{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T23:10:51Z","timestamp":1791587451107,"version":"4.3.4"},"reference-count":100,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2026,7,21]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>At a time when there was no unifying hypothesis and no broadly effective treatments for heart failure with a preserved ejection fraction (HFpEF), it was proposed that HFpEF represented a multitude of different disorders. Accordingly, characterization of phenotypic heterogeneity was envisioned as a means of identifying novel causal pathways that could lead to new treatments while simultaneously discerning patients who would selectively benefit from a specific therapy. However, efforts over the past decade to characterize phenotypic diversity in diverse and complex ways have not achieved these goals. Subgroup analyses of neutral HFpEF trials have failed to reliably identify responders to treatments. Neither proteomics nor unsupervised cluster analysis across multiple phenotypic domains has yielded reproducible results (even in the same dataset), elucidated novel mechanistic pathways for new drug development, or identified patients most likely to benefit from treatment. In marked contrast to these efforts to characterize phenotypic heterogeneity, large-scale trials in HFpEF enrolled patients using broad eligibility criteria, and they established the benefits of sodium-glucose cotransporter 2 inhibitors and mineralocorticoid receptor antagonists without evidence for subgroup effects. However, it is noteworthy that patients enrolled in recent large-scale HFpEF trials were characterized by general uniformity with respect to the presence of excess adiposity, with central obesity being a feature of the vast majority of enrolled participants. Of note, patients with obesity showed particularly large benefits when treated with effective drugs for HFpEF. These observations raise the possibility that, if these trials had permitted the participation of patients with class III obesity or with lower natriuretic peptide levels, the magnitude of the observed treatment effects might have been greater than originally reported. These findings are consistent with a central role for visceral adiposity (and the secretion of an altered suite of adipokines) in the pathogenesis of HFpEF. Therefore, because the field of HFpEF has a unifying hypothesis (applicable to the large majority of patients), enrolled a broad population of patients in large-scale trials without subgroup interactions, and has several broadly applicable effective treatments (as is true for heart failure with a reduced ejection fraction), the motivation to characterize phenotypic heterogeneity in HFpEF in complex ways may no longer be supported or needed.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.126.079235","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T18:00:22Z","timestamp":1784570422000},"page":"271-287","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Does Characterization of Phenotypic Heterogeneity Provide Mechanistic Insights or Influence the Response to Treatment? Experience in Positive and Neutral Trials in Patients With Heart Failure and a Preserved Ejection Fraction"],"prefix":"10.1161","volume":"154","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1828-2387","authenticated-orcid":true,"given":"Milton","family":"Packer","sequence":"first","affiliation":[{"name":"Baylor Heart and Vascular Institute, Dallas, TX (M.P.)."},{"name":"Imperial College, London, UK (M.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7582-7171","authenticated-orcid":true,"given":"Gabriele G.","family":"Schiattarella","sequence":"additional","affiliation":[{"name":"Max Rubner Center for Cardiovascular Metabolic Renal Research (MRC), Deutsches Herzzentrum der Charit\u00e9 (DHZC), Charit\u00e9-Universit\u00e4tsmedizin Berlin, Germany (G.G.S.)."},{"name":"Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy (G.G.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6333-9496","authenticated-orcid":true,"given":"Mark C.","family":"Petrie","sequence":"additional","affiliation":[{"name":"School of Cardiovascular and Metabolic Health, University of Glasgow, UK (M.C.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3995-2466","authenticated-orcid":true,"given":"Daniel","family":"Burkhoff","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Foundation, New York, NY (D.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7683-4720","authenticated-orcid":true,"given":"Javed","family":"Butler","sequence":"additional","affiliation":[{"name":"Baylor Scott &amp; White Research Institute, Dallas, TX (J.B.)."},{"name":"University of Mississippi School of Medicine, Jackson (J.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1903-0018","authenticated-orcid":true,"given":"Carolyn S.P.","family":"Lam","sequence":"additional","affiliation":[{"name":"Cardiovascular and Metabolic Disorders Programme, Duke\u2013National University of Singapore Medical School (C.S.P.L.)."},{"name":"National Heart Centre Singapore (C.S.P.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7456-1570","authenticated-orcid":true,"given":"Faiez","family":"Zannad","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lorraine, Centres d\u2019Investigation Clinique, INSERM, Centre Hospitalier R\u00e9gional Universitaire de Nancy, France (F.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0885-1953","authenticated-orcid":true,"given":"Muthiah","family":"Vaduganathan","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA (M.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9375-0596","authenticated-orcid":true,"given":"Barry A.","family":"Borlaug","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN (B.A.