Targeted Quantitative Plasma Metabolomics Identifies Metabolite Signatures that Distinguish Heart Failure with Reduced and Preserved Ejection Fraction

BackgroundTwo general phenotypes of heart failure (HF) are recognized: HF with reduced ejection fraction (HFrEF) and with preserved EF (HFpEF). To develop HF disease phenotype-specific approaches to define and guide 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. MethodsQuantitative, targeted LC/MS plasma metabolomics was conducted on 787 samples collected by the Penn Medicine BioBank from subjects with HFrEF (n=219), HFpEF (n=357), and matched non-failing Controls (n=211). A total of 90 metabolites were analyzed, comprising 28 amino acids, 8 organic acids, and 54 acylcarnitines. 733 of these samples were also processed via an OLINK protein panel for proteomic profiling. ResultsConsistent with previous studies, unsaturated forms of medium/long chain acylcarnitines were elevated in the HFrEF group to a greater extent than the HFpEF group compared to Controls. A number of amino acid derivatives, including 1- and 3-methylhistidine, homocitrulline, and symmetric (SDMA) and asymmetric (ADMA) dimethylarginine were elevated in HF, with ADMA elevated uniquely in HFpEF. Plasma branched-chain amino acids (BCAA) were not different across the groups; however, short-chain acylcarnitine species indicative of BCAA catabolism were significantly elevated in both HF groups. The ketone body 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 NT-proBNP in both forms of HF, stronger in HFrEF. ConclusionsThese results identify plasma signatures that are shared as well as potentially distinguish between HFrEF and HFpEF. Metabolite markers for ketogenic metabolic re-programming in extra-cardiac tissues were identified as unique signatures in the HFrEF group, possibly related to the lipolytic action of increased levels of BNP. Future studies will be necessary to further validate these metabolites as HF biosignatures that may guide phenotype-specific therapeutics and provide insight into the systemic metabolic responses to HFpEF and HFrEF. Clinical Perspective What Is New?O_LI"Real world" targeted metabolomic profiling on wide range of metabolites in a diverse population of patients with HFrEF and HFpEF. C_LIO_LILevels of 3-hydroxybutyrate and its metabolite C4OH-carnitine were uniquely increased in the HFrEF group and correlated with levels of plasma NT-proBNP in both the heart failure groups, indicating the possibility of a heart-adipose-liver axis. C_LIO_LIAsymmetric dimethylarginine, a known inhibitor of nitric oxide synthase, was uniquely upregulated in HFpEF suggesting that there may also be an underlying component of vascular dysregulation contributing to HFpEF pathophysiology. C_LI What Are the Clinical Implications?O_LIThe plasma metabolomic changes seen in the heart failure cohorts support the existing theory of metabolic reprogramming, providing further rationale for the pursuit of therapeutic targets for the treatment of heart failure. C_LIO_LIQuantitative metabolomic profiling shows promise for guiding therapeutic decisions in HFrEF and HFpEF. C_LIO_LIModulation of natriuretic peptides may enhance the delivery of ketone and fatty acids to the "fuel starved" failing heart. C_LI