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

Liver sinusoidal endothelial cells (LSECs) dysfunction was demonstrated to represent an early and persistent event in chronic heart failure (CHF), preceding congestive hepatopathy and contributing to the pathophysiology of the disease. 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)—perindopril—and sodium-glucose cotransporter 2 inhibitor (SGLT2-I)—empagliflozin—on the cardiohepatic axis and, in particular, on LSEC defenestration in the murine model of CHF.

Untreated 6-month-old Tgαq*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 Tgαq*44 mice) significantly improved the left ventricular (LV) and right ventricular (RV) systolic function and ameliorated liver perfusion in vivo in Tgαq*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 Tgαq*44 mice treated with perindopril. Empagliflozin (300 mg/kg, 8 weeks of treatment, 4- to 6-month-old Tgαq*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.

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 Tgαq*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.