Assessment of response to beta-blockers by expression of βArr2 and RhoA/ROCK2 in antrum mucosa in cirrhotic patients
Graphical abstract
If varices are present, β-Arrestin2-expression in the gastric antrum mucosal might offer an easy and rapid biomarker to distinguish between responder and non-responder to non-selective beta-blockers (NSBB).
Introduction
Morbidity and mortality of patients with liver cirrhosis and portal hypertension is mainly associated with inflammatory response and infections derived from refractory ascites and variceal bleeding [1], [2], [3]. Non-selective beta-blockers (NSBB), especially propranolol as the most studied one, are the standard of care in the primary and secondary prophylaxis of variceal bleeding [4]. Moreover, NSBB might decrease bacterial translocation in cirrhotic patients [5]. The risk of first bleeding or rebleeding is markedly reduced if the hepatic venous pressure gradient (HVPG) is reduced by ⩾20% or to values ⩽12 mmHg (hemodynamic response) or during acute betablockade using propranolol by >10% [6], [7], [8]. However, NSBB might influence the survival in patients with refractory ascites and therefore should be carefully evaluated in these patients [4], [9], [10]. Only 35–40% of patients are hemodynamic responders to NSBB, but although carvedilol might work in 50% of propranolol non-responders, the non-responders have a worse outcome compared to the responders [11], [12]. In addition, non-responders to NSBB seem to be better of with alternatives to NSBB [12]. Thus, the response to NSBB is a clinically important information, which to date can only be obtained invasively by two HVPG measurements [1]. Moreover, a recent study demonstrated that non-responders often bled before the second HVPG measurement to test the hemodynamic response of NSBB [13]. Therefore, the evaluation of NSBB response during or directly after the upper GI endoscopy, if varices are present, would be clinically helpful.
The mechanism by which NSBB decrease portal pressure and prevent complications, is the decrease in splanchnic hyperperfusion due to decreased cardiac output (CO) and increased splanchnic vascular resistance [14], [15]. It has been previously shown that vascular splanchnic dysfunction is crucially involved in splanchnic hyperperfusion and aggravates portal hypertension [16]. This dysfunction is, at least partly, a result of an imbalance in vasoconstricting and vasodilating pathways. The defective Ras homolog family member A (RhoA)/Rho-kinase (ROCK) pathway together with upregulated beta-arrestin2 (βArr2) blunts contraction [17], [18], [19], [20], [21]. Furthermore, a higher production of nitric oxide (NO) deriving from upregulation of endothelial nitric oxide synthase (eNOS) and iNOS induce exaggerated vasodilatation [22], [23], [24]. Both pathomechanisms lead to arterial hypocontractility and splanchnic hyperperfusion.
Interestingly, splanchnic vascular dysfunction was reflected in expression and activity of these pathways in the gastric antral mucosa of cirrhotic patients, which were partly corrected by transjugular intrahepatic portosystemic shunt (TIPS) after 6 months [25]. In the present study we studied the relation of the expression of specific vasoactive proteins and the response to NSBB treatment in patients with cirrhosis.
Section snippets
Patients and data collection
In this study we enrolled 25 patients with clinically diagnosed liver cirrhosis but without previous variceal bleeding in Hvidovre Hospital, University of Copenhagen, Denmark. All patients received a splanchnic and systemic hemodynamic investigation for evaluation of portal hypertension. Additionally, patients with clinically significant portal hypertension received repeated evaluation at the index catheterization after acute NSBB administration using 0.15 mg/kg bodyweight propranolol infusion
General characteristics of patients
Demographics of patients and controls are shown in Table 1, laboratory parameters in Table 2. Among a total number of 25 patients, etiology of liver cirrhosis was alcohol abuse (n = 19), NASH (n = 2), viral hepatitis (n = 3) and PBC (n = 1). Ten patients showed no CSPH defined as HVPG lower than 10 mmHg, and three patients without CSPH were under NSBB treatment already. Patients with CSPH received acute NSBB challenge. HVPG decreased in seven patients more than 10% after acute NSBB administration and
Discussion
The main findings of the present study are that 1. Mucosal transcription levels of vasoactive proteins are more increased in antrum mucosa than in the rest of the ventricle; 2. Higher transcriptional levels correlate with the degree of portal hypertension; 3. RhoA and ROCK2 transcriptions correlate with the portal pressure response to NSBB challenge, 4. Expression of βArr2, RhoA and ROCK2 are lower in acute non-NSBB responders, and 5. Expression of βArr2 is lower in patients bleeding under NSBB
Financial support
This study was supported by grants from the Deutsche Forschungsgemeinschaft (SFB TRR57 to P18), the H. J. & W. Hector Stiftung and the Capital Region of Denmark Foundation of Health Research and Hvidovre Hospital Foundation for Liver Diseases and the NovoNordisk Foundation, Ernst-Bertha-Grimmke-Stiftung (6/15) and European Union’s Horizon 2020 research and innovation programme (No 668031).
Conflict of interest
The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
Authors’ contributions
Jonel Trebicka: study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, statistical analysis, obtained funding, administrative, technical, and material support, study supervision; Matthias von Heydebrand: acquisition of data, analysis and interpretation of data, drafting of the manuscript, statistical analysis; Jennifer Lehmann: acquisition of data, analysis and
Acknowledgements
The authors thank Gudrun Hack, Silke Bellinghausen, Gitte Fisker Søndergaard, and Katrine Lyngby for excellent technical assistance.
