Visitors and Sabbaticals

Internationalization is at the core of IBEC’s scientific and training strategy. Actions enhancing IBEC’s international profile are designed to foster exchange in complementary techniques and trigger new collaborations, as well as to place the institute as an international reference centre in bioengineering.

Mobility plays a key role in research training and career development. Interaction with outstanding complementary researchers, either during stays outside IBEC or by bringing people into IBEC, is essential for the training of staff at all levels.

Thanks to existing mobility schemes, IBEC researchers can enjoy intense transnational and multidisciplinary exchange, as well as the expertise and facilities of the best institutions worldwide. In addition, mobility is the seed for future collaboration and joint projects, and serves to expand the international network of research institutions linked to IBEC.

In the framework of the Severo Ochoa programme, IBEC has launched two new internationalization programmes at Group Leader level: the visiting programme for outstanding external researchers, and the sabbatical programme for internal researchers.

Visiting programme

Severo Ochoa Visiting programme for external outstanding researchers

IBEC will implement, starting February 2017, an annual call for IBEC group leaders to propose visitors. In principle, visitors should stay at least three months, unless exceptional circumstances apply.

Candidate should be PIs of their own research lab and have an outstanding international profile. IBEC’s directorate will evaluate the proposals based on the merits of the candidate, the relevance of the project and the added value of the stay for the hosting research group and IBEC.

Depending on the number of proposals positively evaluated and the complementary cofunding secured by the candidate/group leader, IBEC will co‐fund each visitor’s stay. The level of cofunding will range from the travel expenses to come to Barcelona, to a stipend of 2.000€ per month for three months.

In every case, IBEC will provide its selected visitors with office space and the assistance of IBEC’s support staff. Laboratory space, if needed, should be provided by the hosting research group.

During their stay, meetings with interested group leaders will be organized to explore ideas for collaboration, and each visitor will give a seminar to the whole IBEC community to present their research.

At the end of the stay, the hosting group leader will provide a short report about the activities carried out and the benefits obtained.


  • 2017 call: For stays planned from 1‐3‐2017 to 30‐6‐2018
  • Launch of the call: 21 February 2017
  • Deadline of the call: 5 May 2017
  • 2018 call: For stays planned from 1‐1‐2018 to 30‐6‐2019
  • Launch of the call: 1st December 2017
  • Deadline of the call: 31 January 2018

Application form

Application form: Severo Ochoa Visiting programme for outstanding external researchers

Applications should be sent to together with a CV of the candidate before 31st January 2018. Applications will be evaluated as they are received, so you are encouraged not to wait until the application deadline.

Sabbatical programme

Severo Ochoa Sabbatical programme

** 2nd call opens 1st December 2017 **

IBEC will implement, starting February 2017, an annual call for its Sabbatical Programme for its group leaders, who are encouraged to take sabbatical leave at internationally recognized institutions where they can establish new collaborations and explore unconventional paths that boost their current research.

IBEC’s directorate will evaluate the proposals based on the relevance of the project and the added value of the stay for the group leader and IBEC. In principle, sabbatical leave should last at least three months, unless exceptional circumstances apply.

Depending on the number of proposals positively evaluated, IBEC will co‐fund each sabbatical stay with a maximum of a stipend of 1.000€ per month for six months, plus travel expenses. The funding may be used to cover teaching duties during the stay.

During their sabbatical leave, the group leader will be asked to give a seminar at the hosting institution. At the end of the leave, the group leader will provide a short report about  activities carried out and the benefits obtained, as well as giving a seminar at IBEC about their experience.


  • 2017 call: For sabbatical stays planned from 1‐3‐2017 to 30‐6‐2018
  • Launch of the call: 21 February 2017
  • Deadline of the call: 5 May 2017
  • 2018 call: For sabbatical stays planned from 1‐1‐2018 to 30‐6‐2019
  • Launch of the call: 1st December 2017
  • Deadline of the call: 31 January 2018

Application form

Application form: Severo Ochoa Sabbatical programme

Applications should be sent to before 31st January 2018. Applications will be evaluated as they are received, so you are encouraged not to wait until the application deadline.

Visitor profiles

 IBEC group hosts liver specialist

Xavier Trepat’s Integrative Cell and Tissue Dynamics group is hosting Prof. Jonel Trebicka, Head of the University of Bonn’s Laboratory for Liver Fibrosis and Portal Hypertension in its Department of Internal Medicine, during 2017. During his stay, he will study the mechanobiology of stellate cells in liver fibrosis, harnessing the expertise of the IBEC group in cell mechanics and migration, including traction force and confocal microscopy, durotaxis assays and magnetic cytometry.

His stay at IBEC is funded by the foundation EF-CLIF, the European Foundation for the Study of Chronic Liver Failure.

Former visitors

IBEC group collaborates with microfluidics expert on intelligent delivery systems

Prof. Dong-Pyo Kim, Head of the Center of Intelligent Microfluidic Pharmaceutical Synthesis at POSTECH (Pohang University of Science & Technology) in Korea is spending a six-month research stay in Samuel Sánchez’s Smart nano-bio-devices group at IBEC.

Prof Kim is a world expert in microfluidics, and his collaboration with the IBEC group will aim to develop unique functional drug delivery systems that take advantage of the excellent heat/mass transfer in microfluidics. The ultimate goal of the collaboration will be to develop an intelligent synthetic microreactor system for highly efficient ‘one-flow’, ‘feed-to-end’ production of active pharmaceutical ingredients.

The work will involve creating a microrobot – for which Samuel’s group is key –that will be synthesized by microfluidic systems and in situ loaded drugs into micro- or nanoscaled carriers with self-actuating functions. It’s hoped that by the end of the project, the researchers will be at the stage of assessing the bot’s function in a biomimetic blood vessel.

