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Cardiovascular Research 2004 61(3):363-364; doi:10.1016/j.cardiores.2003.12.020
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

Myocardial reperfusion injury: a new view

David García-Dorado*,1

Laboratorio de Cardiología Experimental, Servicio de Cardiología, Hospitals Vall d'Hebron, Pg. Vall d'Hebron 119-129, Barcelona 08035, Spain

* Tel.: +34-93-4894038; fax: +34-93-4894032. mrmeana{at}vhebron.net

Received 18 December 2003; accepted 18 December 2003

Acute coronary occlusion resulting in myocardial infarction is the main mechanism by which coronary artery disease reduces survival and leads to deterioration of the quality of life, and the extent of cell death is the main determinant of survival in patients with acute myocardial infarction. Early animal studies demonstrated that once the myocardium becomes severely ischemic, restoration of blood flow is a prerequisite for myocardial salvage. They also showed, however, that restoration of blood flow after transient ischemia may be associated with dramatic, deleterious changes such as arrhythmias, enzyme release, or severe intramyocardial hemorrhage. These changes were generally interpreted as manifestations of additional injury occurring at the time of reperfusion, and were termed "reperfusion injury". Oxygen free radicals were clearly shown to be generated upon restoration of blood flow and to be potentially harmful, and their role as main mediators of reperfusion injury was soon widely accepted.

However, the concerns about the potential clinical significance of reperfusion injury were soon put aside by the results of clinical studies. The experience obtained in millions of patients with evolving acute myocardial infarction has demonstrated that reperfusion therapy may be more or less beneficial depending on the circumstances (in particular, on how early it is applied), but that it is always preferable to permanent coronary occlusion. On the other hand, studies aimed at demonstrating the beneficial effects of treatments against injury mediated by reactive oxygen species (ROS) in animals yielded controversial and irreconcilable results, and a few clinical studies were also negative.

In view of this evidence, the therapeutic goals were set to provide recanalization of the occluded artery as early, as completely, and as permanently as possible to the largest number of patients with acute myocardial infarction. Reperfusion injury was considered by many to be either non-existent (reperfusion-associated phenomena as accelerated expression of pre-existent injury) or clinically irrelevant (in relation to the importance of ischemic injury). It must be mentioned here that, in contrast to the skeptical view of cardiologists on the importance of reperfusion injury in patients with acute myocardial infarction, many cardiovascular surgeons were convinced of the existence of potentially relevant adverse effects associated with restoration of normal myocardial perfusion following cardioplegic arrest, and measures aimed at minimizing them, in general by strategies not focused on the prevention of ROS-mediated injury, were soon, and still are, widely used.


   1. A new view
Top
 1. A new view
2. Therapeutic relevance
 References
 
In recent years, different lines of research have shed new light on the mechanisms of cell injury and death during myocardial ischemia/reperfusion. The derangements caused by ischemia in the ionic composition in the cytosol and intracellular compartments, in the phosphorylation status of multiple proteins, and in the activity of critical enzymes and signal transduction pathways are being increasingly understood. The ability of ischemia/reperfusion to trigger apoptosis, and its contribution to total cell death has been extensively investigated. A new vision of lethal reperfusion injury as a solidly documented and potentially relevant phenomenon is now widely shared. According to this view, the largest fraction of cardiomyocyte death associated with reperfusion (a) occurs during the initial minutes of re-flow, (b) involves rupture of the cell membrane, (c) is due to mechanisms originating in the cardiomyocytes rather than vascular or blood-born cells, and (d) can be prevented by interventions applied at the time of reperfusion.

The present Spotlight Issue of Cardiovascular Research attempts to reflect this landscape in a series of reviews and original articles. Among the events leading to cell death during the first few minutes of reperfusion, contracture occupies a prominent position [1], and other mechanisms are also increasingly recognized as important. Mitochondrial alterations, whose role in the genesis of acute lethal reperfusion injury was considered, after some initial enthusiasm, to be of secondary importance, are now seen as prominent factors, mainly through opening of the permeability transition pore [2]. Intercellular communication between adjacent cardiomyocytes is now being identified as a determinant of cell death or survival during reperfusion [3].

In contrast with the initial view of ischemia as being characterized by a deficit of energy, the decisive role of active cellular response to the ischemic insult is now recognized. The signal transduction systems involved in this response and modulating its consequences are now better understood. One of these consequences may be the activation of the programmed cell death pathway [5]. In this issue, the changes in the NO/cGMP pathway [4], the activation of different protein kinase cascades [6], and the changes in gene expression induced by ischemia/reperfusion [7] are reviewed. The potential therapeutic value of activation of protective kinase pathways is also analyzed [8].

