Division of Cardiology (V.S.H., S.M., N.K., E.J.Y., D.A.K., K.S.), Johns Hopkins University School of Medicine, Baltimore, MD.
Cardiovascular Institute, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (C.P., M.-S.K., K.C.B., K.B.M., Z.A., D.P.K.).
Circulation. 2023 Apr 11;147(15):1147-1161. doi: 10.1161/CIRCULATIONAHA.122.061846. Epub 2023 Mar 1.
The human heart primarily metabolizes fatty acids, and this decreases as alternative fuel use rises in heart failure with reduced ejection fraction (HFrEF). Patients with severe obesity and diabetes are thought to have increased myocardial fatty acid metabolism, but whether this is found in those who also have heart failure with preserved ejection fraction (HFpEF) is unknown.
Plasma and endomyocardial biopsies were obtained from HFpEF (n=38), HFrEF (n=30), and nonfailing donor controls (n=20). Quantitative targeted metabolomics measured organic acids, amino acids, and acylcarnitines in myocardium (72 metabolites) and plasma (69 metabolites). The results were integrated with reported RNA sequencing data. Metabolomics were analyzed using agnostic clustering tools, Kruskal-Wallis test with Dunn test, and machine learning.
Agnostic clustering of myocardial but not plasma metabolites separated disease groups. Despite more obesity and diabetes in HFpEF versus HFrEF (body mass index, 39.8 kg/m versus 26.1 kg/m; diabetes, 70% versus 30%; both <0.0001), medium- and long-chain acylcarnitines (mostly metabolites of fatty acid oxidation) were markedly lower in myocardium from both heart failure groups versus control. In contrast, plasma levels were no different or higher than control. Gene expression linked to fatty acid metabolism was generally lower in HFpEF versus control. Myocardial pyruvate was higher in HFpEF whereas the tricarboxylic acid cycle intermediates succinate and fumarate were lower, as were several genes controlling glucose metabolism. Non-branched-chain and branched-chain amino acids (BCAA) were highest in HFpEF myocardium, yet downstream BCAA metabolites and genes controlling BCAA metabolism were lower. Ketone levels were higher in myocardium and plasma of patients with HFrEF but not HFpEF. HFpEF metabolomic-derived subgroups were differentiated by only a few differences in BCAA metabolites.
Despite marked obesity and diabetes, HFpEF myocardium exhibited lower fatty acid metabolites compared with HFrEF. Ketones and metabolites of the tricarboxylic acid cycle and BCAA were also lower in HFpEF, suggesting insufficient use of alternative fuels. These differences were not detectable in plasma and challenge conventional views of myocardial fuel use in HFpEF with marked diabetes and obesity and suggest substantial fuel inflexibility in this syndrome.
人体心脏主要代谢脂肪酸，而在射血分数降低的心力衰竭（HFrEF）中，随着替代燃料的使用增加，这种代谢会减少。患有严重肥胖症和糖尿病的患者被认为心肌脂肪酸代谢增加，但在射血分数保留的心力衰竭（HFpEF）患者中是否存在这种情况尚不清楚。
从 HFpEF（n=38）、HFrEF（n=30）和非衰竭供体对照（n=20）中获取血浆和心肌活检。定量靶向代谢组学测量了心肌（72 种代谢物）和血浆（69 种代谢物）中的有机酸、氨基酸和酰基辅酶 A。结果与报告的 RNA 测序数据相结合。使用无偏聚类工具、Kruskal-Wallis 检验和 Dunn 检验以及机器学习分析代谢组学。
心肌代谢物而不是血浆代谢物的无偏聚类可分离疾病组。尽管 HFpEF 中的肥胖症和糖尿病比 HFrEF 更常见（体重指数，39.8kg/m 比 26.1kg/m；糖尿病，70%比 30%；均<0.0001），但从中HFpEF 和 HFrEF 心脏的中链和长链酰基辅酶 A（主要是脂肪酸氧化的代谢物）明显低于对照组。相比之下，血浆水平与对照组没有差异或更高。与对照组相比，HFpEF 中的脂肪酸代谢相关基因表达通常较低。HFpEF 中的心肌丙酮酸较高，而三羧酸循环中间产物琥珀酸和富马酸较低，控制葡萄糖代谢的几个基因也是如此。非支链和支链氨基酸（BCAA）在 HFpEF 心肌中含量最高，但下游 BCAA 代谢物和控制 BCAA 代谢的基因水平较低。酮体水平在 HFrEF 患者的心肌和血浆中较高，但在 HFpEF 中则不然。HFpEF 代谢组学衍生的亚组仅在少数 BCAA 代谢物上存在差异。
尽管存在明显的肥胖症和糖尿病，但 HFpEF 心肌中的脂肪酸代谢物水平仍低于 HFrEF。酮体和三羧酸循环以及 BCAA 的代谢物也较低，提示替代燃料的使用不足。这些差异在血浆中无法检测到，这对具有明显糖尿病和肥胖症的 HFpEF 中心肌燃料使用的传统观点提出了挑战，并表明该综合征的燃料灵活性存在实质性不足。
