The differential activation of cardiovascular hormones across distinct stages of portal hypertension predicts clinical outcomes

Abstract

Background and aims: The cardiovascular hormones renin/angiotensin/aldosterone (RAA), brain-type natriuretic peptide (BNP)and arginine-vasopressin (AVP) are key regulators of systemic circulatory homeostasis in portal hypertension (PH). We assessed (i) the activation of renin, BNP and AVP across distinct stages of PH and (ii) whether activation of these hormones correlates with clinical outcomes.

Methods: Plasma levels of renin, proBNP and copeptin (AVP biomarker) were determined in 663 patients with advanced chronic liver disease (ACLD) undergoing hepatic venous pressure gradient (HVPG) measurement at the Vienna General Hospital between 11/2011 and 02/2019. We stratified for Child stage (A-C), HVPG (6-9 mmHg, 10-15 mmHg, ≥ 16 mmHg) and compensated vs. decompensated ACLD.

Results: With increasing PH, hyperdynamic state was indicated by higher heart rates (6-9 mmHg: median 71.0 [IQR 18.0] bpm, 10-15 mmHg: 76.0 [19.0] bpm, ≥ 16 mmHg: 80.0 [22.0] bpm; p < 0.001), lower mean arterial pressure (6-9 mmHg: 103.0 [13.5] mmHg, 10-15 mmHg: 101.0 [19.5] mmHg, ≥ 16 mmHg: 99.0 [21.0] mmHg; p = 0.032) and lower serum sodium (6-9 mmHg: 139.0 [3.0] mmol/L, 10-15 mmHg: 138.0 [4.0] mmol/L, ≥ 16 mmHg: 138.0 [5.0] mmol/L; p < 0.001). Across HVPG strata (6-9 mmHg vs. 10-15 mmHg vs ≥ 16 mmHg), median plasma levels of renin (21.0 [50.5] vs. 25.1 [70.9] vs. 65.4 [219.6] µIU/mL; p < 0.001), proBNP (86.1 [134.0] vs. 63.6 [118.0], vs. 132.2 [208.9] pg/mL; p = 0.002) and copeptin (7.8 [7.7] vs. 5.6 [8.0] vs. 10.7 [18.6] pmol/L; p = 0.024) increased with severity of PH. Elevated renin levels independently predicted first hepatic decompensation (adjusted hazard ratio [aHR]: 1.69; 95% confidence interval [95% CI] 1.07-2.68; p = 0.025) and mortality in compensated patients (aHR: 3.15; 95% CI 1.70-5.84; p < 0.001) and the overall cohort aHR: 1.42; 95% CI 1.01-2.01; p = 0.046). Elevated copeptin levels predicted mortality in decompensated patients (aHR: 5.77; 95% CI 1.27-26.33; p = 0.024) and in the overall cohort (aHR: 3.29; 95% CI 1.36-7.95; p = 0.008). ProBNP levels did not predict clinical outcomes.

Conclusions: The cardiovascular hormones renin, proBNP and AVP are activated with progression of ACLD and PH. Renin activation is a risk factor for hepatic decompensation and mortality, especially in compensated patients. Increased plasma copeptin is a risk factor for mortality, in particular in decompensated patients.

Keywords: Arginine vasopressin; Ascites; Cirrhosis; Copeptin; Decompensation; Hyperdynamic circulation; Natriuretic peptide; Renin; Renin/angiotensin/aldosterone system; brain; proBNP.