柠檬酸循环
扩张型心肌病
内科学
β氧化
内分泌学
心力衰竭
代谢途径
生物
新陈代谢
中间代谢
丙酮酸脱氢酶复合物
生物化学
酶
医学
作者
Emily Flam,Cholsoon Jang,Danielle Murashige,Yifan Yang,Michael P. Morley,Sunhee Jung,Daniel S. Kantner,Hannah L. Pepper,Kenneth Bedi,Jeff Brandimarto,Benjamin L. Prosser,Thomas P. Cappola,Nathaniel W. Snyder,Joshua D. Rabinowitz,Kenneth B. Margulies,Zoltàn Arany
标识
DOI:10.1038/s44161-022-00117-6
摘要
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. Arany and colleagues integrate metabolomics data, tissue RNA-sequencing data and proteomics data from explanted hearts of patients with end-stage heart failure to provide a comprehensive 'multi-omic' evaluation of the metabolic pathways affected by heart failure.
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