Acyl ghrelin increases cardiac output and preserves right ventricular-pulmonary arterial coupling in patients with heart failure
Authors: Erhardsson M , Ljung Faxen U , Venkateshvaran A , Hage C , Pironti G , Thorvaldsson T , Shahgaldi K , Webb D L , Hellstrom P , Andersson D C , Stalhberg M , Lund L 
Published: November 2023

Abstract

Background
Pulmonary hypertension and right ventricular (RV) failure are common in heart failure with reduced ejection fraction (HFrEF). Acyl ghrelin improves cardiac output (CO) in HFrEF but when CO increases there is a risk of increased pulmonary vascular resistance (PVR). This may impair the right ventricular-pulmonary artery coupling (RVPAC) and in the long term further harm the afterload sensitive RV in HFrEF or in patients with pulmonary arterial hypertension (WHO group 1). Animal data suggest that acyl ghrelin has beneficial effects on the pulmonary vasculature.

Purpose
To investigate if grehlin increases CO without worsening the right-sided hemodynamics in HFrEF assessed by RVPAC measured as the non-invasive surrogate tricuspid annular plane systolic excursion/tricuspid regurgitation velocity (TAPSE/TRV).

Methods
The Karolinska Acyl Ghrelin Trial (ClinicalTrials.gov NCT05277415) was a double-blind placebo-controlled trial of acyl ghrelin vs. placebo in HFrEF. In this secondary analysis we assessed RVPAC. Patients (n = 15+15) received either acyl ghrelin 30 pmol/kg/min or placebo (normal saline) intravenously during 120 min. Echocardiography exams at baseline and 120 min were assessed for RV parameters and patients were included if both TAPSE and TRV could be assessed at both time-points. Changes within groups (acyl ghrelin and placebo) at baseline vs. 120 min were analysed by Wilcoxon rank sign test. Analysis of variance was used to test for difference in change acyl ghrelin vs. placebo, adjusted for baseline values.

Results
A total of 22 patients (acyl ghrelin n = 12, placebo = 10) were included. Clinical characteristics were similar [median (IQR) acyl ghrelin vs. placebo): age 71 (65-77) vs. 74 (72-77) years, EF 29 (20-35) vs. 18 (13-36) %. Despite a 15% increase in CO in the acyl ghrelin group [from 4.0 (3.5-4.6) to 4.6 (3.9-6.1) L/min, p = 0.003], RVPAC remained unchanged; 5.9 (5.3-7.6) to 6.3 (4.8-7.5) mm·(m/s)-1, p = 0.372, while it was reduced in the placebo group, 5.2 (4.3-6.4) to 4.8 (4.2-5.8) mm·(m/s)-1, p = 0.035. Similarly, TAPSE remained unchanged in the acyl ghrelin group 18.0 (14.8-20.5) to 17.5 (13.8-19.3), p = 0.188, while it decreased in the placebo group 14.5 (13.0-17.5) to 13.5 (11.3-15.0), p = 0.028. There were no differences in TRV. When comparing the changes between groups adjusted for baseline, CO increased in the acyl ghrelin group vs. placebo (p = 0.036) while there were no significant differences in RVPAC or TRV (Figure 1).

Conclusion
These preliminary findings indicate that acyl ghrelin may preserve or even improve RVPAC without increasing the RV pressure gradient. This may be due to acyl ghrelin causing improved contractility, reduced PVR and/or reduced left sided filling pressures. These potential effects strengthen the role of acyl ghrelin therapy in HFrEF and suggest potentially beneficial effects also in patients with isolated or combined pre- and post-capillary pulmonary hypertension.