# AbstractPurpose of Review To review the evidence supporting the assessment of hepatic venous pressure gradient (HVPG) response to non-selective beta-blockers (NSBB). Recent Findings HVPG response to NSBB reduces the risks of variceal bleeding, hepatic decompensation due to ascites and its complications, and, finally, mortality. In hemodynamic non-responders to NSBB, their effectiveness is suboptimal, although there is increasing evidence for non-hemodynamic effects. Carvedilol may be a good treatment option for patients with nonresponse to conventional NSBB, as it is more potent in decreasing HVPG. Furthermore, hemodynamic non-responders may also benefit from (the addition of) other HVPG-lowering drugs that are in clinical development, and, depending on the setting, complimentary or alternative treatment strategies. Summary Clinical benefits of HVPG response have been established throughout a broad spectrum of advanced chronic liver disease (ACLD) severity, ranging from compensated patients without varices but with clinically significant portal hypertension (CSPH) to subjects with a history of bleeding and/or non-bleeding hepatic decompensation. HVPG-guided NSBB therapy facilitates personalized medicine in patients with ACLD and portal hypertension. Since the clinical use of HVPG measurement is limited by its invasiveness and its availability is mostly restricted to academic centers, the development of non-invasive surrogates of HVPG response is of high clinical relevance.

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We aimed to assess the systemic and hepatic renin-angiotensin-system (RAS) fingerprint in advanced chronic liver disease (ACLD). This prospective study included 13 compensated (cACLD) and 12 decompensated ACLD (dACLD) patients undergoing hepatic venous pressure gradient (HVPG) measurement. Plasma components (all patients) and liver-local enzymes (n = 5) of the RAS were analyzed using liquid chromatography–tandem mass spectrometry. Patients with dACLD had significantly higher angiotensin (Ang) I, Ang II and aldosterone plasma levels. Ang 1–7, a major mediator of the alternative RAS, was almost exclusively detectable in dACLD (n = 12/13; vs. n = 1/13 in cACLD). Also, dACLD patients had higher Ang 1–5 (33.5 pmol/L versus cACLD: 6.6 pmol/L, p < 0.001) and numerically higher Ang III and Ang IV levels. Ang 1–7 correlated with HVPG (ρ = 0.655; p < 0.001), von Willebrand Factor (ρ = 0.681; p < 0.001), MELD (ρ = 0.593; p = 0.002) and interleukin-6 (ρ = 0.418; p = 0.047). Considerable activity of ACE, chymase, ACE2, and neprilysin was detectable in all liver biopsies, with highest chymase and ACE2 activity in cACLD patients. While liver-local classical and alternative RAS activity was already observed in cACLD, systemic activation of alternative RAS components occurred only in dACLD. Increased Ang 1–7 was linked to severe liver disease, portal hypertension, endothelial dysfunction and inflammation.