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

Emily Flam, Cholsoon Jang, Danielle Murashige, Yifan Yang, Michael P. Morley, Sunhee Jung, Daniel S. Kantner, Hannah Pepper, Kenneth C. Bedi, Jeff Brandimarto, Benjamin L. Prosser, Thomas Cappola, Nathaniel W. Snyder, Joshua D. Rabinowitz, Kenneth B. Margulies, Zolt Arany

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)817-829
Number of pages13
JournalNature Cardiovascular Research
Volume1
Issue number9
DOIs
StatePublished - Sep 2022

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Cell Biology
  • Medicine (miscellaneous)

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