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However, it remains unknown whether classical CHF pharmacotherapy would reverse LSEC defenestration. Herein, we characterized the therapeutic effects of angiotensin-converting enzyme inhibitor (ACE-I)\u2014perindopril\u2014and sodium-glucose cotransporter 2 inhibitor (SGLT2-I)\u2014empagliflozin\u2014on the cardiohepatic axis and, in particular, on LSEC defenestration in the murine model of CHF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Untreated 6-month-old Tg\u03b1q*44 mice exhibited impaired systolic and diastolic cardiac function, impaired liver perfusion, and LSEC defenestration. Perindopril (2 mg\/kg, 8 weeks of treatment, 4- to 6-month-old Tg\u03b1q*44 mice) significantly improved the left ventricular (LV) and right ventricular (RV) systolic function and ameliorated liver perfusion in vivo in Tg\u03b1q*44 mice. Perindopril also displayed a pronounced hepatoprotective effect, as evidenced by proteomic analysis of isolated hepatocytes, reduced total bilirubin, and gamma-glutamyltransferase; however, the number of LSEC fenestrations was unaffected in Tg\u03b1q*44 mice treated with perindopril. Empagliflozin (300 mg\/kg, 8 weeks of treatment, 4- to 6-month-old Tg\u03b1q*44 mice) not only significantly improved LV and RV systolic function and ameliorated liver perfusion but also improved diastolic cardiac function and significantly reduced the defenestration of LSECs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>LSEC defenestration was primarily driven by cardiac diastolic dysfunction, not by impaired liver perfusion or hepatocyte function, and was independent of biomarkers of congestive hepatopathy in the murine model of CHF in Tg\u03b1q*44 mice. As fully reversed by SGLT2-I, but not by ACE-I, LSEC defenestration emerges as a target in the treatment of the cardiohepatic axis in CHF, which is not uniformly improved by CHF pharmacotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvag168","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T11:25:00Z","timestamp":1786361100000},"page":"1992-2008","source":"Crossref","is-referenced-by-count":0,"title":["Liver sinusoidal endothelial cell defenestration in chronic heart failure is primarily dependent on cardiac diastolic dysfunction and is reversed by a sodium-glucose cotransporter 2 inhibitor but not by an angiotensin-converting enzyme inhibitor"],"prefix":"10.1093","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9884-2032","authenticated-orcid":false,"given":"Kamila","family":"Wojnar-Lason","sequence":"first","affiliation":[{"name":"Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University , Krakow, Bobrzynskiego 14, 30-348 Krakow ,","place":["Poland"]},{"name":"Vascular Biology Center, Augusta University, Medical College of Georgia , 1460 Laney Walker Blvd., Augusta, GA 30912 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2291-4068","authenticated-orcid":false,"given":"Marta","family":"Stojak","sequence":"additional","affiliation":[{"name":"Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University , Krakow, Bobrzynskiego 14, 30-348 Krakow ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6783-3590","authenticated-orcid":false,"given":"Grzegorz","family":"Kwiatkowski","sequence":"additional","affiliation":[{"name":"Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University , Krakow, Bobrzynskiego 14, 30-348 Krakow ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5502-200X","authenticated-orcid":false,"given":"Magdalena","family":"Giergiel","sequence":"additional","affiliation":[{"name":"Faculty of Physics, Astronomy and Applied Computer Science, Department of Physics of Nanostructures and Nanotechnology, Jagiellonian University , Lojasiewicza 11, 30-348 Krakow ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2130-0099","authenticated-orcid":false,"given":"Anna","family":"Kurpinska","sequence":"additional","affiliation":[{"name":"Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University , Krakow, Bobrzynskiego 14, 30-348 Krakow ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8228-3416","authenticated-orcid":false,"given":"Urszula","family":"Tyrankiewicz","sequence":"additional","affiliation":[{"name":"Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University , Krakow, Bobrzynskiego 14, 30-348 Krakow ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0391-2502","authenticated-orcid":false,"given":"Marta Z","family":"Pacia","sequence":"additional","affiliation":[{"name":"Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University , Krakow, Bobrzynskiego 14, 30-348 Krakow ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2233-0564","authenticated-orcid":false,"given":"Agnieszka","family":"Kij","sequence":"additional","affiliation":[{"name":"Jagiellonian Centre for 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