In vivo investigation of cardiac metabolism in the rat using MRS of hyperpolarized [1-~(13)C] and [2-~(13)C]pyruvate

摘要

Hyperpolarized ~(13)C MRS allows the in vivo assessment of pyruvate dehydrogenase complex (PDC) flux, which converts pyruvate to acetyl-coenzyme A (acetyl-CoA). [1-~(13)C]pyruvate has been used to measure changes in cardiac PDC flux, with demonstrated increase in ~(13)C-bicarbonate production after dichloroacetate (DCA) administration. With [1-~(13)C]pyruvate, the ~(13)C label is released as ~(13)CO_2/~(13)C-bicarbonate, and, hence, does not allow us to follow the fate of acetyl-CoA. Pyruvate labeled in the C_2 position has been used to track the ~(13)C label into the TCA (tricarboxylic acid) cycle and measure [5-~(13)C]glutamate as well as study changes in [1-~(13)C]acetylcarnitine with DCA and dobutamine. This work investigates changes in the metabolic fate of acetyl-CoA in response to metabolic interventions of DCA-induced increased PDC flux in the fed and fasted state, and increased cardiac workload with dobutamine in vivo in rat heart at two different pyruvate doses. DCA led to a modest increase in the ~(13)C labeling of [5-~(13)C]glutamate, and a considerable increase in [1-~(13)C]acetylcarnitine and [1,3-~(13)C]acetoacetate peaks. Dobutamine resulted in an increased labeling of [2-~(13)C]lactate, [2-~(13)C]alanine and [5-~(13)C]glutamate. The change in glutamate with dobutamine was observed using a high pyruvate dose but not with a low dose. The relative changes in the different metabolic products provide information about the relationship between PDC-mediated oxidation of pyruvate and its subsequent incorporation into the TCA cycle compared with other metabolic pathways. Using a high dose of pyruvate may provide an improved ability to observe changes in glutamate.