{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T01:54:57Z","timestamp":1760234097695,"version":"build-2065373602"},"reference-count":60,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T00:00:00Z","timestamp":1618358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL115036","NS089707"],"award-info":[{"award-number":["HL115036","NS089707"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sodium restriction is often recommended in heart failure (HF) to block symptomatic edema, despite limited evidence for benefit. However, a low-sodium diet (LSD) activates the classical renin-angiotensin-aldosterone system (RAAS), which may adversely affect HF progression and mortality in patients with dilated cardiomyopathy (DCM). We performed a randomized, blinded pre-clinical trial to compare the effects of a normal (human-equivalent) sodium diet and a LSD on HF progression in a normotensive model of DCM in mice that has translational relevance to human HF. The LSD reduced HF progression by suppressing the development of pleural effusions (p &lt; 0.01), blocking pathological increases in systemic extracellular water (p &lt; 0.001) and prolonging median survival (15%, p &lt; 0.01). The LSD activated the classical RAAS by increasing plasma renin activity, angiotensin II and aldosterone levels. However, the LSD also significantly up-elevated the counter-regulatory RAAS by boosting plasma angiotensin converting enzyme 2 (ACE2) and angiotensin (1\u20137) levels, promoting nitric oxide bioavailability and stimulating 3\u2032-5\u2032-cyclic guanosine monophosphate (cGMP) production. Plasma HF biomarkers associated with poor outcomes, such as B-type natriuretic peptide and neprilysin were decreased by a LSD. Cardiac systolic function, blood pressure and renal function were not affected. Although a LSD activates the classical RAAS system, we conclude that the LSD delayed HF progression and mortality in experimental DCM, in part through protective stimulation of the counter-regulatory RAAS to increase plasma ACE2 and angiotensin (1\u20137) levels, nitric oxide bioavailability and cGMP production.<\/jats:p>","DOI":"10.3390\/ijms22084035","type":"journal-article","created":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T15:30:39Z","timestamp":1618414239000},"page":"4035","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A Low-Sodium Diet Boosts Ang (1\u20137) Production and NO-cGMP Bioavailability to Reduce Edema and Enhance Survival in Experimental Heart Failure"],"prefix":"10.3390","volume":"22","author":[{"given":"Ranjana","family":"Tripathi","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Arizona College of Medicine\u2013Phoenix, Phoenix, AZ 85004, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7633-2210","authenticated-orcid":false,"given":"Ryan D.","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Arizona College of Medicine\u2013Phoenix, Phoenix, AZ 85004, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tai-Hwang M.","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Radhika M.","family":"Mehta","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Arizona College of Medicine\u2013Phoenix, Phoenix, AZ 85004, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2501-9029","authenticated-orcid":false,"given":"Inna P.","family":"Gladysheva","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Arizona College of Medicine\u2013Phoenix, Phoenix, AZ 85004, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guy L.","family":"Reed","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Arizona College of Medicine\u2013Phoenix, Phoenix, AZ 85004, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,14]]},"reference":[{"key":"ref_1","first-page":"e240","article-title":"2013 ACCF\/AHA guideline for the management of heart failure: A report of the American College of Cardiology Foundation\/American Heart Association Task Force on practice guidelines","volume":"128","author":"Yancy","year":"2013","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/S0140-6736(16)31713-5","article-title":"Dilated cardiomyopathy","volume":"390","author":"Weintraub","year":"2017","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1056\/NEJM199908193410806","article-title":"Hormones and hemodynamics in heart failure","volume":"341","author":"Schrier","year":"1999","journal-title":"N. 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