Annotation: Heart failure is a leading cause of death worldwide. Yet, the exact metabolic disruptions are not known for the different regions of the failing human heart. Here, we studied metabolic dysfunctions across 17 anatomical regions for 18 subjects with dilated cardiomyopathy and 7 individuals with ischemic cardiomyopathy, in comparison to 25 donors who died with otherwise healthy heart functions. We established a metabolic atlas that showed that 96% of the 2,200 annotated metabolites exhibit region-specific differences in the healthy human heart. Heart failure disrupted metabolic homeostasis through spatially asynchronous remodeling of 77% of these metabolites, leading to a systemic breakdown in cross-region metabolic coordination and a reinforcement of localized metabolic networks. Different regions of the failing heart showed dramatic differences in selecting substrates for energy metabolism. Subsequently, we added RNAseq transcriptomic data to supplement the metabolic results for 13 regions.
Specifically, we deciphered the spatially heterogeneous adaptation of energy metabolism in the failing heart. A systemic energetic crisis was revealed by global suppression of fatty acid oxidation and the TCA cycle, yet individual regions and tissues adopted localized compensatory strategies. Ketone body utilization was upregulated in the myocardium of the failing heart, whereas the valve and vascular regions primarily activated glycolysis and depleted BCAAs. Beyond shifts in substrate utilization, differences in metabolic reprogramming extended to precise regulation of intermediate metabolites supported by the transcript levels and enzyme activities under a high spatial control. These findings highlighted the complexity of spatial heterogeneity in diverse metabolic pathways that were previously overlooked in the pathophysiology of heart failure.
Biography: Dr. Oliver Fiehn is a world-renowned pioneer in metabolomics and a Professor at the UC Davis Genome Center, where he serves as the Director of the West Coast Metabolomics Center. Since establishing his career at the Max Planck Institute in Germany and joining UC Davis in 2004, he has authored over 220 peer-reviewed publications focusing on integrating mass spectrometry and cheminformatics to map biochemical networks. His research is instrumental in understanding cancer metabolism, diabetes, and plant physiology, and he remains one of the most highly cited researchers in his field.
Contact at IPHYS: Tomas Cajka (tomas.cajka@fgu.cas.cz)
