Ischaemia, reperfusion and cardioprotection: successes and failures in the journey from molecule to man
The Rayne Institute, St Thomas' Hospital, London, UK
1 Correspondence: Professor David J. Hearse, Director of Cardiovascular Research, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, U.K.
Abstract
In response to the increasing toll of ischaemic heart disease, the last 50 years have seen an enormous amount of research aimed at understanding the biology of ischaemia and developing methods to control it. Much of this research has used animal models; in some instances the findings have been translated successfully to man, in others they have failed to apply to human ischaemia. Some of the failures may be due to animal models inadequately mimicking the clinical situation - a problem arising from there being is no consensus on a definition of ischaemia. Despite these difficulties, laboratory research has led to a detailed molecular and cellular characterization of experimental ischaemia. From this has emerged the concept of cardioprotection: identifying key changes in the progression of ischaemic injury and developing anti-ischaemic agents to combat these changes, thereby increasing the tolerance of the heart to ischaemia. Effective cardioprotection has been established in the laboratory and has been translated very successfully to man in the arena of cardiac surgery. Unfortunately, because of fundamental conceptual flaws, the application of anti-ischaemic therapy to management of evolving myocardial infarction has, so far, failed.
Laboratory research has revealed the phenomenon of reperfusion injury and, in doing so, established the importance of free radicals and oxidant stress in the genesis of injury during ischaemia and reperfusion. From this, the concept of limiting reperfusion injury has emerged and surgeons have again exploited this concept for the benefit of patients, although cardiologists appear reluctant to combine such an approach with thrombolysis.
Recent research has also revealed the remarkable adaptive powers of the heart and its ability to increase its tolerance to ischaemia through phenomena such as preconditioning. Although preconditioning undoubtedly occurs in man, many hurdles must be overcome before this alternative approach to cardioprotection can impact the management of heart disease.
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