{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:03:08Z","timestamp":1773100988040,"version":"3.50.1"},"reference-count":112,"publisher":"Ovid Technologies (Wolters Kluwer Health)","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">Heart failure with preserved ejection fraction (HFpEF) currently accounts for more than half of patients with HF, with limited approved evidence\u2010based therapies. HFpEF is a complex multifactorial disease associated with hypertension, obesity, diabetes, and renal dysfunction. In addition to our limited understanding of HFpEF pathophysiology, the development of new therapies is partially hindered by the existing translationally relevant preclinical HFpEF models.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">Here, we report the development of a novel 2\u2010hit HFpEF male mouse model through adding hypertensive stress from the activation of the renin\u2010angiotensin\u2010aldosterone system with adeno\u2010associated viral\u2010renin (AAV\u2010renin), to the metabolic syndrome nonalcoholic steatohepatitis (MSNASH, formerly FATZO) mouse (MSNASH+AAV\u2010renin). To further demonstrate model translatability, MSNASH+AAV\u2010renin mice were then treated with approved HFpEF therapies sacubitril\/valsartan or a combination of sacubitril\/valsartan and empagliflozin. We found that the MSNASH+AAV\u2010renin mouse model demonstrates clinically relevant features of human HFpEF, including preserved ejection fraction, cardiac hypertrophy, left atrial enlargement, diastolic dysfunction, elevated natriuretic peptides, inflammation, and low exercise capacity. We also demonstrate that treatment with approved HFpEF therapies sacubitril\/valsartan and the combination of sacubitril\/valsartan with empagliflozin improves the cardiac phenotypes of HFpEF in this model.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">The MSNASH+AAV\u2010renin model faithfully represents a severe cardiometabolic HFpEF phenogroup that can be used as a new tool for HFpEF preclinical research and drug discovery.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.124.035894","type":"journal-article","created":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T11:36:26Z","timestamp":1732275386000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Metabolic Syndrome Nonalcoholic Steatohepatitis Male Mouse With Adeno\u2010Associated Viral Renin as a Novel Model for Heart Failure With Preserved Ejection Fraction"],"prefix":"10.1161","author":[{"given":"Yuji","family":"Shi","sequence":"first","affiliation":[{"name":"Internal Medicine Research Unit Cambridge MA"},{"name":"Pfizer Inc. Cambridge MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"Perez\u2010Bonilla","sequence":"additional","affiliation":[{"name":"Global Discovery, Investigative &amp; Translational Sciences \u2013 Animal Models &amp; Imaging Cambridge MA"},{"name":"Pfizer Inc. Cambridge MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4162-6384","authenticated-orcid":false,"given":"Xian","family":"Chen","sequence":"additional","affiliation":[{"name":"Global Discovery, Investigative &amp; Translational Sciences \u2013 Animal Models &amp; Imaging Cambridge MA"},{"name":"Pfizer Inc. Cambridge MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly","family":"Tam","sequence":"additional","affiliation":[{"name":"Internal Medicine Research Unit Cambridge MA"},{"name":"Pfizer Inc. Cambridge MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mackenzie","family":"Marshall","sequence":"additional","affiliation":[{"name":"Internal Medicine Research Unit Cambridge MA"},{"name":"Pfizer Inc. Cambridge MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1656-296X","authenticated-orcid":false,"given":"Jeffrey","family":"Morin","sequence":"additional","affiliation":[{"name":"Global Discovery, Investigative &amp; Translational Sciences \u2013 Animal Models &amp; Imaging Cambridge MA"},{"name":"Pfizer Inc. Cambridge MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0335-0412","authenticated-orcid":false,"given":"Brianna","family":"LaViolette","sequence":"additional","affiliation":[{"name":"Global Discovery, Investigative &amp; Translational Sciences \u2013 Animal Models &amp; Imaging Cambridge MA"},{"name":"Pfizer Inc. Cambridge MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nouaying R.","family":"Kue","sequence":"additional","affiliation":[{"name":"Internal Medicine Research Unit Cambridge MA"},{"name":"Pfizer Inc. Cambridge MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federico","family":"Damilano","sequence":"additional","affiliation":[{"name":"Internal Medicine Research Unit Cambridge MA"},{"name":"Pfizer Inc. Cambridge MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0268-1391","authenticated-orcid":false,"given":"Russell A.","family":"Miller","sequence":"additional","affiliation":[{"name":"Internal Medicine Research Unit Cambridge MA"},{"name":"Pfizer Inc. Cambridge MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bei B.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Internal Medicine Research Unit Cambridge MA"},{"name":"Pfizer Inc. Cambridge MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2754-828X","authenticated-orcid":false,"given":"Rachel J.","family":"Roth Flach","sequence":"additional","affiliation":[{"name":"Internal Medicine Research Unit Cambridge MA"},{"name":"Pfizer Inc. Cambridge MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5944-6670","authenticated-orcid":false,"given":"Dinesh","family":"Hirenallur\u2010Shanthappa","sequence":"additional","affiliation":[{"name":"Global Discovery, Investigative &amp; Translational Sciences \u2013 Animal Models &amp; Imaging Cambridge MA"},{"name":"Pfizer Inc. Cambridge MA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2024,11,22]]},"reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2021-319605"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-020-0363-2"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurjhf\/hfp103"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa052256"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehab389"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.122.320257"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00380-010-0057-5"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2014.08.036"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2019.09.009"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.327"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.114.010637"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2019-315481"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.050498"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2020.04.006"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1100-z"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-023-01152-0"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2023.131553"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.121.009124"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2016.07.135"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2013.12.031"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.117.029058"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.3390\/jpm11050370"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2022.11.049"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41684-019-0311-0"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00106.2015"