Metabolic phenotyping of the diseased XXXX heart using 13C-substrates and ex vivo perfusion in the working mode.

@entity1 @entity101 @entity3363 @entity39 @entity1792 @entity63 @entity26 @entity7352 @entity3628 @entity880 @entity35 @entity1718 @entity413 @entity2388
The objective of the present study was to compare energy substrate fluxes through metabolic pathways leading to mitochondrial @entity1792 synthesis and release in normal and diseased @entity35 hearts using 13C-substrates and mass isotopomer analysis by gas chromatography-mass spectrometry (GCMS). This study was prompted by our previous finding of a modulated @entity1792 release by perfused @entity35 hearts and by the possibility that a dysregulated myocardial @entity1792 release represents a specific chronic alteration of energy metabolism in cardiac @entity1 . The 15-week-old spontaneously @entity101 @entity35 (SHR) was chosen as our @entity3628 and the @entity35 -Kyoto (WKY) @entity35 as its matched control. Ex vivo work-performing hearts were perfused with a semi-recirculating buffer containing physiological concentrations of unlabeled ( @entity413 ) and @entity7352 -labeled ([U-13C3]( @entity880 + @entity2388 ) and/or [1-(13)C]oleate) substrates. In parallel to the continuous monitoring of indices of the heart's functional and physiological status, the following metabolic parameters were documented: (i) @entity1792 release rates and @entity1792 cycle intermediate tissue levels, (ii) the contribution of @entity1718 as well as @entity2388 decarboxylation and carboxylation to @entity1792 synthesis, and (iii) @entity880 and @entity2388 uptake and efflux rates. Working hearts from both @entity35 species showed a similar percent contribution of @entity3363 for @entity1792 synthesis through decarboxylation (70%) and carboxylation (10%). SHR hearts showed the following metabolic alterations: a higher @entity1792 release rate, which was associated with a parallel increase in its tissue level, a lower contribution of oleate beta-oxidation to @entity1792 synthesis, and an accelerated efflux rate of unlabeled @entity880 from glycolysis. These metabolic changes were not explained by differences in myocardial @entity26 consumption, cardiac performance or efficiency, nor correlated with indices of tissue @entity39 or @entity63 . This study demonstrates how the alliance between ex vivo semi-recirculating working perfused @entity35 hearts with 13C-substrates and mass isotopomer analysis by GCMS, can provide an unprecedented insight into the metabolic phenotype of normal and diseased @entity35 hearts. The clinical relevance of metabolic alterations herein documented in the SHR heart is suggested by its resemblance to those reported in cardiac @entity1 . Taken altogether, our results raise the possibility that the increased @entity1792 release of diseased hearts results from an imbalance between @entity1792 synthesis and utilization rates, which becomes more apparent underconditions of substrate abundance.
