Abstract 3818: Analysis of Metabolic Remodeling in the Transition From Cardiac Hypertrophy to Failure
Background: Congestive heart failure (CHF) is associated with a change in cardiac energy metabolism. However, the mechanism by which the alteration is induced and causes progression of CHF is not clear.
Methods and Results: We analyzed cardiac energy metabolism of Dahl salt-sensitive (DS) rats fed a high salt diet, which show a distinct transition from compensated LV hypertrophy (LVH) to CHF. DS rats fed a low salt diet were used as controls. On in situ 31P MR spectroscopy analysis, the PCr/ATP ratio was decreased by 12% at the LVH stage and 42% at the CHF stage. The uptake of 18FDG, a glucose analogue, increased by 1.4-fold at the LVH stage and 2.4-fold at the CHF stage. The uptake of 125I-9MPA, a fatty acid analogue, was not changed at the LVH stage but decreased by 36% at the CHF stage. The shift of substrate uptake from fatty acids to glucose was associated with decreased FAT mRNA and increased GLUT1 mRNA. The gene expression related to glycolysis, fatty acid oxidation, and mitochondrial function was preserved at the LVH stage and decreased at the CHF stage, associated with decreases in proteins of transcriptional regulators (HIF1α, PPARα, PGC1α). On a comprehensive metabolome analysis, a distinct change in metabolites related to glycolysis and the TCA cycle was observed during the transition. Particularly, the pentose phosphate pathway that regulates the cellular redox state was found to be activated at the CHF stage. Dichloroacetate (DCA), a compound known to enhance glucose oxidation, increased the energy reserve and 18FDG uptake. DCA improved cardiac function and survival of animals, and decreased plasma BNP and myocardial fibrosis. DCA augmented activation of the pentose phosphate pathway in CHF rats and decreased oxidative stress. DCA also decreased generation of oxidative stress and prevented the induction of cell death by hydrogen peroxide in cultured cardiomyocytes.
Conclusions: The transition from LVH to CHF is associated with a distinct change in the metabolic profile of heart. DCA attenuated the transition associated with increased energy reserves, as well as activation of the pentose phosphate pathway and reduced oxidative stress.