Factors involved in salvaging ischemic myocardium

Myocardial ischemia initially causes reversible cellular injury in the sense that reperfusion prevents myocyte death. With longer periods of ischemia, cellular injury becomes irreversible; necrosis occurs even if arterial flow is restored. The transition from reversible to irreversible injury does not occur simultaneously in all cells, but occurs first in the subendocardial region (starting within 20 minutes) and progressively involves more cells in a transmural wave front of cell death until the infarct reaches its maximum size 3-6 hours after occlusion. Vascular injury also becomes more widespread with increasing duration of ischemia, but more slowly than myocyte damage.

In experimental coronary occlusion in the dog, and probably in man as well, the duration of cellular viability and the final transmural extent of an infarct depend chiefly on the amount of collateral arterial blood flow. Both collateral flow and the duration of myocyte survival are lowest in the subendocardial and highest in the subepicardial region of the myocardium.

Reperfusion of ischemic myocardium has several effects: (1) It accelerates the disintegration of irreversibly injured cells. Such cells swell explosively and exhibit a disrupted sarcolemma, loss of cell volume regulation, contraction band necrosis and calcium loading of mitochondria. These changes are associated with an accelerated washout of creatine kinase in the initial phase of reperfusion. (2) If the vasculature has been compromised, reperfusion may not occur. Potential causes of this no-reflow phenomenon include endothelial damage, endothelial or myocyte swelling, development of contracture-rigor, and perhaps plugging of capillaries by granulocytes. Also, vascular damage may result in hemorrhage into parts of the irreversibly injured tissue. Available evidence suggests that hemorrhage is a secondary event that does not contribute to myocyte necrosis. (3) If reperfusion is instituted at a time when viable ischemic myocytes are present in the tissue, it limits infarct size. In experimental ischemic injury, most of the ischemic myocardium that can be salvaged is in the subepicardial region of relatively mild ischemia. In effect, the severely ischemic myocardium dies quickly; the moderately ischemic subepicardium dies more slowly and can be salvaged by later reperfusion. Thus, successful reperfusion converts a potentially transmural infarct into a subendocardial infarct. In both the open-chest and awake dog models, the period within which reperfusion can limit infarct size is about 3 hours. In some animals, small amounts of salvageable myocardium may persist beyond 3 hours, but limitation of infarct size has not been demonstrated experimentally beyond 5-6 hours. (4) Reperfusion of reversibly injured myocytes is followed by recovery of contractile function and of the high-energy phosphate and adenine nucleotide pool. However, this recovery process may require several days.