A current view of the role of the "old" mechanisms of reperfusion injury is also provided in this issue. This includes a review of the mechanisms of generation, elimination, and toxicity of ROS during myocardial reperfusion [9] with a detailed analysis of the contribution of poly(ADP-ribose) activation [10], and an appraisal of the role of myocardial accumulation of neutrophils [11] and platelets [12]. Finally, all the previous cellular and molecular mechanisms are potentially influenced by the pathophysiological and biochemical environment, and their modulation by common concomitant clinical pathologies is analyzed [13].


   2. Therapeutic relevance
Top
 1. A new view
 2. Therapeutic relevance
References
 
In patients with ongoing transmural acute myocardial infarction (i.e. with ST segment elevation in the ECG), the tools to achieve the initial therapeutic objective of early, wide, and permanent recanalization have reached a high degree of efficiency and safety, and further improvements are expected to result in only minor additional benefit. In this context, reduction of reperfusion injury based on treatments targeting the previously discussed mechanisms appears as a logical next step in the effort to minimize the impact of acute coronary syndromes on survival and the quality of life. It must be stressed that myocardial reperfusion injury may occur after a large series of very different situations in addition to severe normothermic ischemia secondary to acute coronary occlusion, including hypothermic ischemic arrest during extracorporeal circulation, deep hypothermic ischemic arrest during donor graft preservation, or different combinations of ischemia and hypoxia occurring during resuscitation maneuvers in cardiac arrest. Therapeutic strategies able to attenuate reperfusion injury in all these situations are very much needed.


   Acknowledgements
 
Partially supported by grant CICYT-SAF 2002-00759.


   Notes
 
1 On behalf of the Guest Editors. Back


   References
Top
 1. A new view
 2. Therapeutic relevance
 References
 

  1. Piper H.M., Abdallah Y., Schäfer C. The first minutes of reperfusion: a window of opportunity for cardioprotection. Cardiovasc. Res. (2004) 61:365–371.[Abstract/Free Full Text]
  2. Halestrap A.P., Clarke S.J., Javadov S.A. Mitochondrial permeability transition pore opening during myocardial reperfusion—a target for cardioprotection. Cardiovasc. Res. (2004) 61:372–385.[Abstract/Free Full Text]
  3. Garcia-Dorado D., Rodriguez-Sinovas A., Ruiz-Meana M. Gap junction-mediated spread of cell injury and death during myocardial ischemia-reperfusion. Cardiovasc. Res. (2004) 61:386–401.[Abstract/Free Full Text]
  4. Schulz R., Kelm M., Heusch G. Nitric Oxide In Ischemia/Reperfusion Injury. Cardiovasc. Res. (2004) 61:402–413.[Abstract/Free Full Text]
  5. Eefting F., Rensing B., Wigman J., et al. Role of apoptosis in reperfusion injury. Cardiovasc. Res. (2004) 61:414–426.[Abstract/Free Full Text]
  6. Armstrong S.C. Protein kinase activation and myocardial ischemia/reperfusion injury. Cardiovasc. Res. (2004) 61:427–436.[Abstract/Free Full Text]
  7. Chi N.C., Karliner J.S. Molecular Determinants of Responses of Myocardial Ischemia/Reperfusion Injury: Focus on Hypoxia-Inducible and Heat Shock Factors. Cardiovasc. Res. (2004) 61:437–447.[Abstract/Free Full Text]
  8. Hausenloy D.J., Yellon D.M. New directions for protecting the heart against reperfusion injury: Targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway. Cardiovasc. Res. (2004) 61:448–460.[Abstract/Free Full Text]
  9. Becker L. New Concepts in Reactive Oxygen Species and Cardiovascular Reperfusion Physiology. Cardiovasc. Res. (2004) 61:461–470.[Abstract/Free Full Text]
  10. Szabó G., Liaudet L., Hagl S., Szabó C. Poly(ADP-ribose) polymerase activation in the reperfused myocardium. Cardiovasc. Res. (2004) 61:471–480.[Abstract/Free Full Text]
  11. Vinten-Johanssen J. Involvement of Neutrophils in the Pathogenesis of Lethal Myocardial Reperfusion Injury. Cardiovasc. Res. (2004) 61:481–497.[Abstract/Free Full Text]
  12. Gawaz M. Role of Platelets in Coronary Thrombosis and Reperfusion of Ischemic Myocardium. Cardiovasc. Res. (2004) 61:498–511.[Abstract/Free Full Text]
  13. Galinanes M., Fowler A.G. Role of Clinical Pathologies in Myocardial Injury Following Ischaemia and Reperfusion. Cardiovasc. Res. (2004) 61:512–521.[Abstract/Free Full Text]

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