Reperfusion injury overview
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Editors-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Shivam Singla, M.D
Overview
The introduction and wide application of reperfusion strategies in patients with STEMI has significantly reduced the mortality rate over last decade. Despite this, the rate of 30-day mortality remains high and approximately 25% of surviving patients develop heart failure. One of the mechanisms responsible for these adverse outcomes is Reperfusion injury. Reperfusion injury refers to myocardial cell death secondary to restoration of blood flow to the ischemic myocardium. The absence of oxygen and nutrients from blood creates a condition in which the restoration of circulation results in inflammation and oxidative damage through the induction of oxidative stress rather than restoration of normal function.
Ischemia-reperfusion injury forms the basis of tissue damage and cellular apoptosis in many pathologic and traumatic processes. The tissue damage follows a natural progression of cellular and metabolic events initiated by an ischemic episode. Ischemia causes intracellular/extracellular changes principally resulting in increased intracellular calcium, pH changes, and adenosine triphosphate depletion that end in cell death if the process is not interrupted. This interruption takes the form of reperfusion, characterized by a "flushing" of tissues with toxic metabolites, principally reactive oxygen species. The immediate effect is mitochondrial pore permeability, complement activation, cytochrome release, cytokine activation, inflammation, edema, neutrophil platelet adhesion, capillary plugging, and thrombosis. This sets the stage for the long recognized "no-reflow" phenomenon and progressive tissue death. Current recognition of cellular "cross-talk" and molecular events have introduced new logical strategies to sequentially combat the events occurring in relation to ischemia-reperfusion injury. These include mechanical preconditioning and pharmacological preconditioning and postconditioning strategies. It is likely that success in reversing or limiting tissue damage will be found in a sequential multitargeted approach using a combination of these strategies-clinical trials in this regard are sorely needed.
Pathophysiology
The pathophysiologic mechanisms underlying reperfusion injury include infarction, inflammation, generation of free radicals, an increase in intracellular calcium, development of edema, mitochodrial damage and activation of coagulation.
Risk Factors
Risk factors for reperfusion injury include hypertension with left ventricular hypertrophy, congestive heart failure, increased age, diabetes, and hyperlipidemia.
Natural History, Complications and Prognosis
Reperfusion injury may be responsible for about 50% of the total infarct size after an acute myocardial infarction as well as myocardial stunning, congestive heart failure and reperfusion arrhythmias such as ventricular arrhythmias.[1]
Medical Therapy
While many pharmacotherapies are successful in limiting reperfusion injury in animal studies or ex-vivo, the majority have failed to improve clinical outcomes in randomized clinical trials in patients. Strategies may have failed as a result of targeting the wrong mechanism, because an inadequate dose was studied, because patients with insufficient potential for benefit were studied, and because the drug was administered too late (after reperfusion had already occurred).