Fatty acid metabolism via ?-oxidation represents the major source of energy of the cardiac myocyte. The efficiency of production of energy from fatty acid oxidation allows the heart to perform its major contractile functions. Conversely, fatty acid oxidation is rapidly inhibited in states of myocardial ischemia and is impaired in states of chronic myocardial dysfunction. To determine the rates of beta-oxidation in vivo, investigators have studied two different approaches. One approach has been the use of radiolabelled fatty acids which undergo ?-oxidation. Measurements are performed to assess the production of ?-oxidation products, either by measuring venous blood samples for reaction product activity in experimental preparations or clinically by measuring the rate of disappearance of activity from the myocardium. Although the measurement of blood samples has proved to be a reliable assessment of ?-oxidation rates, the in vivo imaging of decline in cardiac activity has been less reliable due to the linkage of intact tracer back into the circulation and the retention of the tracer in intermediary pools. A second approach has been the use of fatty acid analogs, which block ?-oxidation. These tracers are essentially trapped since they are unable to proceed further in the oxidative pathway. Although the rate of uptake of the trapped tracers was proposed as an index of ?-oxidation rate, further work has demonstrated that uptake of these tracers is independent of oxidation rates. Recently, a new sulphur substituted fatty acid analog (FTHA) has been developed with a 18F-fluorine label which will allow quantitative imaging with positron emission tomography.
The specific aims of this research are to determine the extraction, degree of back-diffusion, and cellular deposition of FTHA and another trapped fatty acid analog and the first pass kinetics of FTHA in a controlled-perfusion large animal preparation and to utilize tomographic imaging to determine in vivo the changes in FTHA uptake with substrate alteration, hyperemia, ischemia and reperfusion. Classical method of determination of fatty acid beta-oxidation rates will be used in the protocols. The research will establish the applicability of FTHA tracer kinetics to assessment of fatty acid metabolism, an area of applicable to experimental studies and the clinical management of patients with ischemic heart disease or cardiomyopathy.
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