The objective of this proposal are to review the metabolic characterization of myocardial substrate utilization derived from time-activity curves using the methods of positron emission tomography (PET) but with 14C labeled agents. Recent concern has been raised about the validity of PET markers to describe changes in fatty acid metabolism as a function of altered perfusion states. We have demonstrated early transients of 14CO2 production within intracellular lipid and fatty acids pools. Over this same time internal when nonsteady state loading kinetics are occurring, 11C palmitate time-activity curves must be developed. Errors of interpretation might ensure. Moreover, in an intact, working, extracorporeally perfused pig heart model, we showed trends in substrate metabolism during reflow opposite to those predicted by PET.
The aims of this proposal are to explore the reasons for these discrepancies and to focus on possible differences between pulse labeling (as used with PET) vs equilibrium labeling (as used by us). Three species of substrates will be employed at control, ischemia, and reflow states in the pig heart model. Hypotheses will be tested regarding the kinetic validity of short lived isotopes by reduplicating traditional PET experiments using (U-14C) palmitate, (16-14C) glucose, 14C-2-deoxy-D-glucose (DG), and (1- 14C) acetate. Protocols will be structured to address whether in the case of fatty acid and citric acid cycle metabolism time- activity curves generated by pulse labeling (assuming decay is from a single pool) accurately predict the level of substrate oxidation measured by equilibrium labeling. In related studies, mathematical modeling will be employed to determine whether 14C time-activity curves can be described by single or multiple pool kinetics and whether these carbon pool sizes are significantly altered by shifts in regional perfusion from aerobic, ischemic or reperfused states. In the case of carbohydrate metabolism we will address whether DG trapping in heart muscle accurately reflects Embden. Meyerhof metabolism to its end-points of glucose oxidation and/or lactate production whether 14C-glucose by pulse labeling is best described by single vs multiple carbon pools and whether these can be sell correlated with biochemical events at different flow states. Our ultimate purpose in this proposal is to review any limitations in interpreting PET-derived metabolic information and in so doing hopefully provide new clinical confidence in translating these scintigraphic data into meaningful subcellular events.
