Review
Myocardial ischemia/reperfusion-injury, a clinical view on a complex pathophysiological process

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Abstract

Myocardial infarction is the major cause of death in the world. Over the last two decades, coronary reperfusion therapy has become established for the management of acute myocardial infarction (AMI). However, restoration of blood flow to previously ischemic myocardium results in the so-called ischemia/reperfusion (IR)-injury. The different clinical manifestations of this injury include myocardial necrosis, arrhythmia, myocardial stunning and endothelial- and microvascular dysfunction including the no-reflow phenomenon. The pathogenesis of ischemia/reperfusion injury consists of many mechanisms. Recently, there's increasing evidence for an important role in IR-injury on hypercontracture induced by high levels of cytosolic calcium or by low concentrations of ATP.

In the last years, many studies on experimental models were investigated, but the clinical trials confirming these effects remain spare. Recently, the beneficial effect of Na+/H+-exchange inhibitor cariporide and of the oxygen-derived free radical (ODFR) scavenger vitamin E on coronary bypass surgery-induced IR-injury were demonstrated. Also recently, the beneficial effect of allopurinol on the recovery of left ventricular function after rescue balloon-dilatation was demonstrated. The beneficial effect of magnesium and trimetazidine on IR-injury remains controversial. The beneficial effect of adenosine remains to be further confirmed. There's also increasing interest in agentia combining the property of upregulating NO-synthase (e.g. l-arginine) and restoring the balance between NO and free radicals (e.g. tetrahydrobiopterin). One of such agents could be folic acid.

In this review article the authors give an overview of the recent insights concerning pathogenesis and therapeutic possibilities to prevent IR-induced injury.

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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