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Normal cardiac function is predicated on a continuous supply of oxygen and nutritive substances. When coronary perfusion is interrupted, profound myocardial damage can occur at both microscopic and macroscopic levels. Clinically, this scenario gives rise to acute coronary syndromes manifesting as angina, or in the most severe form, acute myocardial infarction. The onset of ischemia triggers homeostatic processes geared at limiting damage but that may act in concert with processes associated with reperfusion to actually exacerbate injury. These potentially deleterious effects of reperfusion have been described as reperfusion injury, or more aptly, ischemia-reperfusion injury, because the pathology associated with reperfusion occurs only in the setting of antecedent ischemia. Ischemia-reperfusion injury is a complex process that is brought about by the interaction of a number of cells, including endothelium and inflammatory cells, with components of the coagulation and complement cascades. This interplay promotes the formation of harmful substances, which may further amplify myocardial cell death after an ischemic insult.

Myocardial ischemia occurs when there is a demand-supply mismatch between the myocardium's energy requirement and the oxygen and other substrate supply delivered via myocardial perfusion.1 With compromise of coronary arterial flow, a number of electrical, mechanical, and chemical changes take place in the ischemic area of myocardium. The myocardium becomes cyanotic with consumption of freely diffusible oxygen and oxymyoglobin oxygen stores causing decreased tissue oxygen tension.2 With increasing tissue hypoxia, intracellular respiration shifts from its aerobic to its anaerobic form. Adenosine triphosphate (ATP) stores are rapidly depleted,3 causing adenosine diphosphate (ADP), adenosine monophosphate (AMP), and adenosine to accumulate in the tissue. At this point, the ischemic region of myocardium loses its ability to maintain its normal negative resting membrane potential.4 Diminished ATP stores and/or alteration in availability of calcium5 lead to cessation of cardiac contraction.4 This is followed by a distension of the ischemic myocardium, which perhaps occurs as the result of stretch due to tugging by adjacent nonischemic (and still contracting) muscle.6 Characteristic metabolic changes occur in the ischemic tissue, including an accumulation of tissue lactate,3,7 H+ ions,8 phosphate,7 and potassium.9,10 There is also an increase in tissue tension of carbon dioxide (Pco2),11 as an accumulating by-product of cellular metabolism in the absence of an egress mechanism during the stasis that characterizes ischemia. In addition, mitochondrial calcium increases,12 a process that may further contribute to ischemic contracture and perhaps even the ultimate death of the vulnerable myocyte. In an autoregulatory attempt to increase blood flow, arterioles exhibit a profound vasodilator response,11 which under nonobstructive conditions might result in a restoration of nutritive flow; however, under severe ischemic conditions, it is often futile. If complete obstruction to blood flow persists for as little as 20 minutes, myocardial necrosis may be observed.13 Under circumstances in which myocardial reperfusion is re-established with great rapidity, however, mechanical function can return to near baseline levels.14


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