Lethal reperfusion injury in acute myocardial infarction: facts and unresolved issues

Abstract

### 1.1 Definitions ‘Reperfusion injury’ has been for some time an imprecise and controversial term referring to a variety of alterations occurring at the time of restoration of blood flow, from functional impairment to cell death. The term ‘lethal reperfusion injury’ specifically refers to cell death associated with transient ischaemia that can be prevented by interventions applied at the time of reperfusion.1 Therefore, it is the component of cell death occurring as a consequence of reperfusion. There are aspects of lethal reperfusion injury upon which there is general agreement based on solid information. ### 1.2 Existence and relevance The existence of lethal myocardial reperfusion injury has been demonstrated by an overwhelming body of evidence obtained mainly in laboratory experiments, but also, and increasingly, in humans.2 Different interventions have consistently been shown to limit myocardial necrosis when applied at the time of reperfusion in a variety of models and preparations, and it is unquestionable that, at least under certain conditions, lethal myocardial reperfusion injury occurs. It is also clear from those studies that lethal reperfusion injury can be responsible for a significant proportion (one-third or more) of cell death caused by transient global or regional myocardial ischaemia. ### 1.3 Initial minutes after reperfusion Many studies have shown a reduction of the protection afforded by several pharmacological interventions and postconditioning protocols when they are first applied only a few minutes later than reperfusion onset.3 Prolonging intracellular acidosis for only 3 min at the onset of reperfusion has a dramatic protective effect.4,5 These observations demonstrate that at least part of lethal reperfusion injury takes place very early after restoration of flow, and they are consistent with the fact that most changes associated with cell death, such as calcium oscillations, calpain activation, hypercontracture, oxidative stress, or mitochondrial permeability transition,6 occur during the very first minutes of reflow. ### 1.4 Necrosis The rapid time course …