Plasma metabolomics identifies signatures that distinguish heart failure with reduced and preserved ejection fraction
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 metabolo...
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Wiley
2025-08-01
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| Series: | ESC Heart Failure |
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| Online Access: | https://doi.org/10.1002/ehf2.15285 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Fawaz Naeem |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-1c947e95d5dc4cd19f5c2f6fd659245f |
| institution | DOAJ |
| issn | 2055-5822 |
| language | English |
| publishDate | 2025-08-01 |
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| series | ESC Heart Failure |
| spelling | doaj-art-1c947e95d5dc4cd19f5c2f6fd659245f2025-08-20T02:50:51ZengWileyESC Heart Failure2055-58222025-08-011242803281310.1002/ehf2.15285Plasma metabolomics identifies signatures that distinguish heart failure with reduced and preserved ejection fractionFawaz Naeem0Teresa C. Leone1Christopher Petucci2Clarissa Shoffler3Ravindra C. Kodihalli4Tiffany Hidalgo5Cheryl Tow‐Keogh6Jessica Mancuso7Iphigenia Tzameli8Donald Bennett9John D. Groarke10Rachel J. Roth Flach11Daniel J. Rader12Daniel P. Kelly13Cardiovascular Institute, Department of Medicine, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USACardiovascular Institute, Department of Medicine, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USACardiovascular Institute, Department of Medicine, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USACardiovascular Institute, Department of Medicine, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USADrug Safety Research and Development Pfizer Inc Groton Connecticut USATranslational Clinical Sciences Pfizer Inc Groton Connecticut USATranslational Clinical Sciences Pfizer Inc Groton Connecticut USANon‐Clinical Statistics, Data Sciences and Analytics Pfizer Inc Cambridge Massachusetts USANon‐Clinical Statistics, Data Sciences and Analytics Pfizer Inc Cambridge Massachusetts USANon‐Clinical Statistics, Data Sciences and Analytics Pfizer Inc Cambridge Massachusetts USAPfizer Internal Medicine, Clinical Development Cambridge Massachusetts USAPfizer Internal Medicine, Clinical Development Cambridge Massachusetts USACardiovascular Institute, Department of Medicine, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USACardiovascular Institute, Department of Medicine, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USAAbstract 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.https://doi.org/10.1002/ehf2.15285biomarkerscardiac energeticsheart failureketone bodieslipid metabolismmetabolomics |
| spellingShingle | 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 Plasma metabolomics identifies signatures that distinguish heart failure with reduced and preserved ejection fraction ESC Heart Failure biomarkers cardiac energetics heart failure ketone bodies lipid metabolism metabolomics |
| title | Plasma metabolomics identifies signatures that distinguish heart failure with reduced and preserved ejection fraction |
| title_full | Plasma metabolomics identifies signatures that distinguish heart failure with reduced and preserved ejection fraction |
| title_fullStr | Plasma metabolomics identifies signatures that distinguish heart failure with reduced and preserved ejection fraction |
| title_full_unstemmed | Plasma metabolomics identifies signatures that distinguish heart failure with reduced and preserved ejection fraction |
| title_short | Plasma metabolomics identifies signatures that distinguish heart failure with reduced and preserved ejection fraction |
| title_sort | plasma metabolomics identifies signatures that distinguish heart failure with reduced and preserved ejection fraction |
| topic | biomarkers cardiac energetics heart failure ketone bodies lipid metabolism metabolomics |
| url | https://doi.org/10.1002/ehf2.15285 |
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