Prof Kim, who has also worked in the USA and been a visiting professor in Europe and Japan, is the winner of many accolades including the National Research Foundation (NRF)’s Scientist of the Month in 2016 and the Korean Chemical Society’s Academic Excellence Award in 2017.


Surfaces experts join forces

Fabio Variola, Associate Professor at the University of Ottawa (Canada), is spending 2017 in the Biomimetic Systems for Cell Engineering group. Having created, for the first time ever, a 3-dimensional hierarchical surface that mimics biologically successful life-forms such as marine diatoms or unicellular algae, Dr. Variola is collaborating with Elena Martinez and her group to determine the bioactive properties of this surface.

By working together at IBEC, Dr. Variola’s experimental knowledge of synthetic nanostructured surfaces and Elena’s extensive experience in biomimetic ones is hoped to lead to new advances in understanding nanoscale hierarchical structures in nature, as these underlie the development of both normal and pathological conditions. The ultimate aim is to develop new diagnostic tools and approaches for health-related research.

Visitor publications

Schierwagen, Robert, Alvarez-Silva, Camila, Madsen, Mette Simone Aae, Kolbe, Carl Christian, Meyer, Carsten, Thomas, Daniel, Uschner, Frank Erhard, Magdaleno, Fernando, Jansen, Christian, Pohlmann, Alessandra, Praktiknjo, Michael, Hischebeth, Gunnar T., Molitor, Ernst, Latz, Eicke, Lelouvier, Benjamin, Trebicka, Jonel, Arumugam, Manimozhiyan, (2019). Circulating microbiome in blood of different circulatory compartments Gut In press,

Pose, Elisa, Trebicka, Jonel, Mookerjee, Rajeshwar P., Angeli, Paolo, Ginès, Pere, (2019). Statins: Old drugs as new therapy for liver diseases? Journal of Hepatology 70, (1), 194-202

In addition to lowering cholesterol levels, statins have pleiotropic effects, particularly anti-inflammatory, antiangiogenic, and antifibrotic, that may be beneficial in some chronic inflammatory conditions. Statins have only recently been investigated as a potential treatment option in chronic liver diseases because of concerns related to their safety in patients with impaired liver function. A number of experimental studies in animal models of liver diseases have shown that statins decrease hepatic inflammation, fibrogenesis and portal pressure. In addition, retrospective cohort studies in large populations of patients with cirrhosis and pre-cirrhotic conditions have shown that treatment with statins, with the purpose of decreasing high cholesterol levels, was associated with a reduced risk of disease progression, hepatic decompensation, hepatocellular carcinoma development, and death. These beneficial effects persisted after adjustment for disease severity and other potential confounders. Finally, a few randomised controlled trials have shown that treatment with simvastatin decreases portal pressure (two studies) and mortality (one study). Statin treatment was generally well tolerated but a few patients developed severe side effects, particularly rhabdomyolysis. Despite these promising beneficial effects, further randomised controlled trials in large series of patients with hard clinical endpoints should be performed before statins can be recommended for use in clinical practice.

Magdaleno, Fernando, Schierwagen, R., Uschner, Frank E., Trebicka, J., (2018). “Tipping” extracellular matrix remodeling towards regression of liver fibrosis: novel concepts Minerva Gastroenterologica e Dietologica , 64, (1), 51-61

Fibrosis development was initially conceived as an incessant progressive condition. Nowadays, it has become evident that fibrotic tissue undergoes a continuous two-way process: fibrogenesis and fibrinolysis, characterizing the remodeling of extracellular matrix (ECM). However, in established fibrosis, this two-way process is tipped towards fibrogenesis and this leads to a self-perpetuating accumulation of ECM, a distinct metabolic unit, together with other cells and processes promoting fibrosis deposition. Several mechanisms promote fibrosis regression, such as degradation of ECM, infiltration of restorative macrophages, prevention of the epithelial-mesenchymal transition of hepatocytes, restoration of the liver sinusoidal endothelial cells’ differentiation phenotype, and reversion to quiescence, apoptosis and senescence of hepatic stellate cells (HSC). Hence, fibrosis is the result of an unbalanced two-way process of matrix remodeling. At the late stage of the disease, antifibrotic interventions could become necessary to reverse self-perpetuating fibrogenesis and accelerate regression of fibrosis even if cause and cofactors of hepatic injury have been eliminated. This review outlines some of the important mechanisms leading towards regression of liver fibrosis.

Keywords: Hepatic stellate cells, Extracellular matrix, remodeling, Rho-associated kinases, Janus kinases

Luetkens, Julian A., Klein, Sabine, Traeber, Frank, Schmeel, Frederic C., Sprinkart, Alois M., Kuetting, Daniel L. R., Block, Wolfgang, Hittatiya, Kanishka, Uschner, Frank E., Schierwagen, Robert, Gieseke, Juergen, Schild, Hans H., Trebicka, Jonel, Kukuk, Guido M., (2018). Quantitative liver MRI including extracellular volume fraction for non-invasive quantification of liver fibrosis: a prospective proof-of-concept study Gut 67, (3), 593-594

Quantitative liver MRI including extracellular volume fraction for non-invasive quantification of liver fibrosis: a prospective proof-of-concept study.

