Utilization of free fatty acids as an energy source requires a higher oxygen cost compared with carbohydrate. In normal subjects without a limited oxygen supply, this probably is not important. However in patients with fixed limited oxygen supply, this added increase in oxygen costs of free fatty acids may be very important and result in the development of ischemia at lower threshold. Many investigators have measured only the arterial-coronary sinus chemical difference in free fatty acids when assessing the contribution of this important substrate to myocardial oxidative metabolism. Using labeled substrates, investigators have found that not all the exogenous free fatty acids extracted by the myocardium undergo oxidation immediately. The first key issue in this proposal is the role of circulating free fatty acids in the regulation of myocardial oxidation of this important substrate in humans. The effects of circulating free fatty acids and myocardial oxidation of free fatty acids on """"""""nonoxidative glycolytic metabolism"""""""" will also be investigated. Using [1-14C] lactate as a tracer, we have found that lactate is released in patients with coronary disease despite net global myocardial lactate extraction. At rest the amount of lactate released appears to be related to the severity of the coronary disease. We believe that this lactate release is due to nonoxidative glycolytic metabolism. Our hypothesis is that an increase in free fatty acid oxidation will lead to an increase in nonoxidative glycolytic metabolism and lactate release in patients with significant coronary artery disease. [1-14C] palmitic acid or [1-14C]oleic acid bound to albumin will be used as a tracer in these studies. The myocardial oxidation of exogenous free fatty acids will be determined by measuring the myocardial production of 14CO2 (coronary sinus-arterial). The amount of myocardial lactate released will be quantitated by using the stable isotope [1,2,3-13C3] lactate. Male patients with significant coronary disease will be studied. Two groups of subjects (young normal subjects and age-matched controls without coronary disease) will serve as controls. The circulating levels of free fatty acids will be altered by various physiologic and pharmacologic methods. Submaximal and maximal stress will be induced by atrial pacing. Thus the fundamental regulatory role of circulating free fatty acids on myocardial substrate utilization and how this relates to the ischemic threshold in coronary disease patients will be investigated.
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