Integrated landscape of cardiac metabolism in end-stage human nonischemic dilated cardiomyopathy.
Integrated landscape of cardiac metabolism in end-stage human nonischemic dilated cardiomyopathy.
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DOI：
10.1038/s44161-022-00117-6
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发表时间：
2022-09
期刊：
影响因子：
--
通讯作者：
Arany, Zolt
中科院分区：
文献类型：
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作者：
Flam, Emily;Jang, Cholsoon;Murashige, Danielle;Yang, Yifan;Morley, Michael P;Jung, Sunhee;Kantner, Daniel S;Pepper, Hannah;Bedi, Kenneth C Jr;Brandimarto, Jeff;Prosser, Benjamin L;Cappola, Thomas;Snyder, Nathaniel W;Rabinowitz, Joshua D;Margulies, Kenneth B;Arany, Zolt
心力衰竭（HF）是死亡的主要原因。衰竭的心脏会经历深刻的代谢变化，但缺乏对人类的全面评估。我们整合了 678 种代谢物的血浆和心脏组织代谢组学、全基因组 RNA 测序和蛋白质组学研究，以检查来自 39 名终末期心力衰竭患者的 87 颗移植心脏的代谢状态，并与 48 名正常供体进行比较。我们证实了人类 HF 的生物能缺陷，并揭示了维持 ATP 水平所需的腺苷酸嘌呤的选择性消耗。我们观察到，尽管血浆升高，但衰竭组织中的脂肪酸和酰基肉碱大幅减少，这表明脂肪酸向心肌细胞的输入存在缺陷。相反，血糖水平升高。控制碳水化合物氧化的丙酮酸脱氢酶被解除抑制，从而增加乳酸和丙酮酸的燃烧。三羧酸循环中间体显着减少。最后，生物活性脂质被深度重新编程，神经酰胺显着减少，溶血甘油磷脂显着升高。这些数据揭示了人类衰竭心脏中严重的代谢异常。
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.