This revised application investigates the relationship between 1H-NMR detected changes in myocardial triglyceride (TG) metabolism, reflecting altered fatty acid metabolism, and the severity of an ischemic insult. Its hypothesis is that during reperfusion, myocardial TG content, monitored by 1H-NMR spectroscopy, increases in reversibly injured myocardium but decreases in irreversibly insulted tissue. In response to previous reviews, this proposal now focusses entirely on determining the mechanisms of this TG accumulation as well as its functional consequences. Studies will be performed only in open- or closed-chest canine models of 30 or 90 minutes of ischemia followed by reperfusion. Proposed experiments test three aims. First, they determine whether 1H- NMR spectroscopy can monitor changes in fatty acid metabolism in non- ischemic hearts. These studies use four pharmacological inhibitors of beta-oxidation to determine how compromised beta-oxidation and dependence on glucose oxidation, affects myocardial TG metabolism, bioenergetics and mechanical performance at physiological and catecholamine-challenged workloads. They assess acutely and chronically-compromised beta-oxidation, one of the major effects of ischemia, without the confounding effects of ischemia itself. Second, the patterns of myocardial TG metabolism, bioenergetics, substrate extraction, flow and mechanical function will be measured in hearts subjected to 30 or 90-minutes of ischemia alone or following 2, 4, or 7 days of reperfusion. Coupled with biochemical analyses, these studies will determine the relationship between 1H-NMR observed TG metabolism, 31P-NMR observed bioenergetics and functional recovery after an ischemic insult. Finally, these opened-chest studies will be extended into close-chested models of ischemia/reperfusion. Using 1H- and 31P-NMR spectroscopic imaging (SI), they will establish the potential of NMR SI to assess the severity of the myocardial ischemic insult. The basic information obtained from this proposal will determine (i) the mechanisms for altered substrate metabolism during reperfusion and (ii) the applicability of 1H-NMR-based observation of myocardial TG metabolism as a means to assess the ischemic insult.
| Shen, H; Balschi, J A; Pohost, G M et al. (2001) 1H-MRS detected lipolysis in diabetic rat hearts requires neutral lipase. J Cardiovasc Magn Reson 3:35-45 |
| Wolkowicz, P E; Urthaler, F; Forrest, C et al. (1999) 2-Tetradecylglycidic acid, an inhibitor of carnitine palmitoyltransferase-1, induces myocardial hypertrophy via the AT1 receptor. J Mol Cell Cardiol 31:1405-12 |
| Balschi, J A; Hai, J O; Wolkowicz, P E et al. (1997) 1H NMR measurement of triacylglycerol accumulation in the post-ischemic canine heart after transient increase of plasma lipids. J Mol Cell Cardiol 29:471-80 |
