TY - JOUR
T1 - Integrated landscape of cardiac metabolism in end-stage human nonischemic dilated cardiomyopathy
AU - Flam, Emily
AU - Jang, Cholsoon
AU - Murashige, Danielle
AU - Yang, Yifan
AU - Morley, Michael P.
AU - Jung, Sunhee
AU - Kantner, Daniel S.
AU - Pepper, Hannah
AU - Bedi, Kenneth C.
AU - Brandimarto, Jeff
AU - Prosser, Benjamin L.
AU - Cappola, Thomas
AU - Snyder, Nathaniel W.
AU - Rabinowitz, Joshua D.
AU - Margulies, Kenneth B.
AU - Arany, Zolt
N1 - Funding Information:
We thank the Gift-of-Life Donor Program, Philadelphia, PA, who helped provide nonfailing heart tissue from unused donor hearts for this research. This work was supported by funding from National Heart, Lung, and Blood Institute (NHLBI; grant nos. R01-HL152446 to Z.A., T32 HL 7954-20 to E.F.), the Gund Family Fund to K.B.M., Department of Defense (grant no. W81XWH18-1-0503 to Z.A.), Edward Mallinckrodt Jr. Foundation to C.J., NHLBI (grant no. F30 HL142186-01A1) and the Blavatnik Family Foundation to D.M., grant no. R01GM132261 to N.W.S. and National Institutes of Health Diabetes Research Center (grant no. P30 DK019525). Human heart tissue was procured via support from the following grants: nos. R01 AG17022, R01 HL089847 and R01 HL105993 to K.B.M.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/9
Y1 - 2022/9
N2 - 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.
AB - 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.
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U2 - 10.1038/s44161-022-00117-6
DO - 10.1038/s44161-022-00117-6
M3 - Article
AN - SCOPUS:85140807559
SN - 2731-0590
VL - 1
SP - 817
EP - 829
JO - Nature Cardiovascular Research
JF - Nature Cardiovascular Research
IS - 9
ER -