. The Götberg pilot study comes close to satisfying the experimental conditions required to prove the existence of significant reperfusion injury in humans but does not completely fulfill all criteria. One requirement to prove reperfusion injury is that the therapy must only be delivered during reperfusion, not beforehand. Both cooled patients and controls had the same length of ischemia; however, the cooled patients had a slightly lessened “ischemic burden” because they were being cooled to 35°C during the last 30 minutes of the 174-minute period of ischemia. So it is fair to suggest that the 2 groups do not have completely identical ischemia injuries. In other words, an insult of 170 minutes of normothermia is expected to be slightly worse than 140 minutes of normothermia plus 30 minutes of ischemia at 35°C. This single criterion to prove the existence of reperfusion injury is what this pilot study lacks. Although most would argue that this very mild reduction in the severity of ischemia alone could not have resulted in the reductions observed in infarct size and troponin release, it is important to note that this study does not completely prove reperfusion injury on the basis of this alternative explanation. But there is another ischemic condition for which the existence of reperfusion injury has already been proven conclusively: cardiac arrest and the use of therapeutic hypothermia after resuscitation from cardiac arrest.10–13 Hypothermia begun after return of spontaneous circulation has been demonstrated to improve long-term outcome and is rapidly becoming the standard of care. It is now recommended by the American Heart Association for selected patients after cardiac arrest and has a solid basis in animal and human survival studies to show its effectiveness.12 Hypothermia after cardiac arrest meets all the criteria needed to prove the existence of reperfusion injury, and thus, the demonstration of a similar The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the University of Pennsylvania, Philadelphia, Pa. Correspondence to Lance B. Becker, MD, Professor, Department of Emergency Medicine, Director, Center for Resuscitation Science, University of Pennsylvania, 125 S 31st St, Ste 1200 Translational Research Laboratories, Philadelphia, PA 19104-3403. E-mail [email protected] (Circ Cardiovasc Interv. 2010;3:397-399.) © 2010 American Heart Association, Inc.