Jonel Trebicka1, Matthias von Heydebrand2, Jennifer Lehmann2, Flemming Tofteng3, Troels Busk4, Helle Lone Jensen5, Johan Rohde6, Thomas Reiberger7, Christian Mortensen8, Robert Schierwagen2, Sabine Klein2, Søren Møller4, Flemming Bendtsen3, Aleksander Krag9. 1. Department of Internal Medicine I, University of Bonn, Bonn, Germany; Gastrounit, Medical Division, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Gastroenterology, Odense University Hospital, University of Southern Denmark, Odense, Denmark. Electronic address: jonel.trebicka@ukb.uni-bonn.de. 2. Department of Internal Medicine I, University of Bonn, Bonn, Germany. 3. Gastrounit, Medical Division, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark. 4. Centre of Functional Imaging and Research, Department of Clinical Physiology and Nuclear Medicine, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark. 5. Department of Pathology, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark. 6. Department of Hepatology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 7. Department of Internal Medicine III, Division of Gastroenterology & Hepatology, Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Austria. 8. Gastrounit, Medical Division, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark; Centre of Functional Imaging and Research, Department of Clinical Physiology and Nuclear Medicine, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark. 9. Department of Gastroenterology, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
Abstract
BACKGROUND & AIMS: Non-selective beta-blockers (NSBB) are first choice for prevention of variceal bleeding. But possible deleterious effects in refractory ascites and frequent non-response are clinical drawbacks. Since levels of vasoactive proteins in antrum mucosa reflect vascular dysfunction in cirrhosis, these expression levels might also reflect hemodynamic response to NSBB. METHODS: Biopsies from the gastric and duodenal mucosa of 25 patients with cirrhosis were collected and the hepatic venous pressure gradient (HVPG) was measured before and after an acute propranolol challenge. Transcription and protein expression of Ras homolog family member A (RhoA), Rho-kinase (ROCK)2, beta-arrestin2 (βArr2), endothelial nitric oxide synthase (eNOS) and the phosphorylation of downstream effectors VASP and moesin were analyzed using PCR and Western blot. Further 21 patients on NSBB were evaluated on their follow up for events of variceal bleeding defined as non-response. RESULTS: Ten patients showed HVPG <10mmHg, further seven patients showed significant hemodynamic response to NSBB, whereas eight patients were non-responders. The mucosal transcription of vasoactive proteins was higher in antrum mucosa compared to corpus and duodenum. The transcriptional levels of vasoactive proteins were higher in patients with HVPG >10mmHg and HVPG >16mmHg. Interestingly, mRNA levels of RhoA and ROCK2 were lower in patients with large varices at endoscopy. Moreover, RhoA and ROCK2 transcription correlated with the decrease of HVPG after acute NSBB challenge. Finally, acute and long-term non-responders showed lower expression of βArr2 in antrum mucosa. CONCLUSION: This study shows for the first time that the expression of βArr2 in antrum mucosa biopsies might reflect the hemodynamic response to NSBB and their long-term protective effect. This finding might offer an easy approach at upper endoscopy to facilitate the decision to treat with NSBB if varices are present.
BACKGROUND & AIMS: Non-selective beta-blockers (NSBB) are first choice for prevention of variceal bleeding. But possible deleterious effects in refractory ascites and frequent non-response are clinical drawbacks. Since levels of vasoactive proteins in antrum mucosa reflect vascular dysfunction in cirrhosis, these expression levels might also reflect hemodynamic response to NSBB. METHODS: Biopsies from the gastric and duodenal mucosa of 25 patients with cirrhosis were collected and the hepatic venous pressure gradient (HVPG) was measured before and after an acute propranolol challenge. Transcription and protein expression of Ras homolog family member A (RhoA), Rho-kinase (ROCK)2, beta-arrestin2 (βArr2), endothelial nitric oxide synthase (eNOS) and the phosphorylation of downstream effectors VASP and moesin were analyzed using PCR and Western blot. Further 21 patients on NSBB were evaluated on their follow up for events of variceal bleeding defined as non-response. RESULTS: Ten patients showed HVPG <10mmHg, further seven patients showed significant hemodynamic response to NSBB, whereas eight patients were non-responders. The mucosal transcription of vasoactive proteins was higher in antrum mucosa compared to corpus and duodenum. The transcriptional levels of vasoactive proteins were higher in patients with HVPG >10mmHg and HVPG >16mmHg. Interestingly, mRNA levels of RhoA and ROCK2 were lower in patients with large varices at endoscopy. Moreover, RhoA and ROCK2 transcription correlated with the decrease of HVPG after acute NSBB challenge. Finally, acute and long-term non-responders showed lower expression of βArr2 in antrum mucosa. CONCLUSION: This study shows for the first time that the expression of βArr2 in antrum mucosa biopsies might reflect the hemodynamic response to NSBB and their long-term protective effect. This finding might offer an easy approach at upper endoscopy to facilitate the decision to treat with NSBB if varices are present.
Authors: Benedikt Simbrunner; Andrea Beer; Katharina Wöran; Fabian Schmitz; Christian Primas; Marlene Wewalka; Matthias Pinter; Werner Dolak; Bernhard Scheiner; Andreas Puespoek; Michael Trauner; Georg Oberhuber; Mattias Mandorfer; Thomas Reiberger Journal: Wien Klin Wochenschr Date: 2020-01-07 Impact factor: 1.704
Authors: Robert Schierwagen; Peter Dietrich; Sabine Klein; Frank Erhard Uschner; Cristina Ortiz; Olaf Tyc; Sandra Torres; Claus Hellerbrand; Tilman Sauerbruch; Jonel Trebicka Journal: Proc Natl Acad Sci U S A Date: 2020-11-03 Impact factor: 12.779