Praktiknjo, M., Book, M., Luetkens, J., Pohlmann, A., Meyer, C., Thomas, D., Jansen, C., Feist, A., Chang, J., Grimm, J., Lehmann, J., Strassburg, C. P., Abraldes, J. G., Kukuk, G., Trebicka, J., (2018). Fat-free muscle mass in magnetic resonance imaging predicts acute-on-chronic liver failure and survival in decompensated cirrhosis Hepatology 67, (3), 1014-1026

Muscle mass seems to be a prognostic marker in patients with liver cirrhosis. However, reported methods to quantify muscle mass are heterogeneous, consented cutoff values are missing, and most studies have used computed tomography. This study evaluated fat-free muscle area (FFMA) as a marker of sarcopenia using magnetic resonance imaging (MRI) in patients with decompensated cirrhosis with transjugular intrahepatic portosystemic shunt (TIPS). The total erector spinae muscle area and the intramuscular fat tissue area were measured and subtracted to calculate the FFMA in 116 patients with cirrhosis by TIPS and MRI. The training cohort of 71 patients compared computed tomography–measured transversal psoas muscle thickness with FFMA. In 15 patients MRI was performed before and after TIPS, and in 12 patients follistatin serum measurements were carried out. The results on FFMA were confirmed in a validation cohort of 45 patients. FFMA correlated with follistatin and transversal psoas muscle thickness and showed slightly better association with survival than transversal psoas muscle thickness Gender-specific cutoff values for FFMA were determined for sarcopenia. Decompensation (ascites, overt hepatic encephalopathy) persisted after TIPS in the sarcopenia group but resolved in the nonsarcopenia group. Sarcopenic patients showed no clinical improvement after TIPS as well as higher mortality, mainly due to development of acute-on-chronic liver failure. FFMA was an independent predictor of survival in these patients. Conclusion: This study offers an easy-to-apply MRI-based measurement of fat-free muscle mass as a marker of sarcopenia in decompensated patients; while TIPS might improve sarcopenia and thereby survival, persistence of sarcopenia after TIPS is associated with a reduced response to TIPS and a higher risk of acute-on-chronic liver failure development and mortality.

Jansen, Christian, Möller, Philipp, Meyer, Carsten, Kolbe, Carl Christian, Bogs, Christopher, Pohlmann, Alessandra, Schierwagen, Robert, Praktiknjo, Michael, Abdullah, Zeinab, Lehmann, Jennifer, Thomas, Daniel, Strassburg, Christian P., Latz, Eicke, Mueller, Sebastian, Rössle, Martin, Trebicka, Jonel, (2018). Increase in liver stiffness after transjugular intrahepatic portosystemic shunt is associated with inflammation and predicts mortality Hepatology 67, (4), 1472-1484

Transjugular intrahepatic portosystemic shunt (TIPS) efficiently treats complications of portal hypertension. Liver and spleen stiffness might predict clinically significant portal hypertension. This prospective study investigated liver stiffness in patients receiving TIPS regardless of indication. Of 83 included patients, 16 underwent transient elastography immediately before and 30 minutes after TIPS (acute group), while 67 received shear wave elastography of liver and spleen 1 day before and 7 days after TIPS (chronic group) and were followed further. In blood samples obtained before TIPS from cubital, portal, and hepatic veins, levels of several interleukins (IL1b, IL6, IL8, IL10, IL18) and interferon-gamma were analyzed. In 27 patients (5 acute, 22 chronic), it resulted in an increase in liver stiffness of >10%. In 56 patients, liver stiffness decreased or remained unchanged (<10%). Importantly, spleen stiffness measured by shear wave elastography decreased in all patients (chronic group). None of the clinical or laboratory parameters differed between patients with increase in liver stiffness and those without. Of note, patients with increased liver stiffness showed higher overall and/or hepatic venous levels of proinflammatory cytokines at TIPS and higher incidence of organ failure and worse survival after TIPS. C-reactive protein values and increase of >10% in liver stiffness after TIPS were the only independent predictors of mortality in these patients. Conclusion: This study demonstrates that the presence of systemic inflammation predisposes patients to develop increased liver stiffness after TIPS, a predictor of organ failure and death.

Piano, Salvatore, Schmidt, Hartmut H., Ariza, Xavier, Amoros, Alex, Romano, Antonietta, Hüsing-Kabar, Anna, Solà , Elsa, Gerbes, Alexander, Bernardi, Mauro, Alessandria, Carlo, Scheiner, Bernhard, Tonon, Marta, Maschmeier, Miriam, Solè, Cristina, Trebicka, Jonel, Gustot, Thierry, Nevens, Frederik, Arroyo, Vicente, Gines, Pere, Angeli, Paolo, (2018). Association between grade of acute on chronic liver failure and response to terlipressin and albumin in patients with hepatorenal syndrome Clinical Gastroenterology and Hepatology 16, (11), 1792-1800

Type 1 hepatorenal syndrome (HRS) is the most high-risk type of renal failure in patients with cirrhosis. Terlipressin and albumin are effective treatments for type 1 HRS. However, the effects of acute on chronic liver failure (ACLF) grade on response to treatment are not clear. We aimed to identify factors associated with response to treatment with terlipressin and albumin in patients with type 1 HRS (reduction in serum level of creatinine to below 1.5 mg/dL at the end of treatment) and factors associated with death within 90 days of HRS diagnosis (90-day mortality).

Luetkens, Julian, A., Klein, Sabine, Träber, Frank, Schmeel, Frederic, C. , Sprinkart, Alois M., Kuetting, Daniel L. R., Block, Wolfgang, Uschner, Frank E., Schierwagen, Robert, Hittatiya, Kanishka, Kristiansen, Glen, Gieseke, Juergen, Schild, Hans, H., Trebicka, Jonel, Kukuk, G.M., (2018). Quantification of liver fibrosis at T1 and T2 mapping with extracellular volume fraction MRI: Preclinical results Radiology 288, (3), 748-754