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0735-1097(92)90167-l"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.2607"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.114.010637"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1908655"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2107038"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2407107"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2410027"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2016.9125"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199610103351504"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2013.04.004"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehl250"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(03)14285-7"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0805450"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2018.14852"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2024.4417"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocp.2023.08.031"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.16641"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.15922"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehw593"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.2805"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehac184"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1510774"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.2024"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehv336"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.124.069340"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehac389"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.123.011381"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-025-03939-6"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocp.2018.11.032"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2017.02.021"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.126.079918"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2025.06.055"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14968"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22031435"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2024.08.021"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2024.1914"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.039586"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2023.1064290"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2508170"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2024.2612"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.122.061828"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2024.0520"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)00016-2"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.124.070870"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.122.059486"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2016.10.047"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1080\/1354750X.2020.1727015"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom12101419"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.116.001633"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2023.08.053"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.123.011208"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.2291"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.045810"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.2709"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.121.009693"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2024.07.013"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.124.038945"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/s44161-024-00516-x"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-98126-1"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.125.013582"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2015.11.012"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvac179"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijop.13246"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11897-023-00615-z"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehaf784.1027"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2022-322181"},{"key":"e_1_3_3_68_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11897-023-00626-w"},{"key":"e_1_3_3_69_2","doi-asserted-by":"publisher","DOI":"10.1002\/ehf2.12660"},{"key":"e_1_3_3_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2019.09.009"},{"key":"e_1_3_3_71_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmg.2021.04.010"},{"key":"e_1_3_3_72_2","doi-asserted-by":"publisher","DOI":"10.1002\/ehf2.13969"},{"key":"e_1_3_3_73_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2023.104795"},{"key":"e_1_3_3_74_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2025.103462"},{"key":"e_1_3_3_75_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2021.01.018"},{"key":"e_1_3_3_76_2","doi-asserted-by":"publisher","DOI":"10.1002\/ehf2.13523"},{"key":"e_1_3_3_77_2","doi-asserted-by":"publisher","DOI":"10.1056\/EVIDoa2300041"},{"key":"e_1_3_3_78_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2024.10.111"},{"key":"e_1_3_3_79_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2025.102714"},{"key":"e_1_3_3_80_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2206286"},{"key":"e_1_3_3_81_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)01643-X"},{"key":"e_1_3_3_82_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehaf057"},{"key":"e_1_3_3_83_2","doi-asserted-by":"publisher","DOI":"10.1002\/ehf2.15396"},{"key":"e_1_3_3_84_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2025.03.530"},{"key":"e_1_3_3_85_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajhb.70165"},{"key":"e_1_3_3_86_2","doi-asserted-by":"publisher","DOI":"10.1002\/osp4.517"},{"key":"e_1_3_3_87_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.123.010618"},{"key":"e_1_3_3_88_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcha.2024.101485"},{"key":"e_1_3_3_89_2","doi-asserted-by":"publisher","DOI":"10.1093\/bjr\/tqae216"},{"key":"e_1_3_3_90_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.2831"},{"key":"e_1_3_3_91_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.3221"},{"key":"e_1_3_3_92_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.123.065134"},{"key":"e_1_3_3_93_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2025.04.059"},{"key":"e_1_3_3_94_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.110.959890"},{"key":"e_1_3_3_95_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.3092"},{"key":"e_1_3_3_96_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2026.103046"},{"key":"e_1_3_3_97_2","doi-asserted-by":"publisher","DOI":"10.1136\/openhrt-2024-002711"},{"key":"e_1_3_3_98_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-023-02836-4"},{"key":"e_1_3_3_99_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12872-021-02080-9"},{"key":"e_1_3_3_100_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2025.08.036"},{"key":"e_1_3_3_101_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2024.02.050"}],"container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCULATIONAHA.126.079235","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T14:10:56Z","timestamp":1789999856000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCULATIONAHA.126.079235"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,21]]},"references-count":100,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,7,21]]}},"alternative-id":["10.1161\/CIRCULATIONAHA.126.079235"],"URL":"https:\/\/doi.org\/10.1161\/circulationaha.126.079235","relation":{},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,21]]},"assertion":[{"value":"2026-01-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}