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 creates the base line for tissue damage and cellular apoptosis. The tissue damage follows a natural progression of cellular and metabolic events initiated by an ischemic episode. Ischemia induces various intracellular or extracellular changes leading ton increased calcium intracellularly and ATP depletion that will end up in the cell death if the ongoing process does not stopped. Reperfusion is considered as a stopper for this and leads to flushing of tissues with toxic metabolites , primarily reactive oxygen species . This leads to Increased mitochondrial pore permeability <math>\longrightarrow</math>complement activation & cytochrome release <math>\longrightarrow</math>Inflammation and edema <math>\longrightarrow</math>Neutrophil platelet adhesion and thrombosis leading to progressive tissue death.
Pathophysiology
The pathophysiologic mechanisms underlying reperfusion injury include infarction, inflammation, generation of free radicals, an increase in intracellular calcium, development of edema, mitochondrial damage and activation of coagulation.
Reperfusion injury occurs after reinstating the flow to myocardium after a period of reduced oxygen delivery. The damage of reperfusion injury is due in part to the inflammatory response of damaged tissues. White blood cells carried to the area by the newly returning blood release a host of inflammatory factors such as interleukins as well as free radicals in response to tissue damage . The restored blood flow reintroduces oxygen within cells that damages cellular proteins, DNA, and the plasma membrane. Damage to the cell's membrane may in turn cause the release of more free radicals. Such reactive species may also act indirectly in redox signaling to turn on apoptosis. Leukocytes may also build up in small capillaries, obstructing them and leading to more ischemia.
Mitochondrial dysfunction plays an important role in reperfusion injury. While the mitochondrial membrane is usually impermeable to ions and metabolites, ischemia alters permeability by elevating intro-mitochondrial calcium concentrations, reducing adenine nucleotide concentrations, and causing oxidative stress. This primes the mitochondrial permeability transition pore (MPTP), which opens when reperfusion occurs. This leads to an increased osmotic load into the mitochondrial body causing swelling and rupture, release of mitochondrial proteins which stimulate apoptosis. Mithochondrial function is disrupted and ATP is hydrolyzed, leading to the activation of degradative enzymes. Finally, excessive Poly ADP ribose polymerase-1 (PARP-1) activation impairs the function of other organelles and accelerates the production of reactive oxygen species.
In prolonged ischemia (60 minutes or more), hypoxanthine is formed as breakdown product of ATP metabolism. The enzyme xanthine dehydrogenase is converted to xanthine oxidase as a result of the higher availability of oxygen. This oxidation results in molecular oxygen being converted into highly reactive superoxide and hydroxyl radicals. Xanthine oxidase also produces uric acid, which may act as both a prooxidant and as a scavenger of reactive species such as peroxinitrite. Excessive nitric oxide produced during reperfusion reacts with superoxide to produce the potent reactive species peroxynitrite. Such radicals and reactive oxygen species attack cell membrane lipids, proteins, and glycosaminoglycans, causing further damage. They may also initiate specific biological processes by redox signaling.
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).