In our animal study, quantitative liver MRI including extracellular volume fraction appears to be a valuable and new diagnostic tool for the detection and quantification of diffuse liver fibrosis. Purpose: To evaluate MRI T1 and T2 mapping with calculation of extracellular volume (ECV) for diagnosis and grading of liver fibrosis. Materials and Methods: Different grades of fibrosis were induced in 60 male Sprague-Dawley rats by bile duct ligation (BDL) and carbon-tetrachloride (CCl4) intoxication. Portal pressure was measured invasively, whereas hepatic fibrosis was quantified by hydroxyproline content, Sirius red staining, and α smooth muscle actin staining. T1 values, T2 values, and ECV were assessed by using quantitative MRI mapping techniques. Results: T1 values in animals 4 weeks after BDL were greater than in control animals (718 msec ± 74 vs 578 msec ± 33, respectively; P < .001). T2 values at 4 weeks were also greater in animals that underwent BDL than in control animals (46 msec ± 6 vs 29 msec ± 2, respectively; P < .001). Similar T1 and T2 findings were observed after CCl4 intoxication. ECV was greater in animals 4 weeks after BDL compared with control animals (31.3% ± 1.3 vs 18.2% ± 3.5, respectively; P < .001), with similar results after CCl4 intoxication. High correlations were found between ECV and hepatic hydroxyproline content (BDL: r = 0.68, P < .001; CCl4: r = 0.65, P < .001), Sirius red staining (BDL: r = 0.88, P < .001; CCl4: r = 0.82, P < .001), α smooth muscle actin staining (BDL: r = 0.70, P < .001; CCl4: r = 0.73, P < .001), and portal pressure (BDL: r = 0.54, P = .003; CCl4: r = 0.39, P = .043). Conclusion: Elevation of T1 and T2 values and ECV was associated with severity of liver fibrosis and portal hypertension in an experimental animal model.

Lehmann, Jennifer M., Claus, Karina, Jansen, Christian, Pohlmann, Alessandra, Schierwagen, Robert, Meyer, Carsten, Thomas, Daniel, Manekeller, Steffen, Claria, Joan, Strassburg, Christian P., Trautwein, Christian, Wasmuth, Hermann E., Berres, Marie-Luise, Trebicka, Jonel, (2018). Circulating CXCL10 in cirrhotic portal hypertension might reflect systemic inflammation and predict ACLF and mortality Liver International 38, (5), 875-884

Background & Aims: CXCR% ligands play an important role in hepatic injury, inflammation and fibrosis. While CXCL9 and CXCL11 are associated with survival in patients receiving transjugular intrahepatic portosystemic shunt (TIPS), the role of CXCL10 in severe portal hypertension remains unknown. Methods: A total of 89 cirrhotic patients were analysed. CXCL10 protein levels were measured in portal and hepatic blood at TIPS insertion and 2 weeks later in 24 patients. CXCL10 and IL8 levels were assessed in portal, hepatic, cubital vein and right atrium blood in a further 25 patients at TIPS insertion. Furthermore, real‐time PCR determined hepatic CXCL10‐mRNA in 40 cirrhotic patients. Results: Hepatic CXCL10 showed no association with decompensation. By contrast, circulating CXCL10‐levels were higher in portal than in hepatic vein blood, suggesting an extrahepatic source of CXCL10 in cirrhosis. However, CXCL10 protein in blood samples from portal, hepatic, cubital veins and right atrium correlated excellently with each other and with IL‐8 levels. Higher CXCL10 circulating levels were associated with presence of ascites and higher Child scores. Higher CXCL10 circulating protein levels were associated with acute decompensation, acute‐on‐chronic liver failure (ACLF) and independently with mortality. Moreover, a decrease in CXCL10 protein levels after TIPS insertion was associated with better survival in each cohort and analysed together. Discussion: Circulating CXCL10 possibly reflects systemic inflammation and it is correlated with acute decompensation, ACLF and complications in patients with severe portal hypertension receiving TIPS. CXCL10 predicts survival in these patients and a decrease in CXCL10 after TIPS may be considered a good prognostic factor.

Ruiz-Margáin, Astrid, Pohlmann, Alessandra, Ryan, Patrick, Schierwagen, Robert, Chi-Cervera, Luis A., Jansen, Christian, Mendez-Guerrero, Osvely, Flores-García, Nayelli C., Lehmann, Jennifer, Torre, Aldo, Macías-Rodríguez, Ricardo Ulises, Trebicka, Jonel, (2018). Fibroblast growth factor 21 is an early predictor of acute-on-chronic liver failure in critically ill patients with cirrhosis Liver Transplantation 24, (5), 595-605

Acute-on-chronic liver failure (ACLF) develops in acute decompensation (AD) of cirrhosis and shows high mortality. In critically ill patients, early diagnosis of ACLF could be important for therapeutic decisions (eg, renal replacement, artificial liver support, liver transplantation). This study evaluated fibroblast growth factor 21 (FGF21) as a marker of mitochondrial dysfunction in the context of ACLF. The study included 154 individuals (112 critically patients and 42 healthy controls) divided into a training and a validation cohort. In the training cohort of 42 healthy controls and 34 critically ill patients (of whom 24 were patients with cirrhosis), levels of FGF21, interleukin (IL) 6, and IL8 were measured. In the validation cohort of 78 patients with cirrhosis, 17 patients were admitted with or developed ACLF during follow-up and underwent daily clinical and nutritional assessment. Levels of FGF21 were higher in critically ill patients, especially in patients with cirrhosis admitted to the intensive care unit (ICU). Moreover, FGF21 as well as IL6 and IL8 levels were higher in patients with ACLF, but they did not increase with the severity of ACLF. Interestingly, in the validation cohort, FGF21 was also elevated in the patients who developed ACLF in the next 7 days. In these patients, FGF21 levels were an independent predictor of ACLF presence and development in multivariate analysis together with Child‐Pugh score. FGF21 levels had no impact on the survival of critically ill patients with cirrhosis. In conclusion, this study demonstrates that FGF21 levels are of specific diagnostic value regarding the presence and development of ACLF in patients admitted to ICU for AD of liver cirrhosis. Further studies are warranted to address pathophysiological and possible therapeutic implications.

