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- W4387244446 abstract "Heart failure with preserved ejection fraction (HFpEF) represents more than 50% of all heart failure world wide and remains a major unmet medical need. The most effective and now approved treatments based on clinical trials have intriguingly been those first developed for diabetes, suggesting that metabolic defects are paramount. Metabolomic analysis of human HFpEF was recently reported, and identified defects in fatty acid and branched chain amino acid catabolism. The status of glycolysis remained unknown. Here we performed targeted glycolysis metabolomics with protein analysis of critical pathway enzymes in myocardial biopsies obtained from patients with HFpEF, and two comparison groups; HF with reduced ejection fraction (e.g. dilated cardiomyopathy), and donor non-failing controls. While glucose was most elevated in HFpEF myocardium, the proximal downstream metabolites: glucose-6 phosphate and fructose 1,6 diphosphate, were much lower in this HFpEF versus the other two groups. Hexokinase and phosphofructokinase isoform protein expression was also more reduced in HFpEF myocardium, supporting blockade in the pathway, and not increased flux. By the late stages of glycolysis, we found pyruvate also most reduced in HFpEF. Proximal suppression of glycolysis was coupled to reduced metabolites and proteins involved with the pentose phosphate shunt, so bypass pathways were also compromised. The marked suppression of proximal glycolysis in HFpEF was independent of diabetes status or level of obesity (indexed by body mass index). These results further evidence that HFpEF myocardium has profound metabolic inflexibility and insufficiency, and identifies very proximal blockade in glucose metabolism as part of the problem. Efforts to improve metabolic capacity in HFpEF will need to consider these findings by targeting the proximal glycolytic enzymes." @default.
- W4387244446 created "2023-10-03" @default.
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- W4387244446 date "2023-10-02" @default.
- W4387244446 modified "2023-10-15" @default.
- W4387244446 title "Depressed Proximal Glycolysis in Myocardium of Human Heart Failure with Preserved Ejection Fraction" @default.
- W4387244446 doi "https://doi.org/10.1101/2023.09.30.23296261" @default.
- W4387244446 hasPublicationYear "2023" @default.
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