Integrated landscape of cardiac metabolism in end-stage human nonischemic dilated cardiomyopathy.

Autor: Flam E; Perelman School of Medicine, Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA., Jang C; Department of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.; Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA., Murashige D; Perelman School of Medicine, Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA., Yang Y; Perelman School of Medicine, Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA., Morley MP; Perelman School of Medicine, Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA., Jung S; Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA., Kantner DS; Center for Metabolic Disease Research, Department of Cardiovascular Science, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA., Pepper H; Center for Metabolic Disease Research, Department of Cardiovascular Science, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA., Bedi KC Jr; Perelman School of Medicine, Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA., Brandimarto J; Perelman School of Medicine, Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA., Prosser BL; Perelman School of Medicine, Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA.; Department of Physiology, Pennsylvania Muscle Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Cappola T; Perelman School of Medicine, Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA., Snyder NW; Center for Metabolic Disease Research, Department of Cardiovascular Science, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA., Rabinowitz JD; Department of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA., Margulies KB; Perelman School of Medicine, Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA., Arany Z; Perelman School of Medicine, Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA.
Jazyk: angličtina
Zdroj: Nature cardiovascular research [Nat Cardiovasc Res] 2022 Sep; Vol. 1 (9), pp. 817-829. Date of Electronic Publication: 2022 Aug 29.
DOI: 10.1038/s44161-022-00117-6
Abstrakt: Heart failure (HF) is a leading cause of mortality. Failing hearts undergo profound metabolic changes, but a comprehensive evaluation in humans is lacking. We integrate plasma and cardiac tissue metabolomics of 678 metabolites, genome-wide RNA-sequencing, and proteomic studies to examine metabolic status in 87 explanted human hearts from 39 patients with end-stage HF compared with 48 nonfailing donors. We confirm bioenergetic defects in human HF and reveal selective depletion of adenylate purines required for maintaining ATP levels. We observe substantial reductions in fatty acids and acylcarnitines in failing tissue, despite plasma elevations, suggesting defective import of fatty acids into cardiomyocytes. Glucose levels, in contrast, are elevated. Pyruvate dehydrogenase, which gates carbohydrate oxidation, is de-repressed, allowing increased lactate and pyruvate burning. Tricarboxylic acid cycle intermediates are significantly reduced. Finally, bioactive lipids are profoundly reprogrammed, with marked reductions in ceramides and elevations in lysoglycerophospholipids. These data unveil profound metabolic abnormalities in human failing hearts.
Competing Interests: Competing interests The authors declare no competing interests.
Databáze: MEDLINE
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