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Cardiovascular Research 2006 69(1):1-3; doi:10.1016/j.cardiores.2005.11.011
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Copyright © 2005, European Society of Cardiology

Postconditioning: Reperfusion of "reperfusion injury" after hibernation

David Garcia-Doradoa,* and Hans Michael Piperb

aLaboratorio de Cardiología Experimental, Hospital Universitari Vall d'Hebron, Barcelona, Spain
bInstitute of Physiology, Justus Liebig University, Giessen, Germany

* Corresponding authors. David Garcia-Dorado is to be contacted at Laboratorio de Investigación Cardiovascular Hospital Universitari Vall d'Hebron, Barcelona, Spain. Hans Michael Piper, Institute of Physiology, Justus Liebig University, Aulweg 129 35392 Giessen, Germany. Tel.: +49 641 99 47242; fax: +49 641 99 47209. Email address: dgdorado{at}hg.vhebron.es michael.piper{at}physiologie.med.uni-giessen.de

The newly developed concept of postconditioning as a way of reducing reperfusion injury has been receiving much attention in the literature, both in basic science and clinical circles. Cardiovascular Research will be hosting a Spotlight Issue entitled "Cardiac Protection by Pre- and Postconditioning" in May of this year. This editorial is thought to serve as an introduction to the upcoming issue.

One of the major advances of all times in cardiovascular therapy has been the development and generalization of reperfusion treatment in patients with acute coronary occlusion and evolving myocardial infarction. The experimental basis for that therapy was provided in the early 1980s by the group of Jennings and Reimer at Duke University with the demonstration that early reperfusion can salvage ischemic myocardium that otherwise would die, and that the effectiveness of reperfusion depends on the severity and duration of prior ischemia [1]. Despite its overall beneficial effect, experimental myocardial reperfusion was associated with prominent arrhythmias, enzyme release, and other adverse phenomena that were grouped under the imprecise term "reperfusion injury". Reperfusion injury attracted the attention of many basic scientists, but the success of large clinical trials demonstrating the beneficial effect of reperfusion in patients pushed research on reperfusion injury into the background [2]. A second origin of the concept of reperfusion injury came from the work of Hearse et al. in London who showed in the mid-1970s that reperfusion of an isolated ischemic heart could provoke myocardial contracture and massive myocytolysis [3]. Since they attributed this phenomenon to tissue reoxygenation and the potentially detrimental role of oxygen, they termed this phenomenon the "oxygen paradox" [3,4]. In hindsight, this term was quite misleading as it focussed most attention on a potential role of oxygen radicals, which ultimately turned out not to be the major players. Nevertheless, different groups identified concrete mechanisms of reperfusion-induced cardiac cell death and proved that infarct size can be limited by interventions applied at the time of reperfusion [5,6]. These results demonstrated clearly that active processes taking place at the time of reperfusion are responsible for a significant fraction of cell death occurring after transient ischemia. In spite of these reports, general interest in reperfusion injury receded for a while since none of these interventions were developed further for clinical applicability [7].

The scientific paradigm underlying much of the scepticism on lethal reperfusion injury was that the main mechanism leading to cell death during ischemia–reperfusion was energy deficiency [8]. According to this concept, injury emerging at the time of reperfusion is only the consequence of a prior surpassing of a point of no return in cellular metabolism. This paradigm was neatly proven inadequate by the discovery of the phenomenon of ischemic preconditioning, in which "pre-treatment" with brief bouts of ischemia–reperfusion without a consistent effect on energy depletion during subsequent prolonged, transient ischemia consistently resulted in a dramatic reduction of infarct size [9]. The studies on ischemic preconditioning have clearly demonstrated that cell death cannot be seen as a mere consequence of energy deficiency. Moreover, an increasing amount of information shows that preconditioning does not alter the progression of ischemic injury, but modifies the consequences of reperfusion, switching cell fate from death to survival [10,11]. Thus, it appears that "preconditioning" of cardiomyocytes before ischemia exerts an important part of its impressive protective effect by inducing tolerance to reperfusion injury. How it does this is a complex and largely unanswered question, but it is clear that it involves different and partially redundant signal transduction systems [12,13].

