Acyl ghrelin improves cardiac function in heart failure and increases fractional shortening in cardiomyocytes without calcium mobilization

Abstract

Background and Aims Ghrelin is an endogenous appetite-stimulating peptide hormone with potential cardiovascular benefits. Effects of acylated (activated) ghrelin were assessed in patients with heart failure and reduced ejection fraction (HFrEF) and in ex vivo mouse cardiomyocytes. Methods and results In a randomized placebo-controlled double-blind trial, 31 patients with chronic HFrEF were randomized to synthetic human acyl ghrelin (0.1 µg/kg/min) or placebo intravenously over 120 min. The primary outcome was change in cardiac output (CO). Isolated mouse cardiomyocytes were treated with acyl ghrelin and fractional shortening and calcium transients were assessed. Acyl ghrelin but not placebo increased cardiac output (acyl ghrelin: 4.08 ± 1.15 to 5.23 ± 1.98 L/min; placebo: 4.26 ± 1.23 to 4.11 ± 1.99 L/min, P < 0.001). Acyl ghrelin caused a significant increase in stroke volume and nominal increases in left ventricular ejection fraction and segmental longitudinal strain and tricuspid annular plane systolic excursion. There were no effects on blood pressure, arrhythmias, or ischaemia. Heart rate decreased nominally (acyl ghrelin: 71 ± 11 to 67 ± 11 b.p.m.; placebo 69 ± 8 to 68 ± 10 b.p.m.). In cardiomyocytes, acyl ghrelin increased fractional shortening, did not affect cellular Ca2+ transients, and reduced troponin I phosphorylation. The increase in fractional shortening and reduction in troponin I phosphorylation was blocked by the acyl ghrelin antagonist D-Lys 3. Conclusion In patients with HFrEF, acyl ghrelin increased cardiac output without causing hypotension, tachycardia, arrhythmia, or ischaemia. In isolated cardiomyocytes, acyl ghrelin increased contractility independently of preload and afterload and without Ca2+ mobilization, which may explain the lack of clinical side effects. Ghrelin treatment should be explored in additional randomized trials. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT05277415

Acyl ghrelin infusion increases circulating growth hormone in patients with heart failure and reduced ejection fraction

“…In the present randomized trial, we previously reported that in patients with HFrEF, intravenous acyl ghrelin significantly increased cardiac output 4 . Here we report that acyl ghrelin caused an appropriate increase in circulating GH.…”

“…Associations between selected baseline characteristics and GH response in acyl ghrelin-treated patients are depicted in online supplementary In the present randomized trial, we previously reported that in patients with HFrEF, intravenous acyl ghrelin significantly increased cardiac output. 4 Here we report that acyl ghrelin caused an appropriate increase in circulating GH. This is consistent with a previous study in HFrEF, where intravenous ghrelin increased GH and cardiac index.…”

“…3 In the Karolinska Acyl Ghrelin Trial (ClinicalTrials.gov NCT05277415), a recent double-blind randomized trial in HF with reduced ejection fraction (HFrEF), intravenous acyl ghrelin but not placebo increased cardiac output by 28%. 4 We assessed acyl ghrelin versus placebo on GH release and the pharmacodynamics of acyl ghrelin treatment on the GH response in this study. In brief, 31 patients with chronic HFrEF were randomized to human acyl ghrelin (0.1 μg/kg/min; n = 15) or placebo (NaCl; n = 16) intravenously over 120 min.…”

Acyl ghrelin increases cardiac output while preserving right ventricular‐pulmonary arterial coupling in heart failure

“…Patients were ambulatory, had chronic HFrEF in New York Heart Association (NYHA) class III or ambulatory class IV, and a left ventricular ejection fraction (LVEF) ≤ 40%, as well as optimal guideline‐directed medical therapy at time of enrolment. Detailed inclusion and exclusion criteria were presented previously 5 . Echocardiography exams at baseline and 120 min were assessed for RV parameters.…”

“…Ghrelin is an endogenous appetite-stimulating peptide hormone with cardiovascular actions, 1,2,3,4 which increases cardiac output (CO) in heart failure with reduced ejection fraction (HFrEF). 5 Apart from inotropic effects, animal data suggest that exogenous ghrelin administration has beneficial effects in the pulmonary vasculature. 6,7 Pulmonary hypertension (PH) and right ventricular (RV) failure are common among patients with HFrEF.…”