Fawaz Naeem, Teresa C. Leone, Christopher Petucci, Clarissa Shoffler, Ravindra C. Kodihalli, Tiffany Hidalgo, Cheryl Tow-Keogh, Jessica Mancuso, Iphigenia Tzameli, Donald Bennett, John D. Groarke, Rachel J. Roth Flach, Daniel J. Rader, Daniel P. Kelly
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引用次数: 0
Abstract
Aims
Two general phenotypes of heart failure (HF) are recognized: HF with reduced ejection fraction (HFrEF) and with preserved EF (HFpEF). To develop phenotype-specific approaches to treatment, distinguishing biomarkers are needed. The goal of this study was to utilize quantitative metabolomics on a large, diverse population to replicate and extend existing knowledge of the plasma metabolic signatures in human HF.
Methods
Plasma metabolomics and proteomics was conducted on 787 samples collected by the Penn Medicine BioBank from subjects with HFrEF (n = 219), HFpEF (n = 357) and matched controls (n = 211). A total of 90 metabolites were analysed, comprising 28 amino acids, 8 organic acids and 54 acylcarnitines. Seven hundred thirty-three of these samples also underwent proteomic profiling via the O-Link proteomics panel.
Results
Unsaturated forms of medium-/long-chain acylcarnitines were elevated in the HFrEF group. Amino acid derivatives, including 1- and 3-methylhistidine, homocitrulline and symmetric and asymmetric (ADMA) dimethylarginine were elevated in HF, with ADMA elevated uniquely in HFpEF. While the branched-chain amino acids (BCAAs) were minimally changed, short-chain acylcarnitine species indicative of BCAA catabolism were elevated in both HF groups. 3-hydroxybutyrate (3-HBA) and its metabolite, C4-OH carnitine, were uniquely elevated in the HFrEF group. Linear regression models demonstrated a significant correlation between plasma 3-HBA and N-terminal pro-brain natriuretic peptide in both forms of HF, stronger in HFrEF.
Conclusions
These results identify plasma signatures that are shared as well as potentially distinguish HFrEF and HFpEF. Metabolite markers for ketogenic metabolic re-programming were identified as unique signatures in the HFrEF group, possibly related to increased levels of BNP. Our results set the stage for future studies aimed at assessing selected metabolites as relevant biomarkers to guide HF phenotype-specific therapeutics.
目的：心力衰竭（HF）的两种一般表型被公认：HF伴射血分数降低（HFrEF）和保留EF （HFpEF）。为了开发表型特异性的治疗方法，需要区分生物标志物。本研究的目的是利用大量不同人群的定量代谢组学来复制和扩展人类心衰血浆代谢特征的现有知识。方法：对宾夕法尼亚大学医学生物银行（Penn Medicine BioBank）收集的787份HFrEF（219例）、HFpEF（357例）和匹配对照组（211例）的样本进行血浆代谢组学和蛋白质组学分析。共分析了90种代谢物，包括28种氨基酸，8种有机酸和54种酰基肉碱。其中733份样品还通过O-Link蛋白质组学面板进行了蛋白质组学分析。结果：HFrEF组中/长链酰基肉碱的不饱和形式升高。氨基酸衍生物，包括1-和3-甲基组氨酸、同胱氨酸和对称和不对称（ADMA）二甲基精氨酸在HF中升高，ADMA在HFpEF中升高。支链氨基酸（BCAAs）变化不大，但指示BCAA分解代谢的短链酰基肉碱种类在两个HF组中均升高。3-羟基丁酸酯（3-HBA）及其代谢物C4-OH肉碱在HFrEF组中唯一升高。线性回归模型显示，两种形式的HF中血浆3-HBA和n端前脑利钠肽之间存在显著相关性，在HFrEF中相关性更强。结论：这些结果确定了共享的血浆特征，并可能区分HFrEF和HFpEF。在HFrEF组中，生酮代谢重编程的代谢物标记物被确定为独特的特征，可能与BNP水平升高有关。我们的研究结果为未来的研究奠定了基础，这些研究旨在评估选定的代谢物作为相关的生物标志物，以指导HF表型特异性治疗。
期刊介绍：
ESC Heart Failure is the open access journal of the Heart Failure Association of the European Society of Cardiology dedicated to the advancement of knowledge in the field of heart failure. The journal aims to improve the understanding, prevention, investigation and treatment of heart failure. Molecular and cellular biology, pathology, physiology, electrophysiology, pharmacology, as well as the clinical, social and population sciences all form part of the discipline that is heart failure. Accordingly, submission of manuscripts on basic, translational, clinical and population sciences is invited. Original contributions on nursing, care of the elderly, primary care, health economics and other specialist fields related to heart failure are also welcome, as are case reports that highlight interesting aspects of heart failure care and treatment.
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