Shifts in myocardial substrate utilization play a key role in normal cardiac development and physiology, as well as in variety of cardiac pathologic states. Positron emission tomography (PET) is the most widely used method to quantify myocardial substrate but has several limitations. No information is provided about the subsequent metabolic fate of the extracted substrate. The contribution of myocardial glycogen and triglyceride, to overall energy metabolism is not accounted for. Measurements are limited to the utilization of extracted glucose and fatty acids, and thus, do not take into account the contributions to energy metabolism of other extracted substrates such as lactate. The goal of this research application is to develop and validate PET approaches that will permit the assessment of the metabolic fate of extracted glucose and fatty acid, the contribution to myocardial energy metabolism of myocardial glycogen and triglycerides, and the quantification of myocardial lactate utilization.
The Specific Aims are: 1. To develop and validate a compartmental modeling approach that will permit the delineation of extracted 1-11C-glucose that enters a slow turnover pool and likely reflects glycogen storage from tracer that rapidly egresses from myocardium and likely reflects the combined effects of glucose oxidation and lactate production; 2. To develop and validate a compartmental modeling approach that will permit the delineation of extracted 1-11C-palmitate that enters a slow turnover pool and thus likely reflects triglyceride formation from tracer that rapidly egresses from the myocardium and likely reflects beta-oxidation; 3. By taking advantage of the improved sensitivity of 3-D PET imaging, protocols will be developed and validated to assess the myocardial turnover of glycogen and triglyceride using 1-11C-glucose and 1-11C-palmitate, respectively and; 4. To develop and validate a compartmental modeling approach that will permit the measurement of myocardial lactate utilization by PET and L-3-11C lactate. The various PET techniques will be developed and validated against a variety of biochemical markers in a well-controlled canine model studied under a wide range of substrate, hormonal and workload conditions.
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