Effects of Regional Ischemia on Metabolism of Glucose and Fatty Acids

The rate of coronary flow reaching the oxygen-lin-ited heart appears to be crucial in determining the myocardial tissue metabolic response. The tissue metabolic response to anoxia, well studied in hearts perfused with anoxic media, differs in many important ways from the response to ischemia. In regional ischemia (developing infarction) there is still a residual oxygen uptake which is reduced approximately to the same extent as the delivery of O₂; there is also decreased delivery of substrates and decreased removal of CO₂ H⁺, and lactate, with increased concentrations of these metabolites. Contents of hexose monophosphates rise rather than fall in anoxia. Measurements of glycolytic intermediates show an initial burst of accelerated glycolytic flux lasting less than 1 minute after coronary artery ligation; thereafter rates of flux decrease to control values or even less at 120 minutes. Relative inhibition of phospho-fructokinase (PFK) activity may be explained by a slow rate of fall of ATP and a developing intracellular acidosis. In this model, glucose accounts for a greater part of the residual oxidative metabolism than does free fatty acid (FFA). Even in the central infarct zone, where in this model the collateral blood flow is less than 10% of the control, the pattern of metabolism is predominantly oxidative and over 90% of ATP is oxidatively produced; however, less than 20% of the basal ATP requirement is met. In the peripheral infarct zone, with flow at about 20% of control, about one-third of basal ATP requirements are met. In the peri-infarct zone blood flow is about three-fourths of control, and contents of ATP, creatine phosphate (CP), and glycogen are decreased approximately to the same extent. The mechanism of reduction of contractile activity in the ischemic zone remains unclear. A progressive deficit of ATP develops in spite of reduced contraction. Increased provision of exogenous glucose (as glucose-insulin-potassium) spares glycogen in infarct and peri-infarct zones but does not cause anaerobic ATP to be a major source of energy as in models perfused with anoxic media. The nature of the border zone depends on the pattern of blood flow reduction and the methods used to define the border. Possible mechanisms provoking or accelerating ischemic cell damage in the presence of reduced but continued rates of oxidative metabolism may include energy phosphate compound changes; "wastage" of ATP; reduced washout and accumulation of protons, lactate, andCO₂; and retention of sodium and edema fluid.