{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T02:32:12Z","timestamp":1789007532788,"version":"build-2803163510"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T00:00:00Z","timestamp":1761696000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"},{"start":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T00:00:00Z","timestamp":1761696000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,12,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Chloride, together with sodium, is one of the major extracellular ions and plays a critical yet often overlooked role in the pathophysiology of heart failure (HF). Beyond its passive role in maintaining electroneutrality and osmotic balance, chloride actively contributes to renal tubular transport via Na+-Cl\u2212 cotransporter (NCC) and Na+-K+-2Cl\u2212 cotransporter (NKCC), regulates acid\u2013base homeostasis through bicarbonate exchange, and modulates neurohormonal activity by influencing renin release at the macula densa. In HF, hypochloraemia (whether dilutional or due to true ionic depletion) activates maladaptive mechanisms including enhanced sodium reabsorption, metabolic alkalosis, and sustained activation of the renin\u2013angiotensin\u2013aldosterone system. These alterations collectively exacerbate fluid retention, promote diuretic resistance, and worsen congestion. Emerging evidence suggests that low serum chloride levels are independently associated with higher mortality, reduced natriuretic response, and poorer decongestion outcomes. This review synthesizes the pathophysiological and clinical significance of chloride in HF and examines emerging therapeutic strategies aimed at restoring chloride homeostasis and improving diuretic response. These include sodium-free chloride formulations, chloride-sparing diuretics, and hypertonic saline solutions, with trials such as SMAC-HF and SALT-HF suggesting clinical benefit, particularly in hypochloraemic patients. Novel technologies, such as automated chloride-balanced diuresis systems, represent a promising tool for individualized fluid management. Recognizing hypochloraemia as a modifiable therapeutic target (rather than a bystander) may lead to a paradigm shift in the approach to congestion and volume overload in HF. A chloride-guided strategy offers the potential for more effective and personalized decongestive therapy.<\/jats:p>","DOI":"10.1002\/ejhf.70081","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T18:29:30Z","timestamp":1761762570000},"page":"3084-3095","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["The Chloride Paradigm Shift in Heart Failure: From Neglected ion to Keystone of Precision Diuretic Therapy"],"prefix":"10.1093","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6548-0805","authenticated-orcid":false,"given":"Jaime","family":"Maz\u00f3n-Ruiz","sequence":"first","affiliation":[{"name":"Nephrology Department, Hospital Carmen y Severo Ochoa , Cangas del Narcea ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9358-7995","authenticated-orcid":false,"given":"Eduardo Josu\u00e9","family":"Banegas-Deras","sequence":"additional","affiliation":[{"name":"Nephrology Department, Hospital Carmen y Severo Ochoa , Cangas del Narcea ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9429-1835","authenticated-orcid":false,"given":"Jose Mar\u00eda","family":"Fern\u00e1ndez-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Internal Medicine Department, Hospital Universitario Central de Asturias , Oviedo ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2935-1272","authenticated-orcid":false,"given":"Mar","family":"Domingo","sequence":"additional","affiliation":[{"name":"Heart Failure Unit, Cardiology Department, Hospital Universitario Germans Trias i Pujol , Badalona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8720-3999","authenticated-orcid":false,"given":"Rafael","family":"de la Espriella","sequence":"additional","affiliation":[{"name":"Cardiology Department, Hospital Cl\u00ednico Universitario, Instituto de Investigaci\u00f3n Sanitaria del Hospital Cl\u00ednico de Valencia (INCLIVA) , Valencia ,","place":["Spain"]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Cardiovasculares (CIBERCV) , Madrid ,","place":["Spain"]},{"name":"Universitat de Val\u00e8ncia , Valencia ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0988-0599","authenticated-orcid":false,"given":"Pau","family":"Ll\u00e0cer","sequence":"additional","affiliation":[{"name":"Internal Medicine Department, Hospital Universitario Ram\u00f3n y Cajal, Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (Irycis) , Madrid ,","place":["Spain"]},{"name":"Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, Universidad de Alcal\u00e1, Alcal\u00e1 de Henares , Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9026-061X","authenticated-orcid":false,"given":"Marta","family":"Cobo-Marcos","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Cardiovasculares (CIBERCV) , Madrid ,","place":["Spain"]},{"name":"Cardiology Department, Hospital Universitario Puerta de Hierro , Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7380-3475","authenticated-orcid":false,"given":"Joan Carles","family":"Trull\u00e0s","sequence":"additional","affiliation":[{"name":"Internal Medicine Department, Hospital d'Olot i comarcal de la Garrotxa , Girona ,","place":["Spain"]},{"name":"Laboratori de Reparaci\u00f3 i Regeneraci\u00f3 Tissular (TR2Lab). Facultat de Medicina, Universitat de Vic\u2014Universitat Central de Catalunya , Carretera de Roda ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9977-7722","authenticated-orcid":false,"given":"Jan","family":"Biegus","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Clinical Department of Intensive Cardiac Care, Wroclaw Medical University, Faculty of Medicine, Institute of Heart Diseases , Wroclaw ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3044-197X","authenticated-orcid":false,"given":"Antoni","family":"Bay\u00e9s-Gen\u00eds","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Cardiovasculares (CIBERCV) , Madrid ,","place":["Spain"]},{"name":"Heart Institute, Hospital Universitari Germans Trias i Pujol, Universitat Autonoma de Barcelona , Barcelona 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