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 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/8
Y1 - 2022/8
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.
UR - http://www.scopus.com/inward/record.url?scp=85140807559&partnerID=8YFLogxK
U2 - 10.1038/s44161-022-00117-6
DO - 10.1038/s44161-022-00117-6
M3 - Article
C2 - 36776621
SN - 2731-0590
VL - 1
SP - 817
EP - 829
JO - Nature Cardiovascular Research
JF - Nature Cardiovascular Research
IS - 9
ER -