Beta-blockers or Placebo for Primary Prophylaxis (BOPPP) of oesophageal varices: study protocol for a randomised controlled trial.

BACKGROUND: Liver disease is within the top five causes of premature death in adults. Deaths caused by complications of cirrhosis continue to rise, whilst deaths related to other non-liver disease areas are declining. Portal hypertension is the primary sequelae of cirrhosis and is associated with the development of variceal haemorrhage, ascites, hepatic encephalopathy and infection, collectively termed hepatic decompensation, which leads to hospitalisation and mortality. It remains uncertain whether administering a non-selective beta-blocker (NSBB), specifically carvedilol, at an earlier stage, i.e. when oesophageal varices are small, can prevent VH and reduce all-cause decompensation (ACD). METHODS/DESIGN: The BOPPP trial is a pragmatic, multicentre, placebo-controlled, triple-blinded, randomised controlled trial (RCT) in England, Scotland, Wales and Northern Ireland. Patients aged 18 years or older with cirrhosis and small oesophageal varices that have never bled will be recruited, subject to exclusion criteria. The trial aims to enrol 740 patients across 55 hospitals in the UK. Patients are allocated randomly on a 1:1 ratio to receive either carvedilol 6.25 mg (a NSBB) or a matched placebo, once or twice daily, for 36 months, to attain adequate power to determine the effectiveness of carvedilol in preventing or reducing ACD. The primary outcome is the time to first decompensating event. It is a composite primary outcome made up of variceal haemorrhage (VH, new or worsening ascites, new or worsening hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), hepatorenal syndrome, an increase in Child-Pugh grade by 1 grade or MELD score by 5 points, and liver-related mortality. Secondary outcomes include progression to medium or large oesophageal varices, development of gastric, duodenal, or ectopic varices, participant quality of life, healthcare costs and transplant-free survival. DISCUSSION: The BOPPP trial aims to investigate the clinical and cost-effectiveness of carvedilol in patients with cirrhosis and small oesophageal varices to determine whether this non-selective beta-blocker can prevent or reduce hepatic decompensation. There is clinical equipoise on whether intervening in cirrhosis, at an earlier stage of portal hypertension, with NSBB therapy is beneficial. Should the trial yield a positive result, we anticipate that the administration and use of carvedilol will become widespread with pathways developed to standardise the administration of the medication in primary care. ETHICS AND DISSEMINATION: The trial has been approved by the National Health Service (NHS) Research Ethics Committee (REC) (reference number: 19/YH/0015). The results of the trial will be submitted for publication in a peer-reviewed scientific journal. Participants will be informed of the results via the BOPPP website ( www.boppp-trial.org ) and partners in the British Liver Trust (BLT) organisation. TRIAL REGISTRATION: EUDRACT reference number: 2018-002509-78. ISRCTN reference number: ISRCTN10324656. Registered on April 24 2019.

The influence of carvedilol posology timing on clinically significant portal hypertension: insights from elastography measurements.

BACKGROUND AND AIMS: Carvedilol has emerged as the preferred ß-blocker for treating portal hypertension. However, there is still a debate in dosing regimen, with a potential lower bioavailability in once-daily regimens. The aim of this study is to assess the acute effects of carvedilol posology in patients with clinically significant portal hypertension (CSPH), as a surrogate marker of bioavailability. METHODS: In this experimental study, 34 patients with CSPH receiving carvedilol twice daily were asked to suppress the night dose of carvedilol, creating a standardized 24-hour dose interval. Spleen stiffness measurement (SSM) and liver stiffness measurement (LSM) by transient elastography (TE) were performed, with the exact interval between the last carvedilol administration and TE measurements consistently maintained at 24 hours and compared with values prior and under treatment. RESULTS: Thirty-four patients were included, predominantly male (82.9%). SSM after suspending carvedilol for 24 hours [mean, 73.9kPa (SD, 17.0)] was significantly higher ( P < 0.001) than under treatment [mean, 56.3kPa (SD, 13.2)] and was not significantly different ( P = 0.908) from SSM prior to introduction of carvedilol [mean, 74.5kPa (SD, 12.4)]. Differences were also found in stratified analysis for carvedilol dosage, D'Amico classification stages, MELDNa scores, MELD3.0 scores, Child-Pugh class A and CSPH due to alcoholic cirrhosis. LSM after suspension was not significantly different from both under treatment and prior to treatment. CONCLUSION: The differences in SSM after skipping one dose of carvedilol show both the importance of strict adherence to the prescribed dosing regimen to achieve the expected therapeutic benefits and the impact of twice daily prescription in bioavailability throughout the day.

