Review article
Reperfusion injury: a review of the pathophysiology, clinical manifestations and therapeutic options

https://doi.org/10.1016/S0167-5273(96)02854-9Get rights and content

Abstract

Lack of blood supply or ischaemia underlies many of the most important cardiovascular and cerebrovascular diseases faced by clinicians in their daily practice. Many of these ischaemic episodes can be reversed at an early stage by surgical or pharmacological means with the ultimate aim of preventing infarction and cell necrosis in the ischaemic tissues. However, reperfusion of ischaemic areas, in particular the readmission of oxygen, may contribute to further tissue damage (reperfusion injury). For example, the use of thrombolytic therapy in acute myocardial infarction and other revascularisation procedures, such as percutaneous transluminal angioplasty and coronary artery bypass surgery, may be associated with reperfusion of ischaemic myocardium. Such ischaemia and reperfusion may result in injury to one of more of the biochemical, cellular and microvascular components of the heart. Our understanding of the significance of reperfusion injury is however restricted by the profuse literature in animal models and limited literature in the clinical situation. This article reviews the pathophysiology, clinical manifestations of reperfusion injury to the heart and discusses the possible therapeutic approaches to avoiding any adverse effects.

Introduction

Lack of blood supply or ischaemia underlies many of the most important diseases faced by physicians and surgeons in their daily practice, including myocardial infarction, thrombotic stroke, embolic vascular occlusions, angina pectoris, peripheral vascular insufficiency, cardiac surgery and organ transplantation. Advances in modern medicine have now made it possible to reverse many of these ischaemic episodes at an early stage by surgical or pharmacological means with the ultimate aim of preventing infarction and cell necrosis in the ischaemic tissues. However, evidence from animal studies suggests that reperfusion of ischaemic areas, in particular the readmission of oxygen, may contribute to further tissue damage (reperfusion injury) [1]. Although ischaemia-reperfusion injury is now an accepted phenomenon in the research laboratory, its relevance to the clinical practice remains less certain. This is due mainly to difficulties in differentiating between pre-existing damage resulting from a period of ischaemia and any subsequent damage that can be attributed to the reperfusion process.

Section snippets

Reperfusion and tissue damage

Does reperfusion actually exacerbate tissue damage beyond that destined to happen following the ischaemic insult or does it merely lead to different biochemical and pathological end points? In other words, is potentially salvageable tissue destroyed by reperfusion per se or does reperfusion merely accelerate the destiny of cells that are already doomed?

These concepts are illustrated in Fig. 1. During a period of ischaemia a large fraction of cells will undergo biochemical and pathological

Changes associated with ischaemia

A severe and sustained reduction in blood flow to the myocardium reduces oxidative phosphorylation leading to failure to resynthesize energy-rich phosphates including ATP and creatine phosphate (Table 1). Eventually, the purine precursors necessary for resynthesis of ATP are degraded to hypoxanthine and xanthine, both substrates for the enzyme xanthine dehydrogenas/oxidase (see below). At the same time the enzyme changes conformation from its dehydrogenase (D) form to become an oxidase (O form)

Vascular and microvascular injury

In the majority of experimental models of reperfusion injury release of vascular occlusion does not lead to full restoration of blood flow to the ischaemic territory. Instead, flow often declines following the initial reactive hyperaemia. Possible causes for the `no reflow' phenomenon are endothelial cell swelling, impaired nitric oxide release and capillary occlusion with platelets/neutrophils 3, 4. A variety of associated processes are also implicated including complement activation,

Biochemical features of reperfusion injury

Many surrogate markers of reperfusion injury have been proposed. These include various biochemical markers (such as changes in glutathione), lipid perioxides and antioxidants.

The free radical hypothesis

Studies in animals and man support the conclusion that myocardial reperfusion generates free radicals. In vitro, free radical generating systems can damage cardiac cells 55, 56and mimic the pathological features of ischaemia-reperfusion injury 57, 58, 59. In addition to many indirect studies, direct identification of free radicals has been possible in reperfused heart using the technique of ESR spectroscopy and spin trapping 18, 57, 60, 61, 62, 63, 64. Free radical generation is significantly

Clinical manifestations of reperfusion injury

Although a variety of factors constitute the phenomenon of cardiac reperfusion injury 2, 108, 109, these can be simply classified into those which directly influence the clinical state of the patient — that is, contractile dysfunction and arrhythmias — and those that are recognised only as experimental phenomena (Table 3). There are three main components of reperfusion injury: myocardial stunning, reperfusion injury and early excess mortality from myocyte injury.

Preventing reperfusion injury (Table 4)

Although little doubt exists that reperfusion of ischaemic myocardium is associated with a variety of specific sequelae including stunning, arrhythmias and lipid peroxidation, this alone does not prove that reperfusion is harmful since there is ultimately no alternative way of salvaging myocardium.

Animal studies in this important area can sometimes be criticised for the following reasons: (i) using interventions that may not merely influence reperfusion but may also reduce ischaemia, possibly

Reperfusion injury: a critical appraisal

By definition reperfusion implies prior ischaemia, the nature of which will influence the reperfusion. Ischaemia and reperfusion may result in injury to one of more of the biochemical, cellular and microvascular components of the heart. Reperfusion injury is not merely the abnormal features that we see in salvaged tissue, it must also be a reflection of damage that is created by suboptimal utilization of the techniques to avoid damage, whether by drugs, vitamins or staged reflow. Our

Conclusion

Although the evidence implicating oxidative stress is strong, it is difficult to decide how great it is and whether antioxidant therapy is important in view of the occasional conflicting results from experimental studies. In man, ischaemia-reperfusion injury is particularly relevant in two situations: (i) patients whom are only seen after the onset of ischaemia, that is post-myocardial infarction; and (ii) patients for whom ischaemia-reperfusion is an elective procedure, such as in cases of

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