Abstract 850: Metabolic Landscape of Human Heart Failure

Abstract

Heart failure is characterized by insufficient pumping to match the needs of the body. Heart failure is thought to be associated with dysfunctional mitochondria and metabolic alterations, but there is little to no direct evidence in humans. The heart metabolizes a variety of substrates for energy production, including fatty acids, glucose, ketones, and branch chain amino acids (BCAAs). In the healthy heart, fatty acids are the main fuel source, and oxidation is balanced with energy need. In heart failure, it is asserted that fatty acid oxidation is suppressed, and glucose utilization is increased, but this has not been directly measured in humans. If true, this metabolic switch toward glucose may contribute to mechanical insufficiency by disrupting the balance between metabolism and energetic need, thus representing a potential area for therapeutic intervention in heart failure. Prior studies were largely performed in animal models, and results are often inconsistent across models and species. Challenges have constrained the use of human myocardium, including costly and cumbersome techniques for in vivo assessment; limited availability of high-quality human myocardial tissue; and low yields and short durability of isolated human cardiomyocytes. We addressed these challenges by taking advantage of human explanted hearts available via the Penn Heart Transplant program to investigate the metabolic differences between failing and healthy human hearts. We performed metabolomics analysis using mass spectrometry on myocardium from 18 failing and 20 nonfailing human hearts. Of the 334 metabolites measured, 99 were significantly different between groups by Wilcoxon test and FDR correction. Metabolite set enrichment analysis revealed that the most enriched pathways included the glycerol phosphate shuttle, ammonia recycling, methylhistidine metabolism, and glutathione metabolism. The mitochondrial electron transport chain, BCAA catabolism, purine metabolism, the urea cycle, gluconeogenesis, glycolysis, ketone body metabolism, and the pentose phosphate pathway were also included in the top 50 most enriched pathways. These data will guide future targeted metabolic studies in human heart failure.