Tofogliflozin Delays Portal Hypertension and Hepatic Fibrosis by Inhibiting Sinusoidal Capillarization in Cirrhotic Rats.

BACKGROUND: Liver cirrhosis leads to portal hypertension (PH) with capillarization of liver sinusoidal endothelial cells (LSECs), although drug treatment options for PH are currently limited. Sodium glucose transporter 2 inhibitors, which are antidiabetic agents, have been shown to improve endothelial dysfunction. We aimed to elucidate the effect of tofogliflozin on PH and liver fibrosis in a rat cirrhosis model. METHODS: Male-F344/NSlc rats repeatedly received carbon tetrachloride (CCl4) intraperitoneally to induce PH and liver cirrhosis alongside tofogliflozin (10 or 20 mg/kg). Portal hemodynamics and hepatic phenotypes were assessed after 14 weeks. An in vitro study investigated the effects of tofogliflozin on the crosstalk between LSEC and activated hepatic stellate cells (Ac-HSC), which are relevant to PH development. RESULTS: Tofogliflozin prevented PH with attenuated intrahepatic vasoconstriction, sinusoidal capillarization, and remodeling independent of glycemic status in CCl4-treated rats. Hepatic macrophage infiltration, proinflammatory response, and fibrogenesis were suppressed by treatment with tofogliflozin. In vitro assays showed that tofogliflozin suppressed Ac-HSC-stimulated capillarization and vasoconstriction in LSECs by enhancing the antioxidant capacity, as well as inhibited the capilliarized LSEC-stimulated contractive, profibrogenic, and proliferative activities of Ac-HSCs. CONCLUSIONS: Our study provides strong support for tofogliflozin in the prevention of liver cirrhosis-related PH.

Impacts of glucagon-like peptide-1 receptor agonists on the risk of adverse liver outcomes in patients with metabolic dysfunction-associated steatotic liver disease cirrhosis and type 2 diabetes.

BACKGROUND/AIMS: We examined the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) initiation on long-term Adverse Liver Outcomes (ALO) in patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) cirrhosis and type 2 diabetes using real-world data from the MarketScan database. METHODS: We conducted a retrospective cohort study of patients with MASLD cirrhosis and type 2 diabetes between 2012 and 2020. Cox proportional hazard models examine the association between GLP-1RAs initiation, modelled as time-dependent, and the risk of ALO, a composite endpoint defined by the first occurrence of hepatic decompensation(s), portal hypertension, hepatocellular carcinoma (HCC) or liver transplantation (LT). We used Overlap Propensity Score Weighting (OPSW) to account for confounding. The study included 459 GLP-1RAs and 4837 non-GLP-1RAs patients. RESULTS: The non-GLP-1RAs patients presented with 1411 (29%) ALO over 7431.7 person years, while GLP-1RAs patients had 32 (7%) ALO over 586.6 person years - risk rate difference 13.5 (95% CI: 11.4-15.7) per 100 person-years. The OPSW-adjusted risk of ALO was reduced by 36% (hazard ratio [HR]: 0.64; 95% CI: 0.54-0.76) in patients with vs. without GLP-1RAs initiation. GLP-1RAs initiation was associated with significant reductions in the adjusted risk of hepatic decompensation (HR: 0.74; 95% CI: 0.61-0.88), portal hypertension (HR: 0.73; 95% CI: 0.60-0.88), HCC (HR: 0.37; 95% CI: 0.20-0.63) and LT (HR: 0.24; 95% CI: 0.12-0.43). CONCLUSION: The use of GLP-1RAs was associated with significant risk reductions in long-term adverse liver outcomes, including hepatic decompensation, portal hypertension, HCC and LT, in MASLD cirrhosis patients with type 2 diabetes.