A discovery made recently has re-awakened reperfusion injury from its state of hibernation and excited the scientific community, since it has opened the long-sought route to clinical applicability: the discovery of postconditioning. Brief, intermittent coronary occlusions at the time of reperfusion resulted in a limitation of infarct size similar in magnitude to that afforded by ischemic preconditioning [14]. The phenomenon of postconditioning is related to the previously described beneficial effect of "staged reperfusion" (in contrast to abrupt, full opening of the occluded coronary artery), but bears also a procedural similarity to preconditioning protocols. This similarity should not distract from the fact that the procedures are in fact quite different. Not only that one is applied before and the other after ischemia (schematically depicted in Fig. 1), but also that the timing of preconditioning is much less critical than that of postconditioning, which must be applied during the first minute of reperfusion to be effective. As an intervention applied at the time of reperfusion, postconditioning is aimed at limiting reperfusion injury. Its efficacy of protecting the heart at the time of reperfusion represents yet another demonstration of the existence of lethal reperfusion injury. In that sense, Heusch was right when he claimed it was "old wine in a new bottle" [15].


Figure 1
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  		Fig. 1 Myocardial injury in ischemia–reperfusion develops in two phases. Reperfusion injury adds to the injury developed during initial ischemia (resulting in the red curve). The extent of reperfusion injury can be influenced by protective procedures, such as postconditioning or protective agents, applied during the first minutes of reperfusion (resulting in the blue curve). When the myocardium is not reperfused, it becomes entirely subject to ischemic cell death (broken black curve). While the past dogma was that protection against ischemia–reperfusion injury achieved by the pre-ischemic application of preconditioning is solely achieved by an effect on ischemic injury, it is now thought that this protection is also largely due to an effect on the causes of reperfusion injury (blue arrows).

 
Nevertheless, the discovery of postconditioning has changed the world. While most of the pharmacological approaches to reperfusion injury have used drugs that cannot be easily tested in patients, postconditioning has the realistic potential to be applied to the large and continuously increasing number of patients with evolving myocardial infarction (acute coronary syndrome with ST segment elevation) receiving primary percutaneous transluminal coronary angioplasty (PTCA). In fact, a first groundbreaking study in patients randomised to receive or not to receive postconditioning after primary PTCA has detected a significant reduction in infarct size in patients receiving brief, intermittent balloon occlusions during the first minutes of re-canalisation [16]. This study is a demonstration that lethal reperfusion injury is a clinically relevant entity and supports the hypothesis that its prevention in patients receiving reperfusion therapy during acute myocardial infarction should result in infarct size limitation, preservation of left ventricular function, and a better prognosis. This is good news at times when desperation about further progress in acute infarct therapy has paved the road for attempts at later tissue replacement by cell therapy.

How should research proceed now? Two lines of action appear to be clearly necessary. Obviously, clinical investigation should define the technical aspects of intermittent balloon inflation during primary PTCA, assess its safety, efficacy, and cost-effectiveness, and establish the guidelines for its optimal application. But at the same time, the cellular mechanisms by which postconditioning exerts its protective effect against lethal reperfusion injury should be defined. Although some reports have suggested the involvement of survival kinases similar to those proposed to participate in preconditioning [17], the issue is far from being resolved. Elucidation of the mechanisms of postconditioning could lead to the definition of new pharmacological strategies that could afford more protection or provide protection to more patients, possibly beyond those receiving primary PTCA. For example, the role of delayed recovery of intracellular acidosis should be defined. Previous studies have shown that postconditioning slows down this recovery, and plenty of information demonstrates that prolonged acidosis can protect cardiomyocytes (and other cell types) during myocardial reperfusion by inhibiting excessive contractile activation ("hypercontracture") [18], attenuating calpain activation (which causes cell fragility [19] and detachment of the Na+ pump from the sarcolemma [20]), and inhibiting mitochondrial permeability transition [21]. If prolonged acidosis is confirmed as an important mechanism of postconditioning, acidic reperfusion (achieved by selective intracoronary acidic infusion) could be complementary or alternative to repetitive balloon inflation [16]. Now more than ever, mechanistic research in the field of reperfusion injury appears to be necessary and clinically relevant. In any case, the discovery of postconditioning has rescued the concept of reperfusion injury from its state of hibernation.


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J. Inserte, I. Barba, V. Hernando, and D. Garcia-Dorado
Delayed recovery of intracellular acidosis during reperfusion prevents calpain activation and determines protection in postconditioned myocardium
Cardiovasc Res, January 1, 2009; 81(1): 116 - 122.
[Abstract] [Full Text] [PDF]

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