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The obese\/cardiometabolic HFpEF phenotype is particularly prevalent and morbid, and obesity is increasingly recognized as a driver of the syndrome, though the underlying mechanisms distinguishing cardiometabolic HFpEF from obesity remain unclear. Comprehensive multi-omics characterization of left ventricular samples from patients with HFpEF and obesity, compared with obese non-failing counterparts, provides an opportunity to deepen our understanding of the pathophysiology of cardiometabolic HFpEF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>We applied an integrated multi-omics approach to compare left ventricular (LV) endomyocardial biopsies (EMB) from overweight\/obese HFpEF patients (n = 19) and non-failing overweight\/obese (NFO) individuals (n = 4). Proteomic, metabolomic, and lipidomic data were integrated with clinical parameters, imaging and invasive haemodynamic to investigate the molecular mechanisms and clinical relevance of metabolic dysregulation in HFpEF. HFpEF patients exhibited distinct proteomic signatures marked by extracellular matrix (ECM) remodelling and impaired energy metabolism compared with NFO individuals. Specifically, HFpEF hearts showed diminished glycolysis, altered glucose metabolism, preserved fatty acid oxidation (FAO) and accumulation of succinate, consistent with myocardial energy deprivation. Changes in purine and pyrimidine metabolism further indicated altered nucleotide homeostasis. Integrative analyses revealed strong correlations between metabolic derangements, ECM proteins expression, and clinical indices of cardiac function and disease severity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings indicate that metabolic remodelling\u2014particularly dysregulated glycolysis and changes in TCA cycle intermediates \u2014characterize myocardial dysfunction in cardiometabolic HFpEF. Importantly, comprehensive multi-omics analysis of LV EMBs identified HFpEF-specific alterations in cardiac metabolism and remodelling occurring independently from obesity. These insights highlight the interplay between metabolic dysregulation, ECM remodelling, and clinical phenotype in cardiometabolic HFpEF, offering a foundation for targeted metabolic interventions in this syndrome.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvag084","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T11:45:54Z","timestamp":1776858354000},"page":"984-1000","source":"Crossref","is-referenced-by-count":7,"title":["Integrated left ventricular multi-omics landscape of human cardiometabolic HFpEF"],"prefix":"10.1093","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8127-5564","authenticated-orcid":false,"given":"Federico","family":"Capone","sequence":"first","affiliation":[{"name":"Translational Approaches in Heart Failure and Cardiometabolic Disease, Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association (MDC) , Robert-R\u00f6ssle-Stra\u00dfe 10, 13125 Berlin ,","place":["Germany"]},{"name":"Department of Medicine (DIMED), Unit of Internal Medicine III, Padua University Hospital, University of Padua , Padova ,","place":["Italy"]},{"name":"Department of Biomedical Sciences, University of Padova , Padova ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl-Philipp","family":"Rommel","sequence":"additional","affiliation":[{"name":"Heart Center at University of Leipzig , Leipzig ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Forbes","sequence":"additional","affiliation":[{"name":"Proteomic and Metabolomics Platform, Berlin Institute for Medical Systems Biology (BIMSB), Max Delbr\u00fcck Center for Molecular Medicine (MDC) in the Helmholtz Association , Berlin ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline","family":"Fahjen","sequence":"additional","affiliation":[{"name":"Proteomics Platform, Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association and Berlin Institute of Health at Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin , Berlin ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Strocchi","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Intensive Care Medicine, Max Rubner Center for Cardiovascular Metabolic Renal Research (MRC), Deutsches Herzzentrum der Charit\u00e9, Charit\u00e9-Universit\u00e4tsmedizin Berlin , Hessische Stra\u00dfe 3-4, 10115 Berlin ,","place":["Germany"]},{"name":"DZHK (German Centre for Cardiovascular Research), Partner Site Berlin , Berlin ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Rosch","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center of the Johannes Gutenberg University , Mainz ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongling","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Intensive Care Medicine, Max Rubner Center for Cardiovascular Metabolic Renal Research (MRC), Deutsches Herzzentrum der Charit\u00e9, Charit\u00e9-Universit\u00e4tsmedizin Berlin , Hessische Stra\u00dfe 3-4, 10115 Berlin ,","place":["Germany"]},{"name":"DZHK (German Centre for Cardiovascular Research), Partner Site Berlin , Berlin ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Bode","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Intensive Care Medicine, Max Rubner Center for Cardiovascular Metabolic Renal Research (MRC), Deutsches Herzzentrum der Charit\u00e9, Charit\u00e9-Universit\u00e4tsmedizin Berlin , Hessische Stra\u00dfe 3-4, 10115 Berlin ,","place":["Germany"]},{"name":"DZHK (German 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,","place":["Germany"]},{"name":"DZHK (German Centre for Cardiovascular Research), Partner Site Berlin , Berlin ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leandro Santiago","family":"Padilla","sequence":"additional","affiliation":[{"name":"Proteomic and Metabolomics Platform, Berlin Institute for Medical Systems Biology (BIMSB), Max Delbr\u00fcck Center for Molecular Medicine (MDC) in the Helmholtz Association , Berlin ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario Luca","family":"Morieri","sequence":"additional","affiliation":[{"name":"Department of Medicine (DIMED), Unit of Internal Medicine III, Padua University Hospital, University of Padua , Padova ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luo","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Intensive Care Medicine, Max Rubner Center for Cardiovascular Metabolic Renal Research (MRC), Deutsches Herzzentrum der Charit\u00e9, Charit\u00e9-Universit\u00e4tsmedizin Berlin , Hessische Stra\u00dfe 3-4, 10115 Berlin ,","place":["Germany"]},{"name":"DZHK (German Centre for Cardiovascular Research), Partner Site Berlin , Berlin ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Farrelly","sequence":"additional","affiliation":[{"name":"Translational Approaches in Heart Failure and Cardiometabolic Disease, Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association (MDC) , Robert-R\u00f6ssle-Stra\u00dfe 10, 13125 Berlin ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Vacca","sequence":"additional","affiliation":[{"name":"Translational Approaches in Heart Failure and Cardiometabolic Disease, Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association (MDC) , 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,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0696-9299","authenticated-orcid":false,"given":"Stefan","family":"Kempa","sequence":"additional","affiliation":[{"name":"Proteomic and Metabolomics Platform, Berlin Institute for Medical Systems Biology (BIMSB), Max Delbr\u00fcck Center for Molecular Medicine (MDC) in the Helmholtz Association , Berlin ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Lurz","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center of the Johannes Gutenberg University , Mainz ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7582-7171","authenticated-orcid":false,"given":"Gabriele G","family":"Schiattarella","sequence":"additional","affiliation":[{"name":"Translational Approaches in Heart Failure and Cardiometabolic Disease, 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