Protection of Ischemic Myocardium From Metabolic Products

Myocardial ischemia results in two major alterations in cellular metabolism that eventually may affect every cellular function. The primary and major alteration is a decrease in oxidative production of ATP and consequently a decrease in all ATP dependent processes as cellular ATP declines to very low levels. The second alteration is accumulation of metabolic products secondary to both decreased coronary flow (washout) and decreased oxidative metabolism. High levels of metabolic products result in inhibition of several enzymatic reactions. Glycolytic inhibition by high NADH results in the loss of anaerobic ATP production. Inhibition of β‐oxidation by high levels of NADH and FADH 2 results in a accumulation of long‐chain acyl CoA and acylcarnitine esters and free fatty acids. These compounds are very active detergents and may alter several membrane functions such as Na + K + ATPase, and sarcoplasmic reticular, Ca ++ ‐stimulated ATPase. Inaddition, the structure and function of mitochondria may be disrupted. Long‐chain acyl CoA is an effective inhibitor of lipolysis which may contribute to triglyceride accumulation in ischemic hearts. It is well known that K + arrest and hypothermia prevents many of the detrimental effects of ischemia. Tissue levels of high energy phosphates and the ability of the heart to recover mechanical function with reperfusion are preserved for much longer periods during hypothermic than during normothermic, hypoxic arrest. Other metabolic consequences of hypothermia and K + arrest were studied in isolated rat hearts. Hypothermia (10°C) without ischemia completely inhibited glycolysis and reduced fatty acid oxidation to about 7% of the normothermic rate. This suggests that attempts to improve energy production by ischemic tissue during hypothermia will not be successful. Hypothermia (10°C) with ischemia not only preserved ATP levels but reduced tissue levels of lactate, acyl CoA and acylcarnitine and increased tissue glycogen. These observations suggest that hypothermia decreases energy production to the same extent as energy utilization and tissue stores of high‐energy phosphates are preserved. In addition, the lack of accumulation of metabolic products decreases the potential for damage to membranes and metabolic pathways. Low levels of lactate and NADH coupled with high levels of glycogen provides a condition for rapid glycolytic rates with reperfusion and rewarming.