Derangements and Reversibility of Energy Metabolism in Failing Hearts Resulting from Volume Overload: Transcriptomics and Metabolomics Analyses

Derangements in cardiac energy metabolism have been shown to contribute to the development of heart failure (HF). This study combined transcriptomics and metabolomics analyses to characterize the changes and reversibility of cardiac energetics in a rat model of cardiac volume overload (VO) with the creation and subsequent closure of aortocaval fistula. Male Sprague-Dawley rats subjected to an aortocaval fistula surgery for 8 and 16 weeks exhibited characteristics of compensated hypertrophy (CH) and HF, respectively, in echocardiographic and hemodynamic studies. Glycolysis was downregulated and directed to the hexosamine biosynthetic pathway (HBP) and O-linked-N-acetylglucosaminylation in the CH phase and was further suppressed during progression to HF. Derangements in fatty acid oxidation were not prominent until the development of HF, as indicated by the accumulation of acylcarnitines. The gene expression and intermediates of the tricarboxylic acid cycle were not significantly altered in this model. Correction of VO largely reversed the differential expression of genes involved in glycolysis, HBP, and fatty acid oxidation in CH but not in HF. Delayed correction of VO in HF resulted in incomplete recovery of defective glycolysis and fatty acid oxidation. These findings may provide insight into the development of innovative strategies to prevent or reverse metabolic derangements in VO-induced HF.

Automated summary

This study investigates the changes and reversibility of cardiac energetics in a rat model of cardiac volume overload (VO) using transcriptomics and metabolomics analyses. The findings suggest that glycolysis is downregulated and redirected towards the hexosamine biosynthetic pathway (HBP) and O-linked-N-acetylglucosaminylation in the compensated hypertrophy (CH) phase, and further suppressed in the progression to heart failure (HF). Derangements in fatty acid oxidation become prominent only in HF. Correction of VO can reverse the differential expression of genes involved in glycolysis, HBP, and fatty acid oxidation in CH but not in HF.