Hemodynamic and Non-Hemodynamic Effects of Non-Selective Betablockers in Patients with Cirrhosis
Besides portal hypertension (PH), bacterial translocation-induced systemic inflammation (SI) has emerged as a main driver of hepatic decompensation, acute-on-chronic liver failure, and death in patients with advanced chronic liver disease (ACLD). Recently, it has been suggested that in patients with cirrhosis and clinically significant portal hypertension (CSPH), the effects of non-selective betablockers (NSBBs) extend beyond their portal pressure lowering qualities, indicating that NSBBs may not only prevent variceal bleeding, but also have disease-modifying effects. These proposed non-hemodynamic effects encompass their impact on the levels of SI, and thus, endothelial dysfunction, and possibly even liver fibrogenesis/fibrolysis. We aim to evaluate these poorly defined non-hemodynamic effects of non-selective betablockers (NSBBs) in thoroughly characterized patients with cirrhosis and CSPH. Within this project, we will extend a previously established database and biobank of patients with cirrhosis and CSPH ho undergo paired hepatic venous pressure gradient (HVPG) measurements at the Vienna Hepatic Hemodynamic Lab (i.e., the second largest facility of its kind in Europe, which has already published several influential clinical and translational studies on hemodynamic and non-hemodynamic effects of NSBB therapy prior to and under NSBB therapy in order to evaluate its impact on bacterial translocation-induced SI (objective #1) and endothelial dysfunction (objective #2), as well as fibrogenesis and fibrolysis (objective #3). We aspire to obtain a comprehensive characterization of the patients included in this project, investigating well-validated biomarkers of bacterial translocation (lipopolysaccharide-binding protein [LBP]) and SI (white blood cell count [WBC], C-reactive protein [CRP], interleukin-6 [IL-6], and procalcitonin [PCT]), endothelial dysfunction (von Willebrand factor [VWF]), and liver fibrogenesis (enhanced liver fibrosis score [ELF]). These biomarkers will be complemented by a series of additional direct/indirect makers of bacterial translocation and cytokines. Moreover, Nordic Bioscience will provide a sophisticated extracellular matrix marker profile (i.e., protein fingerprint technology) via a scientific collaboration at no cost and will additionally perform experimental assays on VWF release and cleavage. Since our patient cohort will also be characterized in regard to hepatic and systemic hemodynamics and circulatory dysfunction (HVPG, mean arterial pressure [MAP], levels of renin and copeptin) we have the unique opportunity to link the hemodynamic with non-hemodynamic effects of NSBB treatment.
Methods and Skills:
Clinical studies; liver vein catheterization
Jachs M, Hartl L, Schaufler D, Desbalmes C, Simbrunner B, Eigenbauer E, Bauer DJM, Paternostro R, Schwabl P, Scheiner B, Bucsics T, Stättermayer AF, Pinter M, Trauner M, Mandorfer M, Reiberger T. Amelioration of systemic inflammation in advanced chronic liver disease upon beta-blocker therapy translates into improved clinical outcomes. Gut 70: 1758-1767, 2021
Jachs M, Hartl L, Simbrunner B, Bauer D, Paternostro R, Scheiner B, Schwabl P, Stättermayer AF, Pinter M, Eigenbauer E, Quehenberger P, Trauner M, Reiberger T, Mandorfer M. Dereasing von Willebrand factor levels upon nonselective beta blocker therapy indicate a decreased risk of further decompensation, acute-on-chronic liver Failure, and death. Clin Gastroenterol Hepatol 10: S1542-3565, 2021