Reducing the impact of myocardial ischaemia/reperfusion injury.

It seems surprising that more than five decades of intense biochemical and molecular research on a leading cause of death and disability globally—ischaemic myocardial injury/myocardial infarction—and the spending of huge sums of money have achieved relatively little in the prevention of cell death secondary to ischaemia. The greatest progress has been made in methods to mechanically or chemically re-open acutely occluded coronary arteries and in increasingly better logistics of pre-hospital treatment and patient transport to hospitals providing this kind of therapy. This has resulted in a very important reduction in mortality among patients with acute myocardial infarction. The understanding of the pathological mechanism of ischaemic cell injury in the heart has also grown impressively, but much of this knowledge concerns the initiation of cell injury as a result of oxygen and energy deprivation, accumulating cellular ion imbalance, proteolytic activation, cell swelling, and similar mechanisms. The effects on ischaemic cell injury of a very effective protective regimen that is provided by the procedure of preconditioning applied prior to ischaemia are also impressive. But apart from the limited applicability of this therapeutic wisdom in cardiac surgery, nothing practical has come out of this knowledge as the much more frequent clinical situation is the one in which cardiac ischaemia is already manifest at the time the patient seeks medical help. There is encouraging preliminary evidence that ischaemic and pharmacological conditioning at the time of reperfusion may also be protective, but the impact of these approaches on clinical practice is negligible. Having made this point, we think it is fortunate that researchers have not given up early on analysing the cellular and subcellular changes in ischaemic myocardial cells. As it turned out, many different mechanisms play a role in cardiomyocyte injury when the ischaemic tissue is reperfused. This is not a trivial finding, since it has been difficult to gain the understanding that after prolonged ischaemia, reperfusion creates a pathophysiological scenario of its own. We first needed hard-to-obtain evidence that even prolonged ischaemic myocardial injury may be reversible by specific interventions at the time of reperfusion. The reversal requires first preventing the deleterious effects of late reperfusion, hereafter termed ‘reperfusion injury’. The possibility that the myocardium can be protected during the acute phase of reperfusion has long remained overlooked, mainly because the window of time for protection is short and therefore easy to miss. Myocardium acutely salvaged from irreversible damage during ischaemia and early reperfusion may end up largely functional. However, secondary effects of tissue damage, such as inflammatory responses or scar formation, may cause progressive failure of myocardial contractile function. Heart failure is, in fact, the most prominent outcome of ischaemia/reperfusion. It is well established that the risk of heart failure increases with the loss of viable tissue in ischaemia/ reperfusion. For this reason, the well-known motto ‘first things first’ also applies to the clinical strategies for treating ischaemic and reperfusion injury: namely to start as early as possible with protective measures during reperfusion. The first of the reviews in the present Spotlight Issue on Reducing the Impact of Myocardial Ischaemia/Reperfusion Injury provides insight into the role of intracellular Ca2+ in cardiomyocyte death during ischaemia/reperfusion. While it has long been known that the level of cytosolic Ca2+ rises in ischaemic cells, it has often been debated whether this is merely a sign of a healthy cell’s ability to maintain an intra-/extracellular Ca2+ gradient. Today, however, it is clear that Ca2+ signalling in the ischaemic and reperfused myocardial cell is intimately intertwined with other signalling mechanisms and contains several targets for protective interference. Important intracellular organelles orchestrating the signalling of cellular Ca2+ are the sarcoplasmic reticulum (SR) and the mitochondria. These constituents of signalling pathways are therefore important targets for reperfusion therapy. Along these lines, the original paper by Cai et al. investigates the importance of a down-regulation of junctin and triadin, regulatory proteins of the SR Ca2+ release mechanism. They show that their down-regulation contributes to the post-ischaemic contractile failure and seems to be caused by a previous Ca2+ overload-induced activation of the protease calpain. The role of mitochondria in the pathogenesis of ischaemia/reperfusion injury of the myocardium is addressed by the reviews of Miura and Tanno and Ong and Gustafsson. It is a relatively recent insight that mitochondria contribute to the development of myocardial cell failure and death not only by the inability to produce ATP under