Beta-blockers and cirrhosis: Striking the right balance.

Decompensated cirrhosis is associated with a significantly increased risk of mortality. Variceal hemorrhage (VH) further increases the risk of mortality, and of future variceal bleed events. Non-selective beta-blockers (NSBBs) are effective therapy for primary and secondary prophylaxis of VH and have become the cornerstone of pharmacologic therapy in cirrhosis. Beta-blockers are associated with reduced overall mortality and GI-bleeding related mortality in patients with decompensated cirrhosis; they may also confer hemodynamically independent beneficial effects. Long-term treatment with beta-blockers may improve decompensation-free survival in compensated cirrhosis with clinically significant portal hypertension (CSPH). Carvedilol more effectively lowers the hepatic vein portal gradient than traditional NSBBs and has been shown to improve survival in compensated cirrhosis. Treatment goals in compensated cirrhosis with CSPH should focus on early utilization of beta-blockers to prevent decompensation and reduce mortality.

Liver-targeted nanoparticles delivering nitric oxide reduce portal hypertension in cirrhotic rats.

Nitric oxide (NO) is a small vasodilator playing a key role in the pathogenesis of portal hypertension. Here, we assessed the potential therapeutic effect of a NO donor targeted to the liver by poly(beta-amino ester) nanoparticles (pBAE NPs) in experimental cirrhosis. Retinol-functionalized NO donor pBAE NPs (Ret pBAE NPs) were synthetized with the aim of actively targeting the liver. Administration of Ret pBAE NPs resulted in uptake and transfection by the liver and spleen. NPs were not found in other organs or the systemic circulation. Treatment with NO donor Ret pBAE NPs (30 mg/ kg body weight) significantly decreased aspartate aminotransferase, lactate dehydrogenase and portal pressure (9.75 ± 0.64 mmHg) compared to control NPs (13.4 ± 0.53 mmHg) in cirrhotic rats. There were no effects on mean arterial pressure and cardiac output. Liver-targeted NO donor NPs reduced collagen fibers and steatosis, activation of hepatic stellate cells and mRNA expression of profibrogenic and proinflammatory genes. Finally, Ret pBAE NPs displayed efficient transfection in human liver slices. Overall, liver-specific NO donor NPs effectively target the liver and mitigated inflammation and portal hypertension in cirrhotic rats. The use of Ret pBAE may prove to be an effective therapeutic strategy to treat advanced liver disease.

Heterogeneity of treatment response to beta-blockers in the treatment of portal hypertension: A systematic review.

BACKGROUND: It has been suggested that a relevant proportion of patients do not respond to nonselective beta-blockers (NSBB)s, which raises questions regarding the need for individualized therapy. The existence of potential heterogeneity in the treatment response can be assessed using the variability ratio (VR) of the outcome measurement (in this case, HVPG) between the treated and placebo groups. We conducted a systematic review and meta-analysis of randomized controlled trials to assess the potential heterogeneity in the portal pressure response to NSBBs. METHODS: After a systematic search, we quantified the heterogeneity of treatment response with the VR between the treatment and control groups, with VR > 1 indicating potential heterogeneity. We used a similar approach to compare carvedilol with propranolol and statins with placebo. RESULTS: We identified 18 studies that included 965 patients. A comparison between beta-blockers and placebo showed a pooled VR of 0.99 (95% CI:0.87-1.14), which suggests a homogeneous HVPG response to NSBB at the individual patient level (ie, no evidence to support that some patients responded to beta-blockers and others did not). For the comparison between carvedilol and propranolol, pooled VR was 0.97 (95% CI 0.82-1.14), suggesting that carvedilol achieves a greater average response (rather than an increase in the proportion of responders). There was no evidence of a heterogeneous response to statins. CONCLUSION: Our analysis did not support the existence of a heterogeneous patient-by-patient response to NSBBs in cirrhosis. These findings challenge the concept of personalized therapy based on portal pressure response and indicate that routine portal pressure measurement may not be necessary to guide NSBB therapy.

