The Orally Available Ghrelin Receptor-Agonist AC01 Improves Systolic Function in HFrEF Mice and Nonhuman Primates

IF 8.4 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

JACC: Basic to Translational Science Pub Date : 2026-08-01 Epub Date: 2026-07-22 DOI:10.1016/j.jacbts.2026.101635

Lars H. Lund MD, PhD, Camilla Hage PhD, Mattias Carlström PhD, Pascal Champéroux PhD, Marcus Ståhlberg MD, PhD, Patrik Strömberg PhD, Göran Westerberg PhD, Emanuela Lovati PhD, Allan Gordon MD, PhD, Johan Sjödahl PhD, Daniel C. Andersson MD, PhD, Gianluigi Pironti PhD

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引用次数: 0

Abstract

Heart failure with reduced ejection fraction (HFrEF) is characterized by impaired cardiac contractility. AC01, a small-molecule ghrelin receptor agonist, enhances contractility in cardiomyocytes. This study evaluated the in vivo hemodynamic effects of AC01 in a mouse HFrEF model and in cynomolgus monkeys. In HFrEF mice, intravenous AC01 significantly increased cardiac output, stroke volume, and ejection fraction versus vehicle, without any apparent detriment to diastolic function. Pressure-volume loop analysis demonstrated load-independent inotropic effects. In monkeys, oral AC01 increased cardiac output and stroke volume while reducing heart rate, without lowering central aortic pressure. These effects were sustained over 14 days of oral dosing. Additionally, AC01 improved autonomic balance by increasing parasympathetic and decreasing sympathetic activity. Overall, AC01 produced rapid, consistent, and sustained improvements in systolic function across species, supporting its potential as a novel, load-independent inotropic therapy for heart failure.

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口服胃饥饿素受体激动剂AC01改善HFrEF小鼠和非人灵长类动物的收缩功能。

心力衰竭伴射血分数降低（HFrEF）的特征是心脏收缩功能受损。AC01是一种小分子胃饥饿素受体激动剂，可增强心肌细胞的收缩性。本研究评价了AC01对小鼠HFrEF模型和食蟹猴体内血流动力学的影响。在HFrEF小鼠中，与载药相比，静脉注射AC01显著增加心排血量、卒中容量和射血分数，对舒张功能无明显损害。压力-体积环分析显示负荷无关的肌力效应。在猴子中，口服AC01增加心输出量和卒中量，同时降低心率，但不降低中央主动脉压。这些效果持续了14天以上的口服剂量。此外，AC01通过增加副交感神经和减少交感神经活动来改善自主神经平衡。总的来说，AC01对不同物种的收缩功能产生了快速、一致和持续的改善，支持其作为一种新型、负荷独立的心力衰竭肌力疗法的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

JACC: Basic to Translational Science CARDIAC & CARDIOVASCULAR SYSTEMS-

CiteScore

14.20

自引率

1.00%

发文量

161

审稿时长

16 weeks

期刊介绍： JACC: Basic to Translational Science is an open access journal that is part of the renowned Journal of the American College of Cardiology (JACC). It focuses on advancing the field of Translational Cardiovascular Medicine and aims to accelerate the translation of new scientific discoveries into therapies that improve outcomes for patients with or at risk for Cardiovascular Disease. The journal covers thematic areas such as pre-clinical research, clinical trials, personalized medicine, novel drugs, devices, and biologics, proteomics, genomics, and metabolomics, as well as early phase clinical trial methodology.