References (31)
- et al.
Complications of cirrhosis. Portal hypertension
J Hepatol
(2000) Baveno VIF. Expanding consensus in portal hypertension report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension
J Hepatol
(2015)- et al.
Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis
J Hepatol
(2013) - et al.
Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage
Gastroenterology
(1990) - et al.
Acute hemodynamic response to beta-blockers and prediction of long-term outcome in primary prophylaxis of variceal bleeding
Gastroenterology
(2009) - et al.
Prognostic value of acute hemodynamic response to i.v. propranolol in patients with cirrhosis and portal hypertension
J Hepatol
(2009) - et al.
Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis
Hepatology
(2003) - et al.
Propranolol – A medical treatment for portal hypertension?
Lancet
(1980) - et al.
The hyperdynamic circulation in cirrhosis: an overview
Pharmacol Ther
(2001) - et al.
Defective RhoA/Rho-kinase signaling contributes to vascular hypocontractility and vasodilation in cirrhotic rats
Gastroenterology
(2006)
Role of aortic nitric oxide synthase 3 (eNOS) in the systemic vasodilation of portal hypertension
Gastroenterology
Role of shear stress in aortic eNOS up-regulation in rats with biliary cirrhosis
Gastroenterology
Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis
Gastroenterology
Future therapy of portal hypertension in liver cirrhosis – A guess
F1000Prime Rep
Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites
Hepatology
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2024, Revista de Gastroenterologia de MexicoPrevention of Variceal Bleeding and Rebleeding by Nonselective Beta-Blockers: A Tailored Approach
2021, Clinics in Liver DiseaseCitation Excerpt :Last, it was shown that MRI-based estimated liver perfusion showed a strong positive correlation with HVPG; however, it remains to be explored in future prospective trials whether MRI perfusion studies are able to predict clinical outcomes.36 Further studies on non–imaging-based HVPG response surrogates have demonstrated that Ras homolog family member A (RhoA) and RhoA-kinase 2 transcription in the antrum mucosa37 as well as serum levels of a phosphatidylcholine and a free fatty acid38 correlated well with acute HVPG-response to intravenous propranolol and, thus, these surrogates warrant further investigation. Importantly, potential predictors that might support clinicians in the evaluation of benefits of NSBB therapy do not solely comprise hemodynamic markers, because beneficial nonhemodynamic effects of NSBB treatment have been reported in previous studies.
Short-term hemodynamic effects of β-blockers influence survival of patients with decompensated cirrhosis
2020, Journal of HepatologyCitation Excerpt :Once collaterals have developed, in addition to reducing portal venous inflow, NSBBs may also induce an increase in portal-collateral resistance which partially offsets the effect on portal pressure.13 The worse response to NSBBs may also be related to more severe vascular dysfunction in decompensated patients, with hypo-contractility induced by a dysregulation of vasoactive proteins, as recently suggested.25 Using a competing-risk analysis, considering death and liver transplantation as competing events, we observed that despite the smaller portal pressure-lowering effect of NSBBs in decompensated cirrhosis, the risk of bleeding was similar in compensated and decompensated patients.
Precision medicine in variceal bleeding: Are we there yet?
2020, Journal of HepatologyCitation Excerpt :Until new data are available, carvedilol cannot be broadly recommended in secondary prophylaxis and efforts to identify the subgroup of patients who may benefit from a more potent portal pressure reduction are strongly needed. Interestingly, as performing HVPG measurements is not widely available, it should be noted that non-invasive methods are being studied in order to evaluate the response to NSBBs and to allow for optimisation of medical therapy without the need to perform HVPG measurements,95,96 although none of these methods can replace HVPG at the moment. Some observational studies in patients with refractory ascites reported that the use of NSBBs in this subpopulation was associated with high mortality and a greater incidence of post-paracentesis circulatory dysfunction.97–99
Emergency TIPS in a Child-Pugh B patient: When does the window of opportunity open and close?
2017, Journal of HepatologyCitation Excerpt :Significantly, systemic activation of vasoconstrictor systems is normalized within six months. Similarly, alterations to intracellular signaling pathways (expression and activation of vasoactive proteins) in different vascular regions lead to better vasoconstriction [22–24]. Earlier findings have demonstrated that TIPS renders a 100% hemodynamic response to NSBB [25].
Beta blockers and cirrhosis, 2016
2017, Digestive and Liver DiseaseCitation Excerpt :Although transient elastography might be useful for monitoring the evolution of portal hypertension after etiological therapy [46], it cannot be used to monitor HVPG-response due to the weak correlation between liver stiffness and HVPG in patients with HVPG values ≥12 mmHg [47]. Recently, Ras homolog family member A (RhoA) and Rho-kinase (ROCK)2 transcription in the antrum mucosa [48] as well as serum levels of two undisclosed lipidic metabolites (area under the receiver operator characteristic curve [95%CI]: 0.872 [0.754–0.989]) [49] were found to be associated with ‘acute’ HVPG-response to i.v. propranolol. The performance of these novel, non-invasive approaches for predicting HVPG-response warrants further evaluation.