Recent advances in promising drugs for primary prevention of gastroesophageal variceal bleeding with cirrhotic portal hypertension.

BACKGROUND: Gastroesophageal variceal bleeding is one of the most severe complications of patients with cirrhosis. Although primary prevention drugs, including non-selective ß-blockers, have effectively reduced the incidence of bleeding, their efficacy is limited due to side effects and related contraindications. With recent advances in precision medicine, precise drug treatment provides better treatment efficacy. DATA SOURCES: Literature search was conducted in PubMed, MEDLINE and Web of Science for relevant articles published up to May 2022. Information on clinical trials was obtained from https://clinicaltrials.gov/ and http://www.chictr.org.cn/. RESULTS: The in-depth understanding of the pathogenesis and advances of portal hypertension has enabled the discovery of multiple molecular targets for promising drugs. According to the site of action, these drugs could be classified into four classes: intrahepatic, extrahepatic, both intrahepatic and extrahepatic targets and others. All these classes of drugs offer advantages over traditional treatments in prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal hypertension. CONCLUSIONS: This review classified and summarized the promising drugs, which prevent gastroesophageal variceal bleeding by targeting specific markers of pathogenesis of portal hypertension, demonstrating the significance of using the precision medicine strategy to discover and develop promising drugs for the primary prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal hypertension.

Recent Advances in the Pathogenesis and Clinical Evaluation of Portal Hypertension in Chronic Liver Disease.

In chronic liver disease, hepatic stellate cell activation and degeneration of liver sinusoidal endothelial cells lead to structural changes, which are secondary to fibrosis and the presence of regenerative nodules in the sinusoids, and to functional changes, which are related to vasoconstriction. The combination of such changes increases intrahepatic vascular resistance and causes portal hypertension. The subsequent increase in splanchnic and systemic hyperdynamic circulation further increases the portal blood flow, thereby exacerbating portal hypertension. In clinical practice, the hepatic venous pressure gradient is the gold-standard measure of portal hypertension; a value of ≥10 mm Hg is defined as clinically significant portal hypertension, which is severe and is associated with the risk of liver-related events. Hepatic venous pressure gradient measurement is somewhat invasive, so evidence on the utility of risk stratification by elastography and serum biomarkers is needed. The various stages of cirrhosis are associated with different outcomes. In viral hepatitis-related cirrhosis, viral suppression or elimination by nucleos(t)ide analog or direct-acting antivirals results in recompensation of liver function and portal pressure. However, careful follow-up should be continued, because some cases have residual clinically significant portal hypertension even after achieving sustained virologic response. In this study, we reviewed the current and future prospects for portal hypertension.

Cediranib ameliorates portal hypertensive syndrome via inhibition of VEGFR-2 signaling in cirrhotic rats.

