Lethal Myocardial Reperfusion Injury

Abstract

Early coronary artery reperfusion reduces infarct size and mortality and improves left ventricular contractile performance after myocardial ischemia compared to permanent occlusion. However, reperfusion itself causes either an acceleration of injury that is not present during ischemia or causes de novo reversible and lethal injury to heart tissue. In vitro and in vivo experimental data strongly suggest that reperfusion injury is initiated during the first few moments of reperfusion and proceeds over minutes to hours in a cascade involving numerous interactive mechanisms leading to damage or death of myocardium and coronary vascular endothelium. This reperfusion injury contributes to contractile dysfunction, metabolic derangements, and ultimately cell death by necrosis, apoptosis, and autophagy. The mechanisms underlying lethal reperfusion injury include: (1) generation of ROS (oxygen paradox) from mitochondria, cytosolic and extracellular compartments, coronary vascular endothelium, and inflammatory cells such as neutrophils in a robust burst followed by sustained increased levels; (2) intracellular calcium accumulation (calcium paradox); (3) rapid normalization of tissue pH (pH paradox); (4) activation of proteolytic enzymes; (5) opening of the mitochondrial permeability transition pore; and (6) an inflammatory-like response. Although inflammatory cells and other cell types involved in inflammation (e.g., endothelium) contribute ROS and proinflammatory mediators during reperfusion, the role of inflammation in lethal reperfusion injury remains incompletely understood. ROS and calcium accumulation and rapid normalization of tissue pH which occur during the early moments of reperfusion create an environment in which the mitochondrial permeability transition pore opens, thereby promoting mitochondrial swelling and the release of proapoptotic substances which directs the cell to pursue a necrotic or an apoptotic pathway to death. Microvascular obliteration, a major physiological consequence of ischemia-reperfusion injury, may lead to no-reflow zones of myocardium and may also be involved in expansion of infarction as the duration of reperfusion increases and no-reflow zones expand. Age and gender may affect the heart’s tolerance to ischemia such that lethal injury is more severe or occurs after shorter periods of ischemia; some mechanisms of reperfusion injury may be more exaggerated in older animal models but is known to occur in humans. Comorbidities such as hypertension, hypercholesterolemia, and diabetes may also exaggerate the response to ischemia-reperfusion by mechanisms that are relevant to reperfusion such as increased oxidant stress at reflow, preexisting endothelial cell dysfunction that limits the bioavailability of nitric oxide (\(N{O}^{•}\)), or downregulation of the endogenous cardioprotective signaling pathways. Endogenous mechanisms exist that may combat reperfusion injury, such as the antioxidants glutathione and glutathione peroxidase, the autacoid adenosine, NO, and certain kinases (reperfusion injury salvage kinases, RISK). However, these are either not sufficiently stimulated or are rapidly overwhelmed. They can be enhanced by mechanical maneuvers such as postconditioning (a series of brief ischemia and reperfusion applied at the onset of reperfusion) or by pharmacological agents administered at the onset of reperfusion. Fully understanding the time course of reperfusion injury will help define and bracket the timing of effective reperfusion interventions. More fully understanding the mechanisms of reperfusion injury will help identify potential candidate therapies. Although previous clinical trials of drugs administered after percutaneous coronary interventions have revealed largely negative or inconclusive results, contemporary large-scale clinical trials should be undertaken with the immediacy and narrow window of reperfusion injury in mind, with the knowledge of effective concentrations of drugs at the target organ with consideration given to direct delivery to the target, and with appropriate duration of treatment to address immediate and delayed reperfusion injury.