Hyperpolarized ketone body metabolism in the rat heart

Abstract

The aim of this work was to investigate the use of 13C-labelled acetoacetate and β-hydroxybutyrate as novel hyperpolarized substrates in the study of cardiac metabolism. [1-13C]Acetoacetate was synthesized by catalysed hydrolysis, and both it and [1-13C]β-hydroxybutyrate were hyperpolarized by dissolution dynamic nuclear polarization (DNP). Their metabolism was studied in isolated, perfused rat hearts. Hyperpolarized [1-13C]acetoacetate metabolism was also studied in the in vivo rat heart in the fed and fasted states. Hyperpolarization of [1-13C]acetoacetate and [1-13C]β-hydroxybutyrate provided liquid state polarizations of 8 ± 2% and 3 ± 1%, respectively. The hyperpolarized T1 values for the two substrates were 28 ± 3 s (acetoacetate) and 20 ± 1 s (β-hydroxybutyrate). Multiple downstream metabolites were observed within the perfused heart, including acetylcarnitine, citrate and glutamate. In the in vivo heart, an increase in acetylcarnitine production from acetoacetate was observed in the fed state, as well as a potential reduction in glutamate. In this work, methods for the generation of hyperpolarized [1-13C]acetoacetate and [1-13C]β-hydroxybutyrate were investigated, and their metabolism was assessed in both isolated, perfused rat hearts and in the in vivo rat heart. These preliminary investigations show that DNP can be used as an effective in vivo probe of ketone body metabolism in the heart.