Portal hypertension (PHT) is a syndrome caused by systemic and portal hemodynamic disturbances with the progression of cirrhosis. However, the exact mechanisms regulating angiogenesis-related responses in PHT remain unclear. Cediranib is a potent inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, exhibiting a greater affinity for VEGFR-2. Liver cirrhosis was induced by common bile duct ligation (BDL) in Sprague-Dawley rats. Sham-operated rats were controls. BDL and sham rats were randomly allocated to receive Cediranib or vehicle after BDL. On the 28th day, portal hypertension related parameters were surveyed. Cediranib treatment could significantly reduce the portal pressure (PP) in BDL rats, while it did not affect the mean arterial pressure (MAP) in sham groups and BDL groups. Cediranib treatment could significantly affect the stroke volume (SV), cardiac output (CO), cardiac index (CI), systemic vascular resistance (SVR), superior mesenteric artery (SMA) flow and SMA resistance in BDL groups and BDL with Cediranib groups. Cediranib treatment could improve the mesenteric vascular remodeling and contractility. Cediranib treatment significantly reduced mesenteric vascular density. And phospho-VEGFR-2 was significantly downregulated by Cediranib. On the other hand, phospho-endothelial Nitric Oxide Synthases (phospho-eNOS) expressions were upregulated. Cediranib not only improved splanchnic hemodynamics, extrahepatic vascular remodeling and vasodilation, but also alleviated intrahepatic fibrosis and collagen deposition significantly. Cediranib treatment could reduce intrahepatic angiogenesis between BDL-vehicle and BDL-Cediranib rats. In conclusion, Cediranib could improve extrahepatic hyperdynamic circulation by inhibiting extrahepatic angiogenesis through inhibition of the VEGFR-2 signaling pathway, portal collateral circulation formation, as well as eNOS-mediated vasodilatation and vascular remodeling, and at the same time, Cediranib improved intrahepatic fibrogenesis and angiogenesis, which together alleviate cirrhotic PHT syndrome.

Atorvastatin for patients with cirrhosis. A randomized, placebo-controlled trial.

BACKGROUND: Patients with cirrhosis and portal hypertension face a high risk of complications. Besides their anti-inflammatory and antifibrotic effects, statins may reduce portal pressure and thus the risk of complications and mortality. We aimed to investigate the effects of atorvastatin on hospital admissions, mortality, inflammation, and lipidomics in cirrhosis with portal hypertension. METHODS: We performed a double-blinded, randomized, placebo-controlled clinical trial among patients with cirrhosis and portal hypertension. Atorvastatin (10-20 mg/d) was administered for 6 months. We measured splanchnic hemodynamics, analyzed inflammatory markers, and performed lipidomics at baseline and after 6 months. RESULTS: Seventy-eight patients were randomized, with 38 patients allocated to atorvastatin and 40 patients to placebo. Fifty-nine patients completed 6 months of intervention. Comparisons between changes in each group were calculated. Liver-related complications and mortality were similar between the groups. The HVPG and Model for End-stage Liver Disease score did not change between groups (p=0.95 and 0.87, respectively). Atorvastatin decreased 3 of 42 inflammatory markers, CD62-L-selectin, matrix metalloproteinases-2, and TNF-α (p-values: 0.005, 0.011, and 0.023, respectively), while lipidomics was not significantly changed. CONCLUSIONS: In patients with cirrhosis, atorvastatin was safe to use, but did not reduce mortality, the risk of liver-related complications, or the HVPG. Atorvastatin induced minor anti-inflammatory effects and minor effects on lipids during a 6-month treatment period.

ß-Blockers in Hepatosplenic Schistosomiasis: A Narrative Review.

Hepatosplenic schistosomiasis (HSS) is a serious complication of chronic schistosomiasis that can result in portal hypertension and variceal bleeding. ß-blockers, a class of medications commonly used to treat hypertension and other cardiovascular conditions, have been investigated for their potential use in preventing variceal bleeding in HSS. Several studies have shown that ß-blockers can reduce portal pressure and prevent variceal bleeding effectively in these patients. However, there are limited data on the long-term efficacy and safety of ß-blockers in this setting, and further research is needed to determine the optimal use of these medications. This review summarizes the evidence supporting current recommendations of ß-blocker use in patients with HSS.

Rituximab and improved nodular regenerative hyperplasia-associated non-cirrhotic liver disease in common variable immunodeficiency: a case report and literature study.

