{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T20:00:16Z","timestamp":1793908816788,"version":"4.8.0"},"reference-count":32,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"European Innovation Council of the European Union","id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004837","name":"Ministry of Science and Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Union\u2019s","id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Plan de Recuperaci\u00f3n, Transformaci\u00f3n y Resiliencia de Espa\u00f1a"},{"name":"Instituto de Salud Carlos III","id":[{"id":"https:\/\/ror.org\/00ca2c886","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Pro CNIC Foundation"},{"name":"Severo Ochoa Center of Excellence","award":["CEX2020-001041-S"],"award-info":[{"award-number":["CEX2020-001041-S"]}],"id":[{"id":"https:\/\/ror.org\/02y9qjz38","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Early diastolic dysfunction precedes the development of HFpEF, but the molecular events that initiate this process remain poorly defined. HFpEF arises in the setting of systemic comorbidities such as obesity (OB), hypertension, hyperglycaemia (HG), and sleep apnoea, which often coexist and make it difficult to distinguish their individual contributions to early cardiac remodelling. Here, we aimed to define the early, comorbidity-specific mechanisms that initiate diastolic dysfunction across major HFpEF-associated conditions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>We performed single-nucleus RNA sequencing (snRNA-seq) of left ventricles from mouse models of OB, systemic arterial hypertension (SAH), chronic intermittent hypoxia (CIH), and HG at the time point corresponding to early diastolic impairment. Findings were validated by qRT\u2013PCR, immunohistochemistry, and targeted interventions.<\/jats:p>\n                    <jats:p>OB and HG induced the most extensive transcriptional remodelling, affecting cardiomyocytes, fibroblasts, endothelial cells, and macrophages, while SAH and CIH produced comparatively more modest changes. Cardiomyocytes developed comorbidity-specific stress programmes, with glucocorticoid receptor (GR)-driven activation in OB, combined FoxO and GR signalling in HG, mitochondrial and sarcomeric remodelling in hypertension, and minimal changes in hypoxia. Fibroblasts and endothelial cells in OB and HG mice adopted profibrotic and angiogenesis-impaired profiles, and macrophages polarized towards GR-regulated or immunomodulatory states, depending on the comorbidity. Correction of OB at mid-life improved ventricular relaxation, delayed HFpEF onset, and reduced GR target expression. Direct GR inhibition through overexpression of the lncRNA GAS5 or with mifepristone treatment rescued diastolic function independently of weight loss. In HG mice, CnA\u03b21 overexpression reduced baseline expression of FoxO target genes, corrected atrophy, but did not prevent FoxO target induction under HG or restore relaxation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Early diastolic dysfunction arises through comorbidity-specific molecular programmes. OB-induced GR activation emerges as a causal and actionable driver of diastolic dysfunction. These findings provide mechanistic insight into comorbidity-specific pathways in HFpEF and support the development of stratified therapeutic approaches.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvag193","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T11:29:30Z","timestamp":1788521370000},"source":"Crossref","is-referenced-by-count":1,"title":["Comorbidity-specific molecular programmes of early diastolic dysfunction identify glucocorticoid receptor activation as a causal driver in obesity"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6407-6918","authenticated-orcid":false,"given":"Antonella","family":"Ausiello","sequence":"first","affiliation":[{"name":"Myocardial Homeostasis and Cardiac Injury Programme, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) , Melchor Fern\u00e1ndez Almagro, 3, Madrid 28029 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Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) , Melchor Fern\u00e1ndez Almagro, 3, Madrid 28029 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Villalba-Orero","sequence":"additional","affiliation":[{"name":"Myocardial Homeostasis and Cardiac Injury Programme, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) , Melchor Fern\u00e1ndez Almagro, 3, Madrid 28029 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Fern\u00e1ndez-Cort\u00e9s","sequence":"additional","affiliation":[{"name":"Myocardial Homeostasis and Cardiac Injury Programme, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) , Melchor Fern\u00e1ndez Almagro, 3, Madrid 28029 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Garc\u00eda-Pav\u00eda","sequence":"additional","affiliation":[{"name":"Myocardial Homeostasis and Cardiac Injury Programme, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) , Melchor Fern\u00e1ndez Almagro, 3, Madrid 28029 ,","place":["Spain"]},{"name":"Centro de investigaci\u00f3n Biom\u00e9dica en Red Cardiovascular (CIBERCV) , 28029 Madrid ,","place":["Spain"]},{"name":"Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, IDIPHIM , 28222 Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Victoria","family":"G\u00f3mez-Gaviro","sequence":"additional","affiliation":[{"name":"Centro de investigaci\u00f3n Biom\u00e9dica en Red Cardiovascular (CIBERCV) , 28029 Madrid ,","place":["Spain"]},{"name":"Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, IDIPHIM , 28222 Madrid ,","place":["Spain"]},{"name":"Department of Cardiology, Instituto de 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