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Both models have important limitations with regard to substrain and sex.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The 2-hit model protocol was modified to reproduce HFpEF in both C57BL\/6N and 6J mice by increasing L-NAME doses (0.5\u2005g\/L to 1.75\u2005g\/L) and protocol lengths (7 weeks to 13 weeks). For the 3-hit model, in addition to deoxycorticosterone pivalate (DOCP), we added 1% NaCl drinking water to enhance and prolong the effect of DOCP (\u20184-hit\u2019). To maintain the phenotype, a second bolus of DOCP was administered after 8 weeks.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>HFpEF was successfully induced in C57BL\/6J mice when exposed to a 13-week 2-hit L-NAME protocol with gradually increasing dosage from 1.0 to 1.75\u2005g\/L. For the 4-hit mice, a clear HFpEF phenotype was observed in C57BL\/6N and 6J mice in both male and females, and maintained for up to 12 weeks.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These modifications ensure the 2-hit model is induced in J substrain of C57BL\/6 mice. The 4-hit model prevents aldosterone escape and enhances reproducibility across sexes and substrains.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/eschf\/xvag072","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T12:35:13Z","timestamp":1773146113000},"source":"Crossref","is-referenced-by-count":2,"title":["Optimized murine HFpEF models for translational preclinical studies"],"prefix":"10.1093","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9948-0242","authenticated-orcid":false,"given":"Bailey","family":"McIntosh","sequence":"first","affiliation":[{"name":"School of Life and Environmental Sciences, Faculty of Science, The University of Sydney , Camperdown, New South Wales 2050 ,","place":["Australia"]},{"name":"Cardiometabolic Medicine, Charles Perkins Centre, The University of Sydney , Camperdown, New South Wales 2050 ,","place":["Australia"]},{"name":"Charles Perkins Centre, The University of Sydney , Camperdown, 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Health, The University of Sydney , Camperdown, New South Wales 2050 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewan R","family":"Cameron","sequence":"additional","affiliation":[{"name":"School of Biodiversity One Health and Veterinary Medicine, College of Medical Veterinary & Life Sciences, University of Glasgow , 464 Bearsden Road, Glasgow G61 1QH ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M","family":"Loughrey","sequence":"additional","affiliation":[{"name":"School of Cardiovascular and Metabolic Health, Glasgow Cardiovascular Research Centre, University of Glasgow , 126 University Place, Glasgow G12 8TA ,","place":["UK"]},{"name":"School of Biodiversity One Health and Veterinary Medicine, College of Medical Veterinary & Life Sciences, University of Glasgow , 464 Bearsden Road, Glasgow G61 1QH ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John 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