{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:56:52Z","timestamp":1790834212225,"version":"4.1.0"},"reference-count":31,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100011958","name":"Danmarks Frie Forskningsfond","doi-asserted-by":"publisher","award":["2034\u201000073B"],"award-info":[{"award-number":["2034\u201000073B"]}],"id":[{"id":"10.13039\/501100011958","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002808","name":"Carlsbergfondet","doi-asserted-by":"publisher","award":["CF19\u20100067"],"award-info":[{"award-number":["CF19\u20100067"]}],"id":[{"id":"10.13039\/501100002808","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF18OC0032728"],"award-info":[{"award-number":["NNF18OC0032728"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"abstract":"\n Abstract<\/jats:title>\n \n Heart failure with preserved ejection fraction (HFpEF) accounts for over half of heart failure cases, yet its underlying mechanisms remain incompletely understood and effective therapies are lacking. Diastolic dysfunction, a hallmark of HFpEF, may arise from impaired active myocardial relaxation, but the contribution of intracellular calcium (Ca\n 2+<\/jats:sup>\n ) handling remains unclear. This study aimed to document impaired lusitropy and diastolic dysfunction in HFpEF, and to determine the contribution of altered ventricular Ca\n 2+<\/jats:sup>\n handling to slowed myocardial relaxation. HFpEF was induced by diet\u2010driven obesity and hypertension. Cardiac function was assessed\n in vivo<\/jats:italic>\n by echocardiography,\n ex vivo<\/jats:italic>\n in preload\u2010controlled isolated hearts and at the cellular level by Ca\n 2+<\/jats:sup>\n imaging of isolated ventricular myocytes. HFpEF mice developed diastolic dysfunction, hypertrophy, reduced cardiac output and exercise intolerance, yet ejection fraction was preserved. Impaired lusitropy was evident\n in vivo<\/jats:italic>\n ,\n ex vivo<\/jats:italic>\n and at the cellular level, where basal cytosolic Ca\n 2+<\/jats:sup>\n handling was preserved, but the \u03b2\u2010adrenergic\u2010recruitable acceleration of Ca\n 2+<\/jats:sup>\n clearance was impaired. This attenuated lusitropic response to \u03b2\u2010adrenergic stimulation in HFpEF myocytes was mirrored\n in vivo<\/jats:italic>\n during echocardiography. Slowed myocardial relaxation is a consistent feature of HFpEF, evident at the organ, tissue and cellular levels. \u03b2\u2010Adrenergic stimulation normally enhances lusitropy, but this response is blunted in HFpEF hearts both\n in vivo<\/jats:italic>\n and in isolated cardiomyocytes. Impaired \u03b2\u2010adrenergic amplification of Ca\n 2+<\/jats:sup>\n removal is associated with slowed ventricular relaxation, reduced cardiac output and exercise intolerance in HFpEF, identifying defective lusitropic reserve as a potential therapeutic target.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n Heart failure with preserved ejection fraction (HFpEF) lacks effective therapies, in part because the disease mechanisms remain incompletely defined.<\/jats:p>\n <\/jats:list-item>\n \n \n Using a mouse model combining obesity and hypertension, we demonstrate diastolic dysfunction, reduced cardiac output and exercise intolerance despite preserved ejection fraction. Ventricular relaxation was impaired in HFpEF mice\n in vivo<\/jats:italic>\n and\n ex vivo<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:list-item>\n \n \n \u03b2\u2010Adrenergic lusitropic reserve was reduced in HFpEF mice during ultrasound echocardiography, which was mirrored by a blunted \u03b2\u2010adrenergic acceleration of cytosolic Ca\n 2+<\/jats:sup>\n removal in disaggregated cells from HFpEF hearts.\n <\/jats:p>\n <\/jats:list-item>\n \n \n These findings identify defective myocyte Ca\n 2+<\/jats:sup>\n handling as a distinct mechanistic contributor to HFpEF pathophysiology and suggest that therapeutic strategies aimed at restoring Ca\n 2+<\/jats:sup>\n removal and lusitropic reserve may improve diastolic performance and functional capacity in HFpEF patients.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp291587","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:00:41Z","timestamp":1790830841000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Slow calcium removal contributes to impaired lusitropic response to \u03b2\u2010adrenergic stimulation in HFpEF mice"],"prefix":"10.1113","author":[{"given":"Tamzin","family":"Zawadzki","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences University of Copenhagen Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana S.","family":"Usai","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Copenhagen Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sif G.","family":"Kaad","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Copenhagen Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrine H.","family":"Rasmussen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Copenhagen Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3549-2207","authenticated-orcid":false,"given":"Mie S.","family":"Larsen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Copenhagen Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens C. B.","family":"Jacobsen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Copenhagen Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2469-6458","authenticated-orcid":false,"given":"Morten B.","family":"Thomsen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Copenhagen Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"issue":"6","key":"e_1_2_5_2_1","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1161\/01.CIR.0000155257.33485.6D","article-title":"Cardiomyocyte stiffness in diastolic heart failure","volume":"111","author":"Borb\u00e9ly A.","year":"2005","journal-title":"Circulation"},{"issue":"6","key":"e_1_2_5_3_1","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1093\/eurheartj\/ehq426","article-title":"Heart failure with preserved ejection fraction: Pathophysiology, diagnosis, and treatment","volume":"32","author":"Borlaug B. 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M.","year":"2017","journal-title":"Nature Reviews Cardiology"},{"issue":"3","key":"e_1_2_5_9_1","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1161\/CIRCRESAHA.119.315891","article-title":"The control of diastolic calcium in the heart: Basic mechanisms and functional implications","volume":"126","author":"Eisner D. A.","year":"2020","journal-title":"Circulation Research"},{"issue":"2","key":"e_1_2_5_10_1","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/s41569-024-01067-1","article-title":"Pathophysiological insights into HFpEF from studies of human cardiac tissue","volume":"22","author":"Fayyaz A. 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C. B.","year":"2024","journal-title":"Acta Physiologica"},{"issue":"22","key":"e_1_2_5_16_1","doi-asserted-by":"crossref","first-page":"5091","DOI":"10.1113\/JP280425","article-title":"Distinct features of calcium handling and \u03b2\u2010adrenergic sensitivity in heart failure with preserved versus reduced ejection fraction","volume":"598","author":"Kilfoil P. J.","year":"2020","journal-title":"The Journal of Physiology"},{"issue":"3","key":"e_1_2_5_17_1","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1093\/cvr\/cvad178","article-title":"Remodelling of cAMP dynamics within the SERCA2a microdomain in heart failure with preserved ejection fraction caused by obesity and type 2 diabetes","volume":"120","author":"Lai P.","year":"2024","journal-title":"Cardiovascular Research"},{"issue":"14","key":"e_1_2_5_18_1","article-title":"Revisiting mouse cardiac myocyte isolation: A simplified langendorff\u2010based method","volume":"16","author":"Larsen M. 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