Common variable immunodeficiency (CVID) associated liver disease is an underrecognized and poorly studied non-infectious complication that lacks an established treatment. We describe a CVID patient with severe multiorgan complications, including non-cirrhotic portal hypertension secondary to nodular regenerative hyperplasia leading to diuretic-refractory ascites. Remarkably, treatment with rituximab, administered for concomitant immune thrombocytopenia, resulted in the complete and sustained resolution of portal hypertension and ascites. Our case, complemented with a literature review, suggests a beneficial effect of rituximab that warrants further research.

Reversal of fibrosis and portal hypertension by Empagliflozin treatment of CCl4-induced liver fibrosis: Emphasis on gal-1/NRP-1/TGF-ß and gal-1/NRP-1/VEGFR2 pathways.

To date, liver fibrosis has no clinically approved treatment. Empagliflozin (EMPA), a highly selective sodium-glucose-cotransporter-2 (SGLT2) inhibitor, has shown ameliorative potential in liver diseases without revealing its full mechanisms. Neuropilin-1 (NRP-1) is a novel regulator of profibrogenic signaling pathways related to hepatic stellate cells (HSCs) and hepatic sinusoidal endothelial cells (HSECs) that modulates intrahepatic profibrogenic and angiogenic pathways. Herein, EMPA's antifibrotic potentials and effects on galactin-1 (Gal-1)/NRP-1 signaling pathways have been evaluated in an experimental liver fibrosis rat model by testing different EMPA dose regimens. EMPA treatment brought a dose-dependent decrease in Gal-1/NRP-1 hepatic expression. This was coupled with suppression of major HSCs pro-fibrotic pathways; transforming growth factor-ß (TGF-ß)/TGF-ßRI/Smad2 and platelet-derived growth factor-beta (PDGF-ß) with a diminution of hepatic Col 1A1 level. In addition, EMPA prompted a protuberant suppression of the angiogenic pathway; vascular endothelial growth factor (VEGF)/VEGF-receptor-2 (VEGFR-2)/SH2-Domain Containing Adaptor Protein-B (Shb), and reversal of altered portal hypertension (PHT) markers; endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS). The amelioration of liver fibrosis was coupled with a remarkable improvement in liver aminotransferases and histologic hepatic fibrosis Ishak scores. The highest EMPA dose showed a good safety profile with minimal changes in renal function and glycemic control. Thus, the current study brought about novel findings for a potential liver fibrosis treatment modality via targeting NRP-1 signaling pathways by EMPA.

Proton pump inhibitor treatment aggravates bacterial translocation in patients with advanced cirrhosis and portal hypertension.

IMPORTANCE: Long-term prescription of proton pump inhibitors (PPIs) in patients with cirrhosis is common practice. However, in recent years, several observational studies have reported increased complications and negative prognostic effects of PPI treatment in these patients. Judging the significance of these associations is complicated by the fact that a plausible underlying pathomechanism has not been identified so far. In the present study, we address this important issue by investigating the impact of PPI treatment on subclinical bacterial translocation from the gut into the blood stream in patients with advanced cirrhosis and portal hypertension. Indeed, we report significantly aggravated bacterial translocation in cirrhosis patients receiving PPI treatment. This finding is highly relevant, as bacterial translocation is known to promote the development of complications and impair prognosis in patients with cirrhosis. Hence, the present study could establish a plausible link between PPI treatment and adverse effects in cirrhosis.

Candesartan cilexetil ameliorates NOSTRIN-NO dependent portal hypertension in cirrhosis and ACLF.

