{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T20:29:02Z","timestamp":1791664142929,"version":"4.3.4"},"reference-count":116,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T00:00:00Z","timestamp":1759708800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The nitric oxide (NO) pathway is a fundamental regulator of vascular tone, myocardial function, and inflammation. In heart failure (HF), especially in advanced stages, dysregulation of NO\u2013soluble guanylate cyclase (sGC)\u2013cyclic guanosine monophosphate (cGMP) signaling contributes to endothelial dysfunction, increased vascular resistance, myocardial fibrosis, and impaired cardiac performance. Chronic inflammation further reduces NO bioavailability, exacerbating HF progression This review synthesizes current knowledge on the role of the NO pathway in HF pathophysiology, with a focus on stable and advanced HF. Special attention is given to patient subgroups with comorbidities such as chronic kidney disease, where modulation of NO signaling may be particularly beneficial. We also evaluate therapeutic strategies targeting NO bioavailability and sGC stimulation. Evidence shows that impaired NO signaling promotes systemic and pulmonary vasoconstriction, elevates ventricular afterload, and worsens cardiac remodeling. Pharmacological agents that restore NO levels or activate downstream effectors such as sGC improve vasodilation, reduce fibrosis, and enhance myocardial relaxation. These effects are especially relevant in advanced HF patients and those with renal impairment, who often exhibit limited responses to conventional therapies. The NO pathway represents a promising therapeutic target in both stable and advanced HF. Modulating this pathway could improve outcomes, particularly in complex populations with multiple comorbidities, highlighting the need for further clinical research and tailored treatments.<\/jats:p>","DOI":"10.3390\/biom15101420","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T15:05:06Z","timestamp":1759763106000},"page":"1420","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The NO Pathway as a Target in Patients with Stable and Advanced Heart Failure: An Additional Arrow in Our Quiver!"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5415-1953","authenticated-orcid":false,"given":"Saverio","family":"D\u2019Elia","sequence":"first","affiliation":[{"name":"Cardiology Unit, Azienda Ospedaliera Universitaria Luigi Vanvitelli, 80138 Naples, Italy"},{"name":"Department of Advanced Medical and Surgical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, Piazza Luigi Miraglia, 2, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmine","family":"Gentile","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Achille","family":"Solimene","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Franzese","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ettore","family":"Luisi","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Caiazzo","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Marotta","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6056-7426","authenticated-orcid":false,"given":"Simona","family":"Covino","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7824-6033","authenticated-orcid":false,"given":"Francesco","family":"Natale","sequence":"additional","affiliation":[{"name":"Department of Life Science, Health, and Health Professions, Link Campus University, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco S.","family":"Loffredo","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80138 Naples, Italy"},{"name":"Vanvitelli Cardiology and Intensive 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Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3203","DOI":"10.1073\/pnas.74.8.3203","article-title":"Nitric oxide activates guanylate cyclase and increases guanosine 3\u2032:5\u2032-cyclic monophosphate levels in various tissue preparations","volume":"74","author":"Arnold","year":"1977","journal-title":"Proc. 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