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0179856"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12876-019-0958-4"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0179808"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1097\/MNH.0b013e32833aff32"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1746.2008.05461.x"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c130040"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.3390\/metabo12050411"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/2211-5463.12810"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20133182"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2017040385"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00208.2022"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0148010"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1113\/JP280389"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2021.111255"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-201X.2004.01315.x"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00004.2014"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11897-017-0361-9"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.73.5.913"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehz641"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1002\/ehf2.13861"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.034646"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1908655"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2107038"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-022-02546-3"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119171"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2002-220835"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.physbeh.2006.03.028"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2016-0177OC"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ijo.0803110"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.73.12.4633"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/8756-3282(96)00047-6"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.115.4.1168"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.111.5.1514"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.6.12.4236-4243.1986"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.67.4.2083-2090.1993"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvaa256"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.120.317933"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2017.07.013"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.112222199"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0605545103"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjhyper.2003.10.007"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.18.8277"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10741-018-9698-8"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11906-017-0709-2"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2017.04.012"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1097\/HJH.0000000000002910"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.845792"},{"key":"e_1_3_2_74_2","doi-asserted-by":"publisher","DOI":"10.1177\/0963689720920830"},{"key":"e_1_3_2_75_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.118.11065"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0070512"},{"key":"e_1_3_2_77_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehl526"},{"key":"e_1_3_2_78_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-010-1682-3"},{"key":"e_1_3_2_79_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.07.008"},{"key":"e_1_3_2_80_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.121.009101"},{"key":"e_1_3_2_81_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehz552"},{"key":"e_1_3_2_82_2","doi-asserted-by":"publisher","DOI":"10.1042\/CS20180276"},{"key":"e_1_3_2_83_2","doi-asserted-by":"publisher","DOI":"10.1210\/jendso\/bvaa007"},{"key":"e_1_3_2_84_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-201X.2005.01459.x"},{"key":"e_1_3_2_85_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2020.e03208"},{"key":"e_1_3_2_86_2","doi-asserted-by":"publisher","DOI":"10.1080\/10641963.2016.1267196"},{"key":"e_1_3_2_87_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hfc.2014.04.001"},{"key":"e_1_3_2_88_2","doi-asserted-by":"publisher","DOI":"10.1080\/07853890500383895"},{"key":"e_1_3_2_89_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00026.2004"},{"key":"e_1_3_2_90_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI25758"},{"key":"e_1_3_2_91_2","doi-asserted-by":"publisher","DOI":"10.1079\/PNS2004349"},{"key":"e_1_3_2_92_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI114857"},{"key":"e_1_3_2_93_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI111938"},{"key":"e_1_3_2_94_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.1988.255.6.E769"},{"key":"e_1_3_2_95_2","doi-asserted-by":"publisher","DOI":"10.1080\/07853890600888413"},{"key":"e_1_3_2_96_2","doi-asserted-by":"publisher","DOI":"10.1042\/BST0330354"},{"key":"e_1_3_2_97_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0265461"},{"key":"e_1_3_2_98_2","article-title":"Entresto wins first FDA nod in hard\u2010to\u2010treat type of heart failure","author":"Caffrey M","year":"2021","unstructured":"Caffrey M. Entresto wins first FDA nod in hard\u2010to\u2010treat type of heart failure. Am J Manag Care. 2021. Accessed April 1, 2024. https:\/\/www.ajmc.com\/view\/entresto\u2010wins\u2010first\u2010fda\u2010nod\u2010in\u2010hard\u2010to\u2010treat\u2010type\u2010of\u2010heart\u2010failure","journal-title":"Am J Manag Care"},{"key":"e_1_3_2_99_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-019-0322-y"},{"key":"e_1_3_2_100_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22073570"},{"key":"e_1_3_2_101_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2020.07.006"},{"key":"e_1_3_2_102_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-02041-5"},{"key":"e_1_3_2_103_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.117.030012"},{"key":"e_1_3_2_104_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.18463"},{"key":"e_1_3_2_105_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehaa943"},{"key":"e_1_3_2_106_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmg.2021.09.017"},{"key":"e_1_3_2_107_2","doi-asserted-by":"publisher","DOI":"10.1111\/liv.13709"},{"key":"e_1_3_2_108_2","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines10051184"},{"key":"e_1_3_2_109_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2006.05.008"},{"key":"e_1_3_2_110_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11883-004-0030-9"},{"key":"e_1_3_2_111_2","doi-asserted-by":"publisher","DOI":"10.1385\/ENDO:18:3:211"},{"key":"e_1_3_2_112_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0181052"},{"key":"e_1_3_2_113_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.042267"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.124.035894","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T11:36:32Z","timestamp":1732275392000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.124.035894"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,22]]},"references-count":112,"alternative-id":["10.1161\/JAHA.124.035894"],"URL":"https:\/\/doi.org\/10.1161\/jaha.124.035894","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,22]]},"assertion":[{"value":"2024-04-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e035894"}}