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While chronic systemic inflammation, triggered by comorbidities, is a critical factor of HFpEF pathophysiology and a relevant target for therapy, mechanisms underlying inflammation remain poorly understood. Here, we aim to understand the upstream mechanisms driving inflammation, including immune dysregulation and cellular senescence.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>ZSF1-Obese rats, a cardiometabolic model of HFpEF, were used to investigate systemic and cardiac inflammation, and to characterise the senescent program in immune, circulating endothelial and cardiac cells, before disease onset and onward. Using patient samples, we further evaluated the association between cellular senescence and diagnostic and prognostic markers of HFpEF. Finally, we administered a senolytic - Navitoclax - at two time-points, before and after the appearance of HFpEF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>ZSF1-Obese rats had increased immune and endothelial senescent cells in their peripheral blood and myocardium, together with exacerbated systemic inflammation and endothelial damage, compared to control ZSF1-Lean rats. Moreover, increased circulating senescent leucocytes were associated with markers of disease severity in patients with HFpEF. Senescent cell clearance decreased circulating B-type natriuretic peptide levels and attenuated inflammation, vascular remodelling, and cardiac fibrosis. Additionally, it improved renal function and reduced pulmonary oedema. Our findings suggest that senotherapeutics may improve the treatment for HFpEF by attenuating systemic effects of the disease whilst reducing cardiac fibrosis and endothelial rarefaction.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvaf208","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T13:15:59Z","timestamp":1761830159000},"page":"2385-2403","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacological clearance of senescent cells reduces inflammation, endothelial damage and cardiac fibrosis in HFpEF"],"prefix":"10.1093","volume":"121","author":[{"given":"Elsa D","family":"Silva","sequence":"first","affiliation":[{"name":"i3S - Institute for Research and Innovation in Health, University of Porto , Rua Alfredo Allen 208, 4200-135 Porto ,","place":["Portugal"]},{"name":"ICBAS - Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, University of Porto , Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto ,","place":["Portugal"]},{"name":"INEB - Instituto Nacional de Engenharia Biom\u00e9dica, University of Porto , Porto ,","place":["Portugal"]}]},{"given":"In\u00eas","family":"Tom\u00e9","sequence":"additional","affiliation":[{"name":"CNC - Center for Neurosciences and Cell Biology, University of Coimbra , Rua Larga Edificio FMUC Piso 1, 3004\u2013504 Coimbra ,","place":["Portugal"]},{"name":"Faculty of Pharmacy, University of Coimbra , P\u00f3lo das Ci\u00eancias da Sa\u00fade, 3000-548 Coimbra ,","place":["Portugal"]},{"name":"CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra , 3004\u2013504 Coimbra ,","place":["Portugal"]}]},{"given":"Francisco","family":"Vasques-N\u00f3voa","sequence":"additional","affiliation":[{"name":"i3S - Institute for Research and Innovation in Health, University of Porto , Rua Alfredo Allen 208, 4200-135 Porto ,","place":["Portugal"]},{"name":"INEB - Instituto Nacional de Engenharia Biom\u00e9dica, University of Porto , Porto ,","place":["Portugal"]},{"name":"Cardiovascular R&D Center, Faculty of Medicine, University of Porto , R. Dr. Pl\u00e1cido da Costa, 4200-450 Porto ,","place":["Portugal"]},{"name":"Internal Medicine Department, Centro Hospitalar Universit\u00e1rio S\u00e3o Jo\u00e3o , Alameda Professor Hern\u00e2ni Monteiro, 4200\u2013319 Porto ,","place":["Portugal"]}]},{"given":"Gl\u00f3ria","family":"Concei\u00e7\u00e3o","sequence":"additional","affiliation":[{"name":"Cardiovascular R&D Center, Faculty of Medicine, University of Porto , R. Dr. Pl\u00e1cido da Costa, 4200-450 Porto ,","place":["Portugal"]}]},{"given":"Andreia","family":"Silva","sequence":"additional","affiliation":[{"name":"i3S - Institute for Research and Innovation in Health, University of Porto , Rua Alfredo Allen 208, 4200-135 Porto ,","place":["Portugal"]},{"name":"INEB - Instituto Nacional de Engenharia Biom\u00e9dica, University of Porto , Porto ,","place":["Portugal"]}]},{"given":"Ant\u00f3nio S","family":"Barros","sequence":"additional","affiliation":[{"name":"Cardiovascular R&D Center, Faculty of