Jansen, Christian, Cox, Alexander, Schueler, Robert, Schneider, Matthias, Lehmann, Jennifer, Praktiknjo, Michael, Pohlmann, Alessandra, Chang, Johannes, Manekeller, Steffen, Nickenig, Georg, Berlakovich, Gabriela, Strassburg, Christian P., Hammerstingl, Christoph, Staufer, Katharina, Trebicka, Jonel, (2018). Increased myocardial contractility identifies patients with decompensated cirrhosis requiring liver transplantation Liver Transplantation 24, (1), 15-25

Late allocation of organs for transplant impairs post–liver transplantation (LT) survival. Cardiac dysfunction, especially diastolic and autonomic dysfunction, is frequent and plays an important role in the prognosis of patients with cirrhosis. However, the role of myocardial contractility is unexplored, and its prognostic value is controversially discussed. This study analyses the role of myocardial contractility assessed by speckle tracking echocardiography in LT allocation. In total, 168 patients with cirrhosis (training cohort, 111; validation cohort [VC], 57) awaiting LT in 2 centers were included in this retrospective study. Also, 51 patients from the training and all patients from the VC were transplanted, 36 patients of the training and 38 of the VC were alive at the end of follow-up, and 21 nontransplanted patients died. Contractility of the left ventricle (LV) increased with severity of the Child-Pugh score. Interestingly, higher LV contractility in the training cohort patients, especially in those with Child-Pugh C, was an independent predictor of reduced transplant-free survival. In male patients, the effects on survival of increased left and right ventricular myocardial contractility were more pronounced. Notably, competing risk analysis demonstrated that increased contractility is associated with earlier LT, which could be confirmed in the VC. Importantly, LV myocardial contractility had no impact on survival of patients not receiving LT or on post-LT survival. In conclusion, this study demonstrates for the first time that increased myocardial contractility in decompensated patients identifies patients who require LT earlier, but without increased post-LT mortality.

Schwabl, Philipp, Brusilovskaya, Ksenia, Supper, Paul, Bauer, David, Königshofer, Philipp, Riedl, Florian, Hayden, Hubert, Fuchs, Claudia Daniela, Stift, Judith, Oberhuber, Georg, Aschauer, Stefan, Bonderman, Diana, Gnad, Thorsten, Pfeifer, Alexander, Uschner, Frank Erhard, Trebicka, Jonel, Rohr-Udilova, Nataliya, Podesser, Bruno Karl, Peck-Radosavljevic, Markus, Trauner, Michael, Reiberger, Thomas, (2018). The soluble guanylate cyclase stimulator riociguat reduces fibrogenesis and portal pressure in cirrhotic rats Scientific Reports 8, (1), 9372

In cirrhotic patients, portal hypertension (PHT) deteriorates survival, yet treatment options are limited. A major contributor to increased intrahepatic vasoconstriction in PHT is dysfunctional nitric-oxide signaling. Soluble guanylate cyclase (sGC) is the receptor of nitric-oxide and can be stimulated by riociguat. Riociguat is approved for pulmonary hypertension but has not been studied in liver cirrhosis. In this study we assessed the effects of riociguat on PHT and liver fibrosis in cholestatic (bile duct ligation, BDL) and toxic (carbon-tetrachloride, CCl4) rat models. In cirrhotic livers sGC expression was upregulated. In BDL rats, riociguat reduced liver fibrosis and decreased portal pressure without affecting systemic hemodynamics. In an early BDL disease stage, riociguat decreased bile duct proliferation, improved sinusoidal vascular dysfunction and inhibited angiogenesis. In advanced BDL riociguat exhibited anti-inflammatory effects. In CCl4 rats the beneficial effects of riociguat treatment were less pronounced and confined to an early disease stage. Similarly, in patients with cholestatic cirrhosis and PHT nitrates (that induce sGC activity) decreased portal pressure more effectively than in patients with non-cholestatic etiology. We also found an improvement of transaminases in patients with pulmonary hypertension receiving riociguat. Our findings support the clinical development of sGC stimulators in patients with cirrhotic PHT.

Beiert, T., Knappe, V., Tiyerili, V., Stöckigt, F., Effelsberg, V., Linhart, M., Steinmetz, M., Klein, S., Schierwagen, R., Trebicka, J., Roell, W., Nickenig, G., Schrickel, J. W., Andrié, R. P., (2018). Chronic lower-dose relaxin administration protects from arrhythmia in experimental myocardial infarction due to anti-inflammatory and anti-fibrotic properties International Journal of Cardiology 250, 21-28

Background: The peptide hormone relaxin-2 (RLX) exerts beneficial effects during myocardial ischemia, but functional data on lower-dose RLX in myocardial infarction (MI) is lacking. Therefore, we investigated the impact of 75 μg/kg/d RLX treatment on electrical vulnerability and left ventricular function in a mouse model of MI. Methods and results: Standardized cryoinfarction of the left anterior ventricular wall was performed in mice. A two week treatment period with vehicle or RLX via subcutaneously implanted osmotic minipumps was started immediately after MI. The relaxin receptor RXFP1 was expressed on ventricular/atrial cardiomyocytes, myofibroblasts, macrophages and endothelial but not vascular smooth muscle cells of small coronary vessels. RLX treatment resulted in a significant reduction of ventricular tachycardia inducibility (vehicle: 91%, RLX: 18%, p < 0.0001) and increased epicardial conduction velocity in the left ventricle and borderzone. Furthermore, left ventricular function following MI was improved in RLX treated mice (left ventricular ejection fraction; vehicle: 41.1 ± 1.9%, RLX: 50.5 ± 3.5%, p = 0.04). Interestingly, scar formation was attenuated by RLX with decreased transcript expression of connective tissue growth factor. Transcript levels of the pro-inflammatory cytokines interleukin-6 and interleukin-1β were upregulated in hearts of vehicle treated animals compared to mice without MI. Application of RLX attenuated this inflammatory response. In addition, macrophage infiltration was reduced in the borderzone of RLX treated mice. Conclusion: Treatment with lower-dose RLX in mice prevents post-infarction ventricular tachycardia due to attenuation of scar formation and cardiac inflammation. Therefore, RLX could be evaluated as new therapeutic option in the treatment of MI.

