{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:17:08Z","timestamp":1785406628972,"version":"3.56.0"},"reference-count":154,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","award":["PNRR-POC-2023-12378186 CUP I73C24000330006"],"award-info":[{"award-number":["PNRR-POC-2023-12378186 CUP I73C24000330006"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"award":["PNRR-POC-2023-12378186 CUP I73C24000330006"],"award-info":[{"award-number":["PNRR-POC-2023-12378186 CUP I73C24000330006"]}],"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Heart failure (HF) classification is still primarily based on left ventricular ejection fraction, even though this parameter only partially reflects the biological mechanisms determining disease progression and therapeutic response. The aim of this review was to present a conceptual interpretive framework that analyzes the HFrEF (heart failure with reduced ejection fraction) and HFmrEF (heart failure with mildly reduced ejection fraction) phenotypes through the lens of the network organization of pathophysiological processes. This review integrates data on molecular and cellular mechanisms, clinical phenotypes, clinical trial results, and therapeutic recommendations. Particular attention was paid to the concepts of network coherence, pathway dominance, and the relationship between the disease\u2019s biological architecture and treatment response. The proposed conceptual framework suggests that HFrEF is more often characterized by a relatively coherent pathophysiological architecture, in which neurohormonal activation, disturbances in calcium metabolism, mitochondrial dysfunction, and extracellular matrix remodeling constitute mutually reinforcing processes. HFmrEF, on the other hand, is presented as a heterogeneous category, encompassing patients with partial improvement of previous systolic dysfunction, patients progressing towards HFrEF, and HFpEF (heart failure with preserved ejection fraction)\u2014like phenotypes associated with inflammation, endothelial dysfunction, microcirculatory disturbances, and metabolic dysregulation. In this approach, therapeutic response depends on whether the targeted pathway occupies a central position in the disease network. This review proposes a hypothesis-generating conceptual framework that complements, rather than replaces, the current ejection fraction-based classification of heart failure. Although the proposed framework requires prospective validation, it may facilitate a more mechanistic interpretation of HF phenotypes, support future biologically informed therapeutic strategies, and stimulate the design of mechanistically oriented clinical studies.<\/jats:p>","DOI":"10.3390\/ijms27146370","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T07:54:13Z","timestamp":1784534053000},"page":"6370","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Heart Failure with Reduced and Mildly Reduced Ejection Fraction: A Network Interpretive Framework of Mechanisms, Phenotypes, and Therapeutic Response"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3464-1645","authenticated-orcid":false,"given":"Beata","family":"Krasi\u0144ska","sequence":"first","affiliation":[{"name":"Department of Hypertensiology, Angiology, and Internal Medicine, Poznan University of Medical Sciences, 61-848 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7141-2561","authenticated-orcid":false,"given":"Giuseppe Maria","family":"Raffa","sequence":"additional","affiliation":[{"name":"Department of Research, IRCCS-ISMETT (Mediterranean Institute for Transplantation and Specialized Therapies), 90127 Palermo, Italy"},{"name":"Department of Precision Medicine in Medical Surgical and Critical Area (Me.Pre.C.C.), University of Palermo, 90134 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6488-1965","authenticated-orcid":false,"given":"Calogera","family":"Pisano","sequence":"additional","affiliation":[{"name":"Department of Research, IRCCS-ISMETT (Mediterranean Institute for Transplantation and Specialized Therapies), 90127 Palermo, Italy"},{"name":"Department of Precision Medicine in Medical Surgical and Critical Area (Me.Pre.C.C.), University of Palermo, 90134 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9643-2697","authenticated-orcid":false,"given":"Vincenzo","family":"Nuzzi","sequence":"additional","affiliation":[{"name":"Department of Clinical Cardiology and Heart Failure, IRCCS ISMETT (Mediterranean Institute for Transplantation and Advanced Specialized Therapies), 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Manca","sequence":"additional","affiliation":[{"name":"Department of Clinical Cardiology and Heart Failure, IRCCS ISMETT (Mediterranean Institute for Transplantation and Advanced Specialized Therapies), 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6563-0877","authenticated-orcid":false,"given":"Krzysztof J.","family":"Filipiak","sequence":"additional","affiliation":[{"name":"The Centre of Postgraduate Medical Education, 99\/103 Marymoncka Street, 01-813 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mansur","family":"Rahnama","sequence":"additional","affiliation":[{"name":"Department of Dental Surgery, Medical University of Lublin, 6 Chod\u017aki Street, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5478-3245","authenticated-orcid":false,"given":"Mariusz","family":"Kowalewski","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Center of Postgraduate Medical Education, Central Clinical Hospital of the Ministry of Interior, 02-507 Warszawa, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2798-1959","authenticated-orcid":false,"given":"Zbigniew","family":"Krasi\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Vascular, Endovascular Surgery, Angiology and Phlebology, Poznan University of Medical Science, \u00bd Dluga Street, 61-848 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Suwalski","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Center of Postgraduate Medical Education, Central Clinical Hospital of the Ministry of Interior, 02-507 Warszawa, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7121-1396","authenticated-orcid":false,"given":"Sebastian","family":"Mertowski","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9530-6659","authenticated-orcid":false,"given":"Paulina","family":"Mertowska","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewelina","family":"Grywalska","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8080-2764","authenticated-orcid":false,"given":"Tomasz","family":"Urbanowicz","sequence":"additional","affiliation":[{"name":"Cardiac Surgery and Transplantology Department, Poznan University of Medical Sciences, \u00bd D\u0142uga, 61-848 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e11","DOI":"10.15420\/cfr.2023.05","article-title":"Global Public Health Burden of Heart Failure: An Updated Review","volume":"9","author":"Shahim","year":"2023","journal-title":"Card. 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