{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T15:11:18Z","timestamp":1789830678118,"version":"4.0.1"},"reference-count":36,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T00:00:00Z","timestamp":1760918400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100020884","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"crossref","award":["1221585"],"award-info":[{"award-number":["1221585"]}],"id":[{"id":"10.13039\/501100020884","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100020884","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"crossref","award":["1231685"],"award-info":[{"award-number":["1231685"]}],"id":[{"id":"10.13039\/501100020884","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100020884","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"crossref","award":["1231909"],"award-info":[{"award-number":["1231909"]}],"id":[{"id":"10.13039\/501100020884","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100020884","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"crossref","award":["11241074"],"award-info":[{"award-number":["11241074"]}],"id":[{"id":"10.13039\/501100020884","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100020884","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"crossref","award":["ACT240058"],"award-info":[{"award-number":["ACT240058"]}],"id":[{"id":"10.13039\/501100020884","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100020884","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"crossref","award":["15130011"],"award-info":[{"award-number":["15130011"]}],"id":[{"id":"10.13039\/501100020884","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100020884","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"crossref","award":["1523A0008"],"award-info":[{"award-number":["1523A0008"]}],"id":[{"id":"10.13039\/501100020884","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome characterized by left ventricular diastolic dysfunction, exercise intolerance, low-grade chronic inflammation, and comorbidities such as hypertension, obesity, and glucose intolerance. Myocardial infiltration by activated macrophages has been proposed as a mechanism linking low-grade inflammation to increased diastolic LV stiffness in HFpEF. Changes in the relative abundance of cardiac macrophage populations may precede and promote the development of HFpEF in the aged heart. This study aimed to characterize the cardiac macrophage subsets that predominate during progression from experimental preclinical to established HFpEF. To generate the model, wild-type male C57BL\/6N mice were randomized to control chow or a combination of high-fat diet plus L-NAME in drinking water for 5 weeks (asymptomatic pre-HFpEF) or 15 weeks (established HFpEF). At the end of each period, we measured body weight, running distance, metabolic biomarkers, systolic and diastolic blood pressure, myocardial function and morphology, cardiac remodeling by hypertrophic markers, morphometric analyses, fibrosis, cytokines TNF-\u03b1 and IL-10, cardiac macrophage phenotype profiles (CCR2+ and CCR2\u2212), and AMP-Activated Protein Kinase (AMPK)activity.Significant changes in myocardial macrophage populations were observed at 5 weeks (pre-HFpEF), specifically a decrease in resident reparative CCR2\u2212MHCII\u2212 and increase in proinflammatory CCR2+MHCII+ macrophages. These early changes were associated with higher circulating TNF-\u03b1, decreased myocardial AMPK activation, and more severe myocardial fibrosis. At 15 weeks (established HFpEF), proinflammatory CCR2+MHCII+ macrophage levels remained elevated in the myocardium; whereas the initial number of resident reparative CCR2\u2212MHCII- levels was reduced, it subsequently returned to baseline. In this model of HFpEF induced by a high-fat diet and L-NAME, which produced obesity, glucose intolerance, and hypertension, myocardial resident reparative CCR2\u2212MHCII\u2212 macrophages decreased and proinflammatory CCR2+MHCII+ macrophages increased during preclinical stages. These early changes in cardiac macrophage profile were associated with low-grade inflammation and myocardial remodeling and preceded the onset of HFpEF.<\/jats:p>","DOI":"10.3390\/ijms262010196","type":"journal-article","created":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T13:54:41Z","timestamp":1760968481000},"page":"10196","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Early Changes in Cardiac Macrophage Subsets in Heart Failure with Preserved Ejection Fraction"],"prefix":"10.3390","volume":"26","author":[{"given":"Danae","family":"Guti\u00e9rrez","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Cat\u00f3lica de Chile, Diagonal Paraguay 362, Piso 7, Santiago 7820436, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karina","family":"Cordero","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Cat\u00f3lica de Chile, Diagonal Paraguay 362, Piso 7, Santiago 7820436, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3914-9625","authenticated-orcid":false,"given":"Ruth","family":"Sep\u00falveda","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Cat\u00f3lica de Chile, Diagonal Paraguay 362, Piso 7, Santiago 7820436, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilo","family":"Venegas","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Cat\u00f3lica de Chile, Diagonal Paraguay 362, Piso 7, Santiago 7820436, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Altamirano","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Cat\u00f3lica de Chile, Diagonal Paraguay 362, Piso 7, Santiago 7820436, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila","family":"Candia","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Cat\u00f3lica de Chile, Diagonal Paraguay 362, Piso 7, Santiago 7820436, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gigliola","family":"Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Cat\u00f3lica de Chile, Diagonal Paraguay 362, Piso 7, Santiago 7820436, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5089-5998","authenticated-orcid":false,"given":"Patricio","family":"Araos","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Universidad Autonoma de Chile, Santiago 8581151, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6802-6811","authenticated-orcid":false,"given":"Cristian A.","family":"Amador","sequence":"additional","affiliation":[{"name":"Faculty of Sciences, Universidad San Sebastian, Santiago 8420524, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcela A.","family":"Hermoso","sequence":"additional","affiliation":[{"name":"Laboratory of Innate Immunity, Program of Immunology, Faculty of Medicine, Institute of Biomedical Sciences, Universidad de Chile, Santiago 7800003, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Gabrielli","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Cat\u00f3lica de Chile, Diagonal Paraguay 362, Piso 7, Santiago 7820436, Chile"},{"name":"Advanced Center for Chronic Diseases (ACCDiS), Pontificia Universidad Cat\u00f3lica de Chile, Santiago 7820436, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge E.","family":"Jalil","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Cat\u00f3lica de Chile, Diagonal Paraguay 362, Piso 7, Santiago 7820436, Chile"},{"name":"Center of New Drugs for Hypertension and Heart Failure (CENDHY), Division of Cardiovascular Diseases, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 7820436, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4915-6378","authenticated-orcid":false,"given":"Mar\u00eda Paz","family":"Ocaranza","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Cat\u00f3lica de Chile, Diagonal Paraguay 362, Piso 7, Santiago 7820436, Chile"},{"name":"Advanced Center for Chronic Diseases (ACCDiS), Pontificia Universidad Cat\u00f3lica de Chile, Santiago 7820436, Chile"},{"name":"Center of New Drugs for Hypertension and Heart Failure (CENDHY), Division of Cardiovascular Diseases, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 7820436, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2780","DOI":"10.1093\/eurheartj\/ehy301","article-title":"Heart Failure with Preserved Ejection Fraction: From Mechanisms to Therapies","volume":"39","author":"Lam","year":"2018","journal-title":"Eur. 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