Keywords: Arrhythmia, Myocardial infarction, Relaxin-2, Ventricular tachycardia

Trebicka, Jonel, (2018). Non-cirrhotic portal hypertension: A possibly benign but complicated disease Digestive and Liver Disease 50, (8), 845-846

n the last Baveno Consensus Conference held in 2015 a dedicated section described the management of patients with portal vein thrombosis, in presence or absence of cirrhosis [1]. In this specific collective of patients few studies have described their natural history and therefore new studies are urgently needed in order to recommend evidence-based management. So far the recommendation regarding the treatment of complications of portal hypertension are aligned with the recommendation in the presence of cirrhosis.

Anadol, Evrim, Lust, Kristina, Boesecke, Christoph, Schwarze-Zander, Carolynne, Mohr, Raphael, Wasmuth, Jan-Christian, Rockstroh, Jürgen Kurt, Trebicka, Jonel, (2018). Exposure to previous cART is associated with significant liver fibrosis and cirrhosis in human immunodeficiency virus-infected patients PLoS ONE 13, (1), e0191118

Introduction Combined antiretroviral therapy (cART) has improved survival in HIV-patients. While the first antiretrovirals, which became available in particular D-drugs (especially didanosine and stavudine) and unboosted protease inhibitors, may impair liver function, the modern cART seems to decrease liver fibrosis. This study assessed the influence of exposure to previous antiretrovirals on liver fibrosis in HIV-infected patients. Methods This observational cross-sectional single-center study recruited 333 HIV patients and assessed liver fibrosis using transient elastography (TE). Results 83% were male with a median age of 45, while 131 were co-infected with viral hepatitis. Overall, 18% had significant fibrosis and 7.5% had cirrhosis. 11% of HIV mono-infected patients had significant fibrosis and 2% had cirrhosis. HCV infection (OR:5.3), history of exposure to didanosine (OR:2.7) and HIV load below 40copies/mL (OR:0.5) were independently associated with significant fibrosis, while HCV (OR:5.8), exposure to didanosine (OR:2.9) and azidothymidine (OR:2.8) were independently associated with cirrhosis. Interestingly, in HIV mono-infected patients, a HIV-load below 40copies/mL (OR:0.4) was independently associated with significant fibrosis, and didanosine (OR:20.8) with cirrhosis. Conclusion In conclusion, history of exposure to didanosine and azidothymidine continues to have an impact on the presence of liver cirrhosis in HIV patients. However, HCV co-infection and ongoing HIV-replication have the strongest effect on development of significant fibrosis in these patients.

Jansen, Christian, Al-Kassou, Baravan, Lehmann, Jennifer, Pohlmann, Alessandra, Chang, Johannes, Praktiknjo, Michael, Nickenig, Georg, Strassburg, Christian P., Schrickel, Jan W., Andrié, René, Linhart, Markus, Trebicka, Jonel, (2018). Severe abnormal Heart Rate Turbulence Onset is associated with deterioration of liver cirrhosis PLoS ONE 13, (4), e0195631

Background: In patients with liver cirrhosis, cardiac dysfunction is frequent and is associated with increased morbidity and mortality. Cardiac dysfunction in cirrhosis seems to be linked to autonomic dysfunction. This study investigates the role of autonomic dysfunction assessed by Heart Rate Turbulence (HRT) analyses in patients with liver cirrhosis. Methods and patients: Inclusion criteria was (1) diagnosis of cirrhosis by clinical, imaging or biopsy and (2) evaluation by standard 12-lead-ECG and 24h holter monitoring and (3) at least 3 premature ventricular contractions. The exclusion criterion was presence of cardiac diseases, independent of liver cirrhosis. Biochemical parameters were analysed using standard methods. HRT was assessed using Turbulence onset (TO) and slope (TS). The endpoint was deterioration of liver cirrhosis defined as increased MELD and readmission for complications of liver cirrhosis. Results: Out of 122 cirrhotic patients, 82 patients (63% male) with median Child score of 6 (range 5–12) and median MELD score of 10 (range 6–32) were included. Increasing Child score, INR and decreasing albumin were correlated with TO. In addition, decompensated patients with ascites showed more abnormal TO and TS. During the observation period, patients with more abnormal TO showed significantly higher rate of rising MELD Score at 6 months (p = 0.03). Nevertheless, at least in our collective HRT-parameters were not independent predictors of deterioration of cirrhosis.

Lange, C. M., Bechstein, W. O., Berg, T., Engelmann, C., Bruns, T., Canbay, A., Moreau, R., Trebicka, J., (2018). Acute-on-chronic liver failure Visceral Medicine 34, (4), 296-300

Systemic inflammation is a hallmark of (acutely) decompensated liver cirrhosis and in particular of acute-on-chronic liver failure (ACLF). Frequently, it is challenging to discriminate infection from sterile inflammation in these patients. Which patient – in the absence of proven infection – do you treat with antibiotics in these scenarios, and are there any preferred antibiotic regimens?

