Effect of ET-A blockade on portal pressure and hepatic arterial perfusion in patients with cirrhosis: A proof of concept study

Abstract

Background/aim: Endothelin causes vasoconstriction via the endothelin-A receptor (ET-A) in the intrahepatic circulation in cirrhosis and its increase leads to portal hypertension. The aim of the study was to investigate the acute effect of a selective ET-A antagonist in patients with portal hypertension and cirrhosis. Methods: Proof-of-concept study with two different substudies: (a) local intrahepatic administration of the ET-A antagonist BQ 123 and (b) systemic oral administration of the ET-A antagonist Ambrisentan. Portal pressure was determined by hepatic venous pressure gradient (HVPG, both substudies) and hepatic arterial blood flow (HABF) by intra-arterial Doppler measurements (substudy 1) before and under the ET-A antagonist. Systemic haemodynamic parameters were measured in substudy 2. Results: Twelve patients (Child-Pugh [CP] B/C n = 7/5) were included in substudy 1 and 14 patients (CP A/B/C n = 4/6/4) in substudy 2. The relative decrease in HVPG was −12.5% (IQR: −40% to 0%; P =.05) in substudy 1 and −5.0% (IQR: −11.5% to 0%; P =.01) in substudy 2. Substudy 1 revealed higher decrease in HVPG in CP B patients. HABF increased significantly and patients without portal pressure decrease showed a higher increase of HABF. Substudy 2 showed a slight decrease in the mean arterial pressure without changes of other systemic haemodynamic parameters. Conclusion: Administration of a selective ET-A antagonist decreases the portal pressure in cirrhotic patients. This decrease was higher in CP B patients and the non-responders showed a higher increase in hepatic arterial flow. Selective ET-A antagonists might be a future treatment option in patients with portal hypertension.