In decompensated cirrhosis, the severity of portal hypertension (PHT) is associated with increased hepatic endothelial nitric oxide synthase (eNOS) trafficking inducer (Nostrin), but the mechanism remains unclear. AIM: To investigate: (1) Whether in cirrhosis-PHT models, ± superimposed inflammation to mimic acute-on-chronic liver failure (ACLF) modulates hepatic nitric oxide synthase trafficking inducer (NOSTRIN) expression, nitric oxide (NO) synthesis, and/or endothelial dysfunction (ED); and (2) Whether the "angiotensin II type 1 receptor blocker" candesartan cilexetil (CC) affects this pathway. CD-1 mice received intraperitoneal carbon tetrachloride injections (CCl4 15% v/v in corn oil, 0.5 mL/kg) twice weekly for 12 wk to induce cirrhosis. After 12 wk, mice were randomized to receive 2-wk oral administration of CC (8 mg/kg) ± LPS. At sacrifice, plasma (biochemical indicators, cytokines, and angiotensin II) and liver tissues (histopathology, Sirius-red stains, and molecular studies) were analysed. Moreover, Nostrin gene knockdown was tested in human umbilical vein endothelial cells (HUVECs). When compared to naïve animals, CCl4-treated animals showed markedly elevated hepatic Nostrin expression (P < 0.0001), while hepatic peNOS expression (measure of eNOS activity) was significantly reduced (P < 0.05). LPS challenge further increased Nostrin and reduced peNOS expression (P < 0.05 for both) in cirrhotic animals. Portal pressure and subsequent hepatic vascular resistance were also increased in all cirrhotic animals following LPS challenge. In CCl4 ± LPS-treated animals, CC treatment significantly reduced Nostrin (P < 0.05) and increased hepatic cGMP (P < 0.01). NOSIP, caveolin-1, NFκB, and iNOS protein expression were significantly increased in CCl4-treated animals (P < 0.05 for all). CC treatment non-significantly lowered NOSIP and caveolin-1 expression while iNOS and NFκB expression was significantly reduced in CCl4 + LPS-treated animals (P < 0.05 for both). Furthermore, Nostrin knockdown significantly improved peNOS expression and associated NO synthesis and reduced inflammation in HUVECs. This study is the first to indicate a potential mechanistic role for the Nostrin-eNOS-NO pathway in cirrhosis and ACLF development. Moreover, this pathway provides a potential therapeutic target given the ameliorative response to Candesartan treatment.

Dual angiotensin receptor and neprilysin inhibitor reduced portal pressure through peripheral vasodilatation and decreasing systemic arterial pressure in cirrhotic rats.

BACKGROUND: Portal hypertension develops along with the progression of liver cirrhosis. Natriuretic peptides have been shown to reduce portal pressure but concomitantly activate the renin-angiotensin-aldosterone system (RAAS). Angiotensin receptor-neprilysin inhibitors (ARNIs) upregulate natriuretic peptides and avoid the adverse effects of RAAS activation. ARNIs have been shown to reduce portal pressure in rats with pre-hepatic portal hypertension, which involves relatively little liver injury. This study aimed to evaluate the relevant effects of an ARNI in rats with both liver cirrhosis and portal hypertension. METHODS: Male Sprague-Dawley rats received common bile duct ligation to induce liver cirrhosis and portal hypertension. Sham-operated rats served as surgical controls. All rats were randomly allocated into three groups to receive distilled water (vehicle), LCZ696 (an ARNI), or valsartan for 4 weeks. Portal hypertension and relevant derangements were assessed after treatment. RESULTS: Portal hypertension and hyperdynamic circulation developed in the cirrhotic rats. In the rats with cirrhosis and portal hypertension, both LCZ696 and valsartan reduced portal hypertension, mean arterial pressure, and systemic vascular resistance. The decrease in portal pressure was highly associated with the reduction in arterial pressure and systemic vascular resistance. Blood flow in hepatic, splanchnic, and portosystemic collateral systems was not altered. LCZ696 did not significantly influence liver injury or plasma cytokine levels. Liver fibrosis and splanchnic angiogenesis were not affected. CONCLUSION: ARNI treatment exerted portal pressure lowering effects via peripheral vasodilatation and decreasing systemic arterial pressure in the rats with liver cirrhosis and portal hypertension. Caution should be taken when using ARNIs in liver cirrhosis.