Trebicka, J., Reiberger, T., Laleman, W., (2018). Gut-liver axis links portal hypertension to acute-on-chronic liver failure Visceral Medicine 34, (4), 270-275

Acute-on-chronic liver failure (ACLF) is considered a distinct syndrome in patients with liver disease, with systemic inflammation playing a central role. Portal hypertension (PHT) is also aggravated by inflammation and may subsequently impact the course of ACLF. PHT is more than just an increase in portal pressure in the portal venous system; it aggravates the course of liver disease and, thus, also facilitates the development of acute decompensation and ACLF. A critical mechanistic link between PHT and ACLF might be the gut-liver axis, which is discussed in this review.

Madsen, Bjørn Stæhr, Trebicka, Jonel, Thiele, Maja, Israelsen, Mads, Arumugan, Manimozhiyan, Havelund, Troels, Krag, Aleksander, (2018). Antifibrotic and molecular aspects of rifaximin in alcoholic liver disease: study protocol for a randomized controlled trial Trials 19, (1), 143

Alcoholic liver disease is the leading cause of cirrhosis worldwide. Due to an increase in alcohol overuse, alcoholic liver disease has become an increased burden on health care systems. Abstinence from alcohol remains the cornerstone of alcoholic liver disease treatment; however, this approach is hampered by frequent relapse and lack of specific therapy for treating advanced cases of liver disease. In the present study, we hypothesized that gut microbiota drive the development of liver fibrosis and that modulation of gut microbiota with the gut-selective, nonabsorbable antibiotic rifaximin attenuates alcoholic liver fibrosis.

Mohr, Raphael, Boesecke, Christoph, Dold, Leona, Schierwagen, Robert, Schwarze-Zander, Carolynne, Wasmuth, Jan-Christian, Weisensee, Insa, Rockstroh, Jürgen Kurt, Trebicka, Jonel, (2018). Return-to-health effect of modern combined antiretroviral therapy potentially predisposes HIV patients to hepatic steatosis Medicine 97, (17), e0462

Prevalence and risk factors for hepatic steatosis (HS) in the human immunodeficiency virus (HIV)-positive population of western countries are controversially discussed and potentially confounded by coinfection with viral hepatitis. Significant HS (more than 10% of hepatocytes) can be accurately assessed using controlled attenuation parameter (CAP) determination. Aim of this study was to assess prevalence and factors associated with significant HS in HIV monoinfected patients. A total of 364 HIV-infected patients (289 monoinfected) were included in this prospective, cross-sectional study. All patients underwent CAP determination. Steatosis was classified as S1 (significant steatosis) with CAP > 238 dB/m, S2 with CAP > 260 dB/m, and S3 with CAP > 292 dB/m. Multivariable logistic regression analyses were performed to assess the factors associated with HS in this cohort. Significant HS was detected in 118 monoinfected patients (149 in the total cohort). In the total cohort as well as in the monoinfected patients alone, HS grade distribution showed a similar pattern (S1:29%, S2:34%, and S3:37%). Interestingly, patients with HS had a longer history of HIV infection and combined antiretroviral therapy (cART). Interalia, age, gender, ethnicity, and metabolic factors were strongly associated with HS, while body mass index (BMI), triglyceride, and glycated hemoglobin (HbA1c) levels were independently associated with significant HS. HS is highly prevalent among HIV monoinfected patients. Although metabolic risk factors, such as obesity and poorly controlled diabetes, are independently associated with HS in HIV monoinfected patients, cART and control of HIV seem to play an indirect role in the development of HS, probably through the return-to-health effect.

Keywords: CAP, cART, HIV monoinfection, liver injury, NAFLD

Laleman, Wim, Claria, Joan, Van der Merwe, Schalk, Moreau, Richard, Trebicka, Jonel, (2018). Systemic inflammation and acute-on-chronic liver failure: Too much, not enough Canadian Journal of Gastroenterology and Hepatology 2018, 1027152

ACLF is a specifc, but complex and multifactorial form of acute decompensation of cirrhosis and is characterized by an extraordinary dynamic natural course, rapidly evolving organ failure, and high short-term mortality. Dysbalanced immune function is central to its pathogenesis and outcome with an initial excessive systemic infammatory response that drives organ failure and mortality. Later in its course, immuno-exhaustion/immunoparalysis prevails predisposing the patient to secondary infectious events and reescalation in end-organ dysfunction and mortality. Te management of patients with ACLF is still poorly defned. However, as its pathophysiology is gradually being unravelled, potential therapeutic targets emerge that warrant further study such as restoring or substituting albumin via plasma exchange or via albumin dialysis and evaluating usefulness of TLR4 antagonists, modulators of gut dysbiosis (pre- or probiotics), and FXR-agonists.

Trebicka, J., Gluud, L. L., (2017). Reply to: “Adding embolization to TIPS implantation: A better therapy to control bleeding from ectopic varices?” Journal of Hepatology 67, (1), 202-203

We would like to thank the Perricone and colleagues for their letter and for the interest in the article “Emergency TIPS in a Child-Pugh B patient: When does the window of opportunity open and close?”.1 The letter raises an important question, namely the management of bleeding from ectopic varices. Bleeding from ectopic varices other than fundic varices represents a rare and challenging complication. Guidance for clinical practice is needed.

