Ghrelin improves cardiac output in HFrEF

Intravenous ghrelin significantly increased the cardiac output of patients with heart failure with reduced ejection fraction (HFrEF), with no apparent hypotension, tachycardia, arrhythmia, or ischaemia in a phase 2 trial. Thus, ghrelin might be a promising inotrope/myotrope therapy for patients with HFrEF.

“Ghrelin is a peptide hormone, that stimulates the release of growth hormone via the growth hormone secretagogue receptor and triggers appetite centrally,” outlined Prof. Lars Lund (Karolinska Institutet, Sweden) [1]. Since ghrelin receptors are widely distributed in people, including the vasculature and myocardium, and ghrelin is elevated in patients with HFrEF, Prof. Lund and colleagues aimed to test whether intravenous acyl ghrelin can increase the cardiac output of patients with HFrEF. For this purpose, the phase 2 MetAnEnd-HF trial (NCT05277415) randomised 30 patients with New York Heart Association (NYHA) class III or IV HFrEF 1:1 to receive a placebo infusion or ghrelin intravenously for 120 minutes. The cardiac output was measured continuously via inert gas rebreathing.

After 120 minutes of infusion, the mean cardiac output was significantly increased in participants who received ghrelin (4.08 L/min to 5.23 L/min; P_{interaction with time}<0.001), representing a 28% increase in the cardiac output in participants on ghrelin, compared with participants who received placebo, in whom the cardiac output decreased slightly over time (4.26 L/min to 4.11 L/min; see Figure). Secondary efficacy outcomes, including left ventricular ejection fraction (LVEF), tricuspid annular plane systolic excursion (TAPSE), strain rate, and stroke volume, all favoured the experimental arm over the placebo arm numerically, but only the increase in stroke volume was significant over time (54.3 mL to 62.2 mL; P_{interaction with time}=0.021).

Figure: Primary outcome measure—change in cardiac output [1]



The safety analysis showed that ghrelin was not associated with hypotension, tachycardia, arrhythmia, or ischaemia. However, in the ghrelin group, almost half of the participants experienced flushing. Also, the NT-proBNP levels of participants on ghrelin were slightly elevated after 2–5 days (2,080 ng/L to 2,450 ng/L; P=0.01). Furthermore, analysis of ex-vivo beating cardiomyocytes displayed that ghrelin increased the contractility in a load-independent fashion and that the effect of ghrelin was calcium-sensitising rather than calcium-inducing.

“These results show that ghrelin, with its mechanism of action, has potential as a safe inotrope/myotrope therapy for the treatment of patients with HFrEF,” concluded Prof. Lund.

1. Lund LH, et al. Ghrelin-HF: intravenous ghrelin in heart failure with reduced ejection fraction. LBT Pharmacotherapy, Heart Failure 2022, 21–24 May, Madrid, Spain.

 

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Posted on 28 July, 2022