Myocardial reperfusion injury: etiology, mechanisms, and therapies.
Reperfusion of ischemic myocardium is required for tissue survival; however, reperfusion elicits pathologic consequences. Myocardial reperfusion injury is a multifarious process that is mediated in part by oxygen free radicals, neutrophil-endothelium interactions, apoptosis, and intracellular calcium overload. The oxygen paradox describes the contradictory need to delivery oxygen to ischemic tissue and the resultant reduction of oxygen to form free radicals that are involved in macromolecule oxidation, membrane disfunction, apoptosis, and damaged calcium sequestering ability, which results in hypercontracture. These cell-damaging crises are amplified by the excessive activation of neutrophils, which promote the formation of proinflammatory mediators, oxygen radicals, and the reduction of endothelial nitric oxide formation, leading to increased neutrophil-endothelium interactions and capillary occlusion. Neutrophil action is twofold, however, because it is required for necrotic debris removal after severe ischemia. The oxygen radicals produced by neutrophils, endothelium, and myocytes may also play a role in activating the apoptotic cascade. Although the role of apoptosis in reperfusion injury is controversial, apoptotic cells are found in infarcted tissue. One of the key mediators may be increased inner mitochondrial membrane permeability, resulting in reduced ATP formation, release of cytochrome c, and caspase activation, which is key to promotion of apoptosis. Increased mitochondrial membrane permeability occurs during exposure to supraphysiological calcium concentrations. This occurs because of compensatory Na+/Ca2+ exchange to remove the excess intracellular sodium resulting from decreased Na+/K+ pumping during ischemia and increased Na+/H+ exchange following reperfusion. Supraphysiological calcium elicits hypercontracture and cellular damage. The various therapies being developed to diminish myocardial reperfusion injury involve inhibition of the processes described above as well as others. Although single therapies have shown some promise, the complexity of the response to reperfusion has made dramatic improvement elusive. Effective treatment will most likely require multifaceted antagonism of the numerous pathological cascades initiated by reperfusion.
Hoffman
John W
JW
Towson University, Towson, Maryland, USA. jhoffman@kcumb.edu
Gilbert
Timothy B
TB
Poston
Robert S
RS
Silldorff
Erik P
EP
D000975:Antioxidants / Q000378:metabolism / Q000493:pharmacokinetics; D017209:Apoptosis; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008955:Models, Cardiovascular; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D018375:Neutrophil Activation; D009504:Neutrophils / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D012307:Risk Factors
D000975:Antioxidants; D017382:Reactive Oxygen Species