Jansen, C., Thiele, M., Verlinden, W., Krag, A., Francque, S., Trebicka, J., (2017). Prediction of presence of oesophageal varices just by shear-wave elastography of the liver and spleen Liver International 37, (9), 1406-1407

Reiberger, T., Trebicka, J., (2017). New liver – Fresh microbiome: Implications on brain function Liver Transplantation 23, (7), 873-874

Schierwagen, R., Uschner, F. E., Magdaleno, F., Klein, S., Trebicka, J., (2017). Rationale for the use of statins in liver disease American Journal of Physiology - Gastrointestinal and Liver Physiology , 312, (5), G407-G412

The evolution of chronic liver injuries from benign and manageable dysfunction to life threatening end-stage liver disease with severe complications renders chronic liver disease a global health burden. Because of the lack of effective medication, transplantation remains the only and final curative option for end-stage liver disease. Since the demand for organ transplants by far exceeds the supply, other treatment options are urgently required to prevent progression and improve end-stage liver disease. Statins are primarily cholesterol-lowering drugs used for primary or secondary prevention of cardiovascular diseases. In addition to the primary effect, statins act beneficially through different pleiotropic mechanisms on inflammation, fibrosis, endothelial function, thrombosis, and coagulation to improve chronic liver diseases. However, concerns remain about the efficacy and safety of statin treatment because of their potential hepatotoxic risks, and as of now, these risks impede broader use of statins in the treatment of chronic liver diseases. The aim of this review is to comprehensively describe the mechanisms by which statins improve prospects for different chronic liver diseases with special focus on the pathophysiological rationale and the clinical experience of statin use in the treatment of liver diseases.

Beiert, T., Tiyerili, V., Knappe, V., Effelsberg, V., Linhart, M., Stöckigt, F., Klein, S., Schierwagen, R., Trebicka, J., Nickenig, G., Schrickel, J. W., Andrié, R. P., (2017). Relaxin reduces susceptibility to post-infarct atrial fibrillation in mice due to anti-fibrotic and anti-inflammatory properties Biochemical and Biophysical Research Communications , 490, (3), 643-649

Background Relaxin-2 (RLX) is a peptide hormone that exerts beneficial anti-fibrotic and anti-inflammatory effects in diverse models of cardiovascular disease. The goal of this study was to determine the effects of RLX treatment on the susceptibility to atrial fibrillation (AF) after myocardial infarction (MI). Methods Mice with cryoinfarction of the left anterior ventricular wall were treated for two weeks with either RLX (75 μg/kg/d) or vehicle (sodium acetate) delivered via subcutaneously implanted osmotic minipumps. Results RLX treatment significantly attenuated the increase in AF-inducibility following cryoinfarction and reduced the mean duration of AF episodes. Furthermore, epicardial mapping of both atria revealed an increase in conduction velocity. In addition to an attenuation of atrial hypertrophy, chronic application of RLX reduced atrial fibrosis, which was linked to a significant reduction in atrial mRNA expression of connective tissue growth factor. Transcript levels of the pro-inflammatory cytokines interleukin-6 and interleukin-1β were reduced in RLX treated mice, but macrophage infiltration into atrial myocardium was similar in the vehicle and RLX treated groups. Conclusion Treatment with RLX in mice after MI reduces susceptibility to AF due to anti-inflammatory and anti-fibrotic properties. Because to these favorable actions, RLX may become a new therapeutic option in the treatment of AF, even when complicating MI.

Keywords: Atrial fibrillation, Atrial fibrosis, Myocardial infarction, Relaxin-2

Schwab, S., Lehmann, J., Lutz, P., Jansen, C., Appenrodt, B., Lammert, F., Strassburg, C. P., Spengler, U., Nischalke, H. D., Trebicka, J., (2017). Influence of genetic variations in the SOD1 gene on the development of ascites and spontaneous bacterial peritonitis in decompensated liver cirrhosis European Journal of Gastroenterology and Hepatology , 29, (7), 800-804

Background The balance between generation and elimination of reactive oxygen species by superoxide dismutase (SOD) is crucially involved in the pathophysiology of liver cirrhosis. Reactive oxygen species damage cells and induce inflammation/fibrosis, but also play a critical role in immune defense from pathogens. As both processes are involved in the development of liver cirrhosis and its complications, genetic variation of the SOD1 gene was investigated. Patients and methods Two SOD1 single nucleotide polymorphisms (rs1041740 and rs3844942) were analyzed in 49 cirrhotic patients undergoing liver transplantation. In addition, 344 cirrhotic patients with ascites were analyzed in a cohort of 521 individuals in terms of the relationship of these polymorphisms with spontaneous bacterial peritonitis (SBP). Results Although rs3844942 showed no associations with complications of cirrhosis, we observed a significant association between rs1041740 and the presence of ascites and SBP in the discovery cohort of patients with cirrhosis. Importantly, the association with SBP was not confirmed in the validation cohort of patients with ascites. By contrast, a trend toward lower SBP rates was observed in carriers of rs1041740. In this cohort, rs1041740 was not associated with survival. Conclusion These data suggest a complex role of SOD1 in different processes leading to complications of liver cirrhosis. rs1041740 might be associated with the development of ascites and possibly plays a role in SBP once ascites has developed.

Keywords: Ascites, Genetic polymorphism, Liver cirrhosis, Reactive oxygen stress, Spontaneous bacterial peritonitis, Superoxide dismutases

Klein, S., Schierwagen, R., Uschner, F. E., Trebicka, J., (2017). Mouse and rat models of induction of hepatic fibrosis and assessment of portal hypertension Fibrosis (Methods in Molecular Biology) (ed. Rittié, L.), Humana Press (New York, USA) 1627, 91-116

Portal hypertension either develops due to progressive liver fibrosis or is the consequence of vascular liver diseases such as portal vein thrombosis or non-cirrhotic portal hypertension. This chapter focuses on different rodent models of liver fibrosis with portal hypertension and also in few non-cirrhotic portal hypertension models. Importantly, after the development of portal hypertension, the proper assessment of drug effects in the portal and systemic circulation should be discussed. The last part of the chapter is dedicated in these techniques to assess the in vivo hemodynamics and the ex vivo techniques of the isolated liver perfusion and vascular contractility.

Keywords: Aortic ring contraction, Bile duct ligation, Carbon tetrachloride, Colored microsphere technique, High-fat diet, Isolated in situ liver perfusion, Methionine-choline-deficient diet, Partial portal vein ligation, Portal hypertension