{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:27:52Z","timestamp":1790836072747,"version":"4.1.0"},"reference-count":62,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Heart Failure"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>The therapeutic armamentarium for heart failure with preserved ejection fraction (HFpEF) remains notably constrained. A factor contributing to this problem could be the scarcity of in vitro models for HFpEF, which hinders progress in developing new therapeutic strategies. Here, we aimed at developing a novel, comorbidity-inspired, human, in vitro model for HFpEF.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>Human induced pluripotent stem cells\u2013derived cardiomyocytes were used to produce cardiac organoids. The generated organoids were then subjected to HFpEF-associated, comorbidity-inspired conditions, such as hypertension, diabetes, and obesity-related inflammation. To assess the development of HFpEF pathophysiological features, organoids were thoroughly evaluated for their structural, functional, electrophysiological, and metabolic properties.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              Exposure to the combination of all comorbidity-mimicking conditions resulted in the largest cellular volume of 1692\u00b152 versus 1346\u00b184 \u00b5m\n              <jats:sup>3<\/jats:sup>\n              in RPMI (Roswell Park Memorial Institute medium) control group (\n              <jats:italic>P<\/jats:italic>\n              =0.003), while lower in obesity, hypertension, and diabetes groups: 1059\u00b140 \u00b5m\n              <jats:sup>3<\/jats:sup>\n              (\n              <jats:italic>P<\/jats:italic>\n              =0.014), 1276\u00b135 \u00b5m\n              <jats:sup>3<\/jats:sup>\n              (\n              <jats:italic>P<\/jats:italic>\n              =0.940), and 1575\u00b170 \u00b5m\n              <jats:sup>3<\/jats:sup>\n              (\n              <jats:italic>P<\/jats:italic>\n              =0.146), respectively. Similarly, ultrastructural fibrosis was most significantly observed after exposure to the combination of all HFpEF-inducing conditions 14.6\u00b11.2% compared with single condition exposure 5.2\u00b11.3% (obesity), 6.7\u00b13.5% (hypertension), and 9.0\u00b11.1% (diabetes;\n              <jats:italic>P<\/jats:italic>\n              &lt;0.001). Moreover, HFpEF-related conditions led to an increase in passive force compared with control (7.52\u00b11.08 versus 2.33\u00b10.46 mN\/mm,\n              <jats:italic>P<\/jats:italic>\n              &lt;0.001), whereas no significant alterations were noted in active contractile forces. Relaxation constant \u03c4 was significantly prolonged after exposure to HFpEF conditions showing a prolongation of 95.9 ms (36.4\u2013106.4;\n              <jats:italic>P<\/jats:italic>\n              =0.028) compared with a shortening of 35.6 ms (43.3\u201367.3;\n              <jats:italic>P<\/jats:italic>\n              =0.80) in the control. Finally, organoid exposure to HFpEF conditions led to a significant increase in oxidative stress levels and a significant decline in oxygen consumption rate.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>We established a novel, human, in vitro model for HFpEF, based on comorbidity-inspired conditions. The model faithfully recapitulated the structural, functional, and mechanistic features of HFpEF. This model holds the potential to provide mechanistic insights and facilitate the identification of novel therapeutic targets.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circheartfailure.124.011690","type":"journal-article","created":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T10:00:19Z","timestamp":1738058419000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":14,"title":["Modeling Heart Failure With Preserved Ejection Fraction Using Human Induced Pluripotent Stem Cell\u2013Derived Cardiac Organoids"],"prefix":"10.1161","volume":"18","author":[{"given":"Idan Refael","family":"Haim","sequence":"first","affiliation":[{"name":"Bruce Rapport Faculty of Medicine, Technion\u2013Israel Institute of Technology, Haifa, Israel (I.R.H., N.K., C.B., O.C.)."},{"name":"The Clinical Research Institute at Rambam, Haifa, Israel (I.R.H., A.G., N.K., C.B., H.L.K., O.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6366-3093","authenticated-orcid":true,"given":"Amit","family":"Gruber","sequence":"additional","affiliation":[{"name":"The Clinical Research Institute at Rambam, Haifa, Israel (I.R.H., A.G., N.K., C.B., H.L.K., O.C.)."},{"name":"The Heart Failure Unit, Department of Cardiology, Rambam Health Care Campus, Haifa, Israel (A.G., H.L.K., O.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noam","family":"Kazma","sequence":"additional","affiliation":[{"name":"Bruce Rapport Faculty of Medicine, Technion\u2013Israel Institute of Technology, Haifa, Israel (I.R.H., N.K., C.B., O.C.)."},{"name":"The Clinical Research Institute at Rambam, Haifa, Israel (I.R.H., A.G., N.K., C.B., H.L.K., O.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Bashai","sequence":"additional","affiliation":[{"name":"Bruce Rapport Faculty of Medicine, Technion\u2013Israel Institute of Technology, Haifa, Israel (I.R.H., N.K., C.B., O.C.)."},{"name":"The Clinical Research Institute at Rambam, Haifa, Israel (I.R.H., A.G., N.K., C.B., H.L.K., O.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hava","family":"Lichtig Kinsbruner","sequence":"additional","affiliation":[{"name":"The Clinical Research Institute at Rambam, Haifa, Israel (I.R.H., A.G., N.K., C.B., H.L.K., O.C.)."},{"name":"The Heart Failure Unit, Department of Cardiology, Rambam Health Care Campus, Haifa, Israel (A.G., H.L.K., O.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2464-7357","authenticated-orcid":true,"given":"Oren","family":"Caspi","sequence":"additional","affiliation":[{"name":"Bruce Rapport Faculty of Medicine, Technion\u2013Israel Institute of Technology, Haifa, Israel (I.R.H., N.K., C.B., O.C.)."},{"name":"The Clinical Research Institute at Rambam, Haifa, Israel (I.R.H., A.G., N.K., C.B., H.L.K., O.C.)."},{"name":"The Heart Failure Unit, Department of Cardiology, Rambam Health Care Campus, Haifa, Israel (A.G., H.L.K., 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