ReviewMyocardial ischemia/reperfusion-injury, a clinical view on a complex pathophysiological process
Introduction
Early reperfusion is an absolute prerequisite for the survival of ischemic myocardium. However, reperfusion has been referred by Braunwald and Kloner [1] as the “double edged sword” because reperfusion itself may lead to accelerated and additional myocardial injury beyond that generated by ischemia alone. This results in a spectrum of reperfusion-associated pathologies, collectively called “reperfusion injury” [2].
The first concerns about myocardial reperfusion were expressed by Jennings et al. [3] in 1960 when they suggested that reperfusion may accelerate the development of necrosis in irreversible injured myocytes. They observed an ultrastructural appearance of “explosive swelling”, which included architectural disruption, contraction bands, and intramitochondrial calcium phosphate granules.
In 1977, Bulkley and Hutchins [4] reported the paradox of myocardial necrosis after successful revascularization by coronary artery bypass graft surgery and suggested that the lesions were surgery related and represented contracture due to calcium loading and myocardial cellular edema in the distribution of widely patent grafts. They further concluded that “prevention of intraoperative myocardial injury must also focus on characteristics of the phase of myocardial reperfusion”.
The recognition, that thrombotic occlusion of a coronary artery results in a wave front of irreversible myocardial cell injury extending from the subendocardium to the subepicardium in a time-dependent fashion, led to the introduction of reperfusion therapy for acute myocardial infarction [5], [6]. Modalities for reperfusion include thrombolysis, percutaneous coronary intervention (PCI) and coronary bypass grafting. Reperfusion injury has been observed in each of these situations. In this review, an overview is given of the clinical consequences of ischemia/reperfusion (IR), its mechanisms and the therapeutic modalities to prevent IR-injury, with a special attend to the spare recent clinical trials to prevent IR-injury.
Section snippets
Clinical consequences
In the clinical setting, reperfusion injury after revascularisation of the ischemia-related artery is manifested by myocardial stunning, reperfusion arrhythmia, myocyte death, and endothelial- and microvascular dysfunction including the no-reflow phenomenon.
Mechanisms
The underlying pathophysiological mechanisms of IR have not been fully elucidated. It has been suggested that an overproduction of oxygen-derived free radicals [43] and intracellular calcium overload or redistribution [44] during the first minutes of reflow might be involved. However, oxygen-derived free radicals and hypercontracture due to calcium-overload are not the only candidates responsible for reperfusion injury. Other factors of importance in the pathogenesis of reperfusion injury
Treatment of IR-injury
There are two possibilities to influence the injury caused by ischemia: Induction of preconditioning and a pharmacological approach. Precondition can be induced by ischemia itself, the so-called “pre-infarction angina”, and by drugs. These drugs are adenosine, opioids (e.g. morphine used as an analgeticum in the ischemic period) and bradykinin B2-receptor agonists. This latter is not available at this moment for human use, but ACE-inhibitors and glibenclamide are good indirect alternatives.
The
Discussion
Acute coronary occlusion is the leading cause of morbidity and mortality in the Western World, and according to the World Health Organisation, it will be the major cause of death in the world by the year 2020 [126]. Reperfusion through thrombolysis, percutaneous coronary angioplasty or bypass surgery is the standard treatment in impending acute myocardial infarction, meaning that reperfusion injury will be a major clinical problem in the near future. Therefore, further clinical research is
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