{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T03:14:32Z","timestamp":1783566872865,"version":"3.55.0"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T00:00:00Z","timestamp":1762905600000},"content-version":"vor","delay-in-days":1003,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2023,2,13]],"date-time":"2023-02-13T00:00:00Z","timestamp":1676246400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Boehringer-Ingelheim International GmbH"},{"DOI":"10.13039\/100001003","name":"Boehringer Ingelheim","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001003","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Large outcome studies demonstrated a reduction of heart failure hospitalization or cardiovascular death in patients with chronic heart failure (CHF). The renin\u2013angiotensin system (RAS) is a key player in fluid and sodium regulation. The classic angiotensin-converting enzyme\u2013angiotensin II\u2013angiotensin-1 receptor axis (Ang I\u2013ACE\u2013Ang II receptor axis) is predominantly angiotensin II (Ang-II) induced and promotes vasoconstriction. In contrast, the angiotensin-converting-enzyme-2\u2013angiotensin-(1-7)\u2013Mas axis (Mas-axis) is mediated by the metabolites angiotensin-1-7 (Ang-(1-7)) and angtiotensin-1-5 (Ang-(1-5)) and exerts cardioprotective effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We previously investigated the effect of empagliflozin on the systemic haemodynamic in patients with stable CHF (NYHA II\u2013III) in a randomized placebo-controlled clinical trial \u2018Analysing the Effect of Empagliflozin on Reduction of Tissue Sodium Content in Patients With Chronic Heart Failure (ELSI)\u2019. In a post hoc analysis, we now analysed whether empagliflozin has an effect on the RAS by measuring detailed RAS profiles (LC-MS\/MS-based approach) in 72 patients from ELSI. We compared RAS parameters after 1-month and 3-months treatment with empagliflozin or placebo to baseline. The secondary goal was to analyse whether the effect of empagliflozin on RAS parameters was dependent on angiotensin-receptor-blocking (ARB) or angiotensin-converting-enzyme-inhibitor (ACEI) co-medication.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Empagliflozin medication induced a significant rise in Ang-II [68.5 pmol\/L (21.3\u2013324.2) vs. 131.5 pmol\/L (34.9\u2013564.0), P = 0.001], angiotensin-I (Ang-I) [78.7 pmol\/L (21.5\u2013236.6) vs. 125.9 pmol\/L (52.6\u2013512.9), P &amp;lt; 0.001], Ang-(1-7) [3.0 pmol\/L (3.0\u201315.0) vs. 10.1 pmol\/L (3.0\u201331.3), P = 0.006], and Ang-(1-5) [5.4 pmol\/L (2.0\u201322.9) vs. 9.9 pmol\/L (2.8\u201336.4), P = 0.004], which was not observed in the placebo group (baseline to 3-months treatment). A significant rise in Ang-II (206.4 pmol\/L (64.2\u2013750.6) vs. 568.2 pmol\/L (164.7\u20131616.4), P = 0.001), Ang-(1-7) (3.0 pmol\/L (3.0\u201314.1) vs. 15.0 pmol\/L (3.0\u201331.3), P = 0.017), and Ang-(1-5) [12.2 pmol\/L (3.8\u201346.6) vs. 36.4 pmol\/L (11.1\u201390.7), P = 0.001] under empagliflozin treatment was only seen in the subgroup of patients with ARB co-medication, whereas no change of Ang-II (16.7 pmol\/L (2.0\u201360.8) vs. 26.4 pmol\/L (10.7\u201363.4), P = 0.469), Ang-(1-7) (6.6 pmol\/L (3.0\u201320.7) vs. 10.5 pmol\/L (3.0\u201350.5), P = 0.221), and Ang-(1-5) (2.7 pmol\/L (2.0\u20138.4) vs. 2.8 pmol\/L (2.0\u20136.9), P = 0.851) was observed in patients with empagliflozin that were on ACEI co-medication (baseline to 3-months treatment).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our data indicate that empagliflozin might lead to an activation of both the Ang I\u2013ACE\u2013Ang II receptor axis and the Mas-axis pathway. Activation of the Ang I\u2013ACE\u2013Ang II receptor axis and the protective Mas-axis pathway after initiating treatment with empagliflozin was only seen in patients with ARB co-medication, in contrast to co-medication with ACEI.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ehf2.14313","type":"journal-article","created":{"date-parts":[[2023,2,13]],"date-time":"2023-02-13T23:59:57Z","timestamp":1676332797000},"page":"1635-1642","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Angiotensin Pathways Under Therapy with Empagliflozin in Patients with Chronic Heart Failure"],"prefix":"10.1093","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6952-4660","authenticated-orcid":false,"given":"Agnes","family":"Bosch","sequence":"first","affiliation":[{"name":"Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-N\u00fcrnberg (FAU) , Erlangen 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