Medicine, University of Porto , R. Dr. Pl\u00e1cido da Costa, 4200-450 Porto ,","place":["Portugal"]}]},{"given":"Pedro","family":"Mendes-Ferreira","sequence":"additional","affiliation":[{"name":"Cardiovascular R&D Center, Faculty of Medicine, University of Porto , R. Dr. Pl\u00e1cido da Costa, 4200-450 Porto ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6402-4245","authenticated-orcid":false,"given":"Diana","family":"Santos-Ribeiro","sequence":"additional","affiliation":[{"name":"i3S - Institute for Research and Innovation in Health, University of Porto , Rua Alfredo Allen 208, 4200-135 Porto ,","place":["Portugal"]}]},{"given":"Alexandre","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Cardiovascular R&D Center, Faculty of Medicine, University of Porto , R. Dr. Pl\u00e1cido da Costa, 4200-450 Porto ,","place":["Portugal"]}]},{"given":"Ant\u00f3nio","family":"Ang\u00e9lico-Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Cardiovascular R&D Center, Faculty of Medicine, University of Porto , R. Dr. Pl\u00e1cido da Costa, 4200-450 Porto ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2203-436X","authenticated-orcid":false,"given":"Rui","family":"Ad\u00e3o","sequence":"additional","affiliation":[{"name":"Cardiovascular R&D Center, Faculty of Medicine, University of Porto , R. Dr. Pl\u00e1cido da Costa, 4200-450 Porto ,","place":["Portugal"]}]},{"given":"Carolina","family":"Caetano","sequence":"additional","affiliation":[{"name":"CNC - Center for Neurosciences and Cell Biology, University of Coimbra , Rua Larga Edificio FMUC Piso 1, 3004\u2013504 Coimbra ,","place":["Portugal"]},{"name":"CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra , 3004\u2013504 Coimbra ,","place":["Portugal"]}]},{"given":"Daniel","family":"Sousa","sequence":"additional","affiliation":[{"name":"i3S - Institute for Research and Innovation in Health, University of Porto , Rua Alfredo Allen 208, 4200-135 Porto ,","place":["Portugal"]},{"name":"INEB - Instituto Nacional de Engenharia Biom\u00e9dica, University of Porto , Porto ,","place":["Portugal"]}]},{"given":"Daniela","family":"Miranda-Silva","sequence":"additional","affiliation":[{"name":"Cardiovascular R&D Center, Faculty of Medicine, University of Porto , R. Dr. Pl\u00e1cido da Costa, 4200-450 Porto ,","place":["Portugal"]}]},{"given":"Rio P","family":"Juni","sequence":"additional","affiliation":[{"name":"Amsterdam University Medical Centers, Vrije Universiteit Amsterdam , De Boelelaan 1105, 1081 HV Amsterdam ,","place":["The Netherlands"]},{"name":"Amsterdam Cardiovascular Sciences, Microcirculation , Meibergdreef 9, 1105 AZ Amsterdam Amsterdam ,","place":["The Netherlands"]}]},{"given":"Tamara","family":"Tchkonia","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biomedical Engineering, Mayo Clinic , 200 First St. SW Rochester, Rochester, MN 55905 ,","place":["USA"]}]},{"given":"James L","family":"Kirkland","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biomedical Engineering, Mayo Clinic , 200 First St. SW Rochester, Rochester, MN 55905 ,","place":["USA"]},{"name":"Department of Medicine, Mayo Clinic , 200 First St. SW Rochester, Rochester, MN 55905 ,","place":["USA"]}]},{"given":"Francisco","family":"Caramelo","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Coimbra , Polo III \u2013 Polo das Ci\u00eancias da Sa\u00fade, 3000-548 Coimbra ,","place":["Portugal"]}]},{"given":"N\u00e1dia","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Cardiovascular R&D Center, Faculty of Medicine, University of Porto , R. Dr. Pl\u00e1cido da Costa, 4200-450 Porto ,","place":["Portugal"]}]},{"given":"Vasco","family":"Sampaio-Pinto","sequence":"additional","affiliation":[{"name":"i3S - Institute for Research and Innovation in Health, University of Porto , Rua Alfredo Allen 208, 4200-135 Porto ,","place":["Portugal"]},{"name":"ICBAS - Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, University of Porto , Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto ,","place":["Portugal"]},{"name":"INEB - Instituto Nacional de Engenharia Biom\u00e9dica, University of Porto , Porto ,","place":["Portugal"]}]},{"given":"Jo\u00e3o S","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"i3S - Institute for Research and Innovation in Health, University of Porto , Rua Alfredo Allen 208, 4200-135 Porto ,","place":["Portugal"]},{"name":"ICBAS - Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, University of Porto , Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto ,","place":["Portugal"]},{"name":"INEB - Instituto Nacional de Engenharia Biom\u00e9dica, University of Porto , Porto ,","place":["Portugal"]}]},{"given":"Reinier A","family":"Boon","sequence":"additional","affiliation":[{"name":"Amsterdam University Medical Centers, Vrije Universiteit Amsterdam , De Boelelaan 1105, 1081 HV Amsterdam ,","place":["The Netherlands"]},{"name":"Amsterdam Cardiovascular Sciences, Microcirculation , Meibergdreef 9, 1105 AZ Amsterdam Amsterdam ,","place":["The Netherlands"]},{"name":"Institute for Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University , Theodor-Stern-Kai 7, 60590 Frankfurt am Main ,","place":["Germany"]},{"name":"German Centre for Cardiovascular Research, Partner Site Frankfurt Rhein\/Main , Frankfurt ,","place":["Germany"]}]},{"given":"Adelino","family":"Leite-Moreira","sequence":"additional","affiliation":[{"name":"Cardiovascular R&D Center, Faculty of Medicine, University of Porto , R. Dr. Pl\u00e1cido da Costa, 4200-450 Porto ,","place":["Portugal"]}]},{"given":"Patr\u00edcia","family":"Pitrez","sequence":"additional","affiliation":[{"name":"CNC - Center for Neurosciences and Cell Biology, University of Coimbra , Rua Larga Edificio FMUC Piso 1, 3004\u2013504 Coimbra ,","place":["Portugal"]},{"name":"CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra , 3004\u2013504 Coimbra ,","place":["Portugal"]}]},{"given":"Perp\u00e9tua","family":"Pinto-do-\u00d3","sequence":"additional","affiliation":[{"name":"i3S - Institute for Research and Innovation in Health, University of Porto , Rua Alfredo Allen 208, 4200-135 Porto ,","place":["Portugal"]},{"name":"ICBAS - Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, University of Porto , Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto ,","place":["Portugal"]},{"name":"INEB - Instituto Nacional de Engenharia Biom\u00e9dica, University of Porto , Porto ,","place":["Portugal"]}]},{"given":"Susana G","family":"Santos","sequence":"additional","affiliation":[{"name":"i3S - Institute for Research and Innovation in Health, University of Porto , Rua Alfredo Allen 208, 4200-135 Porto ,","place":["Portugal"]},{"name":"ICBAS - Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, University of Porto , Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto ,","place":["Portugal"]},{"name":"INEB - Instituto Nacional de Engenharia Biom\u00e9dica, University of Porto , Porto ,","place":["Portugal"]}]},{"given":"In\u00eas","family":"Falc\u00e3o-Pires","sequence":"additional","affiliation":[{"name":"Cardiovascular R&D Center, Faculty of Medicine, University of Porto , R. Dr. Pl\u00e1cido da Costa, 4200-450 Porto ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8985-9302","authenticated-orcid":false,"given":"Lino","family":"Ferreira","sequence":"additional","affiliation":[{"name":"CNC - Center for Neurosciences and Cell Biology, University of Coimbra , Rua Larga Edificio FMUC Piso 1, 3004\u2013504 Coimbra ,","place":["Portugal"]},{"name":"CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra , 3004\u2013504 Coimbra ,","place":["Portugal"]},{"name":"Faculty of Medicine, University of Coimbra , Polo III \u2013 Polo das Ci\u00eancias da Sa\u00fade, 3000-548 Coimbra ,","place":["Portugal"]}]},{"given":"Diana S","family":"Nascimento","sequence":"additional","affiliation":[{"name":"i3S - Institute for Research and Innovation in Health, University of Porto , Rua Alfredo Allen 208, 4200-135 Porto ,","place":["Portugal"]},{"name":"ICBAS - Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, University of Porto , Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto ,","place":["Portugal"]},{"name":"INEB - Instituto Nacional de Engenharia Biom\u00e9dica, University of Porto , Porto ,","place":["Portugal"]}]}],"member":"286","published-online":{"date-parts":[[2025,10,27]]},"reference":[{"key":"2025120912271764600_cvaf208-B1","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1016\/j.jchf.2020.10.002","article-title":"Standardised definitions for evaluation of heart failure therapies: scientific expert panel from the Heart Failure Collaboratory and Academic Research Consortium","volume":"8","author":"Abraham","year":"2020","journal-title":"JACC Heart Fail"},{"key":"2025120912271764600_cvaf208-B2","doi-asserted-by":"crossref","first-page":"2476","DOI":"10.1016\/j.jacc.2017.08.074","article-title":"Heart failure with preserved, borderline, and reduced ejection fraction: 5-year outcomes","volume":"70","author":"Shah","year":"2017","journal-title":"J Am Coll 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