Effects of geranylgeranylacetone on diastolic and microvascular function in patients with heart failure with a preserved ejection fraction: A phase 2, randomized, placebo-controlled, crossover trial.

IF 10.8 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Soufiane Nassiri,Geert H D Voordes,Loek van Heerebeek,Daniël H van Raalte,Marianne C Verhaar,Daan J Touw,Merle M Krebber,Dirk J Duncker,Etto C Eringa,M Louis Handoko,Adriaan A Voors,
{"title":"Effects of geranylgeranylacetone on diastolic and microvascular function in patients with heart failure with a preserved ejection fraction: A phase 2, randomized, placebo-controlled, crossover trial.","authors":"Soufiane Nassiri,Geert H D Voordes,Loek van Heerebeek,Daniël H van Raalte,Marianne C Verhaar,Daan J Touw,Merle M Krebber,Dirk J Duncker,Etto C Eringa,M Louis Handoko,Adriaan A Voors, ","doi":"10.1002/ejhf.3711","DOIUrl":null,"url":null,"abstract":"AIMS\r\nHeart failure with preserved ejection fraction (HFpEF) is a major healthcare burden with limited treatment options. Geranylgeranylacetone (GGA) has been shown to improve myocardial compliance and endothelial function in preclinical models. Given the mechanistic profile of GGA and established safety as an over-the-counter drug in Asia, we performed a phase 2 clinical trial in patients with HFpEF.\r\n\r\nMETHODS AND RESULTS\r\nGLADIATOR-HFpEF (NCT05672134, EudraCT2022-000655-36-NL) is a phase 2, double-blind, randomized, placebo-controlled, crossover trial. Patients were randomized 1:1 to GGA or placebo and treated for 3 months with a washout-period of 6 weeks. The dual primary endpoints were diastolic function (E/e') and reactive hyperaemia index (RHI). Secondary endpoints were renal haemodynamic measurements; measured glomerular filtration rate and effective renal plasma flow, New York Heart Association class and 6-min walking test distance, cardiac biomarkers (N-terminal pro-B-type natriuretic peptide [NT-proBNP], high-sensitivity C-reactive protein), quality of life and laser speckle contrast analysis. Between March 2023 and December 2023, 43 patients were randomized and 39 were included in the per-protocol analysis. The cohort consisted of 28 women (72%), mean left ventricular ejection fraction was 59% and median NT-proBNP was 238 ng/L. There were no significant differences in the primary outcomes; E/e' (-0.24 [-0.90-0.41], p = 0.46) and RHI (-0.02 [-0.36-0.33], p = 0.92). We found a decrease in BSA-adjusted ERPF (-29.62[-57.52;1.71], p = 0.038) and BSA-adjusted RBF (-50.20 [-95.80; -4.61], p = 0.032). There were no significant differences in safety outcomes.\r\n\r\nCONCLUSIONS\r\nGeranylgeranylacetone, a drug that showed promising effects on myocardial relaxation and endothelial function in preclinical studies, had no effects on diastolic function, endothelial function and exercise capacity in patients with HFpEF. GGA reduced effective renal plasma flow and renal blood flow. There were no differences in safety outcomes between GGA and placebo.","PeriodicalId":164,"journal":{"name":"European Journal of Heart Failure","volume":"59 1","pages":""},"PeriodicalIF":10.8000,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Heart Failure","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/ejhf.3711","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0

Abstract

AIMS Heart failure with preserved ejection fraction (HFpEF) is a major healthcare burden with limited treatment options. Geranylgeranylacetone (GGA) has been shown to improve myocardial compliance and endothelial function in preclinical models. Given the mechanistic profile of GGA and established safety as an over-the-counter drug in Asia, we performed a phase 2 clinical trial in patients with HFpEF. METHODS AND RESULTS GLADIATOR-HFpEF (NCT05672134, EudraCT2022-000655-36-NL) is a phase 2, double-blind, randomized, placebo-controlled, crossover trial. Patients were randomized 1:1 to GGA or placebo and treated for 3 months with a washout-period of 6 weeks. The dual primary endpoints were diastolic function (E/e') and reactive hyperaemia index (RHI). Secondary endpoints were renal haemodynamic measurements; measured glomerular filtration rate and effective renal plasma flow, New York Heart Association class and 6-min walking test distance, cardiac biomarkers (N-terminal pro-B-type natriuretic peptide [NT-proBNP], high-sensitivity C-reactive protein), quality of life and laser speckle contrast analysis. Between March 2023 and December 2023, 43 patients were randomized and 39 were included in the per-protocol analysis. The cohort consisted of 28 women (72%), mean left ventricular ejection fraction was 59% and median NT-proBNP was 238 ng/L. There were no significant differences in the primary outcomes; E/e' (-0.24 [-0.90-0.41], p = 0.46) and RHI (-0.02 [-0.36-0.33], p = 0.92). We found a decrease in BSA-adjusted ERPF (-29.62[-57.52;1.71], p = 0.038) and BSA-adjusted RBF (-50.20 [-95.80; -4.61], p = 0.032). There were no significant differences in safety outcomes. CONCLUSIONS Geranylgeranylacetone, a drug that showed promising effects on myocardial relaxation and endothelial function in preclinical studies, had no effects on diastolic function, endothelial function and exercise capacity in patients with HFpEF. GGA reduced effective renal plasma flow and renal blood flow. There were no differences in safety outcomes between GGA and placebo.
香叶酮对保留射血分数的心力衰竭患者舒张和微血管功能的影响:一项随机、安慰剂对照的2期交叉试验
保留射血分数(HFpEF)的心力衰竭是一种主要的医疗负担,治疗方案有限。香叶乙酸酮(GGA)在临床前模型中已被证明可以改善心肌顺应性和内皮功能。鉴于GGA在亚洲的作用机理和作为非处方药的安全性,我们在HFpEF患者中进行了2期临床试验。方法与结果gladiate - hfpef (NCT05672134, EudraCT2022-000655-36-NL)是一项2期、双盲、随机、安慰剂对照的交叉试验。患者按1:1随机分为GGA组或安慰剂组,治疗3个月,洗脱期6周。两个主要终点是舒张功能(E/ E’)和反应性充血指数(RHI)。次要终点是肾脏血流动力学测量;测量肾小球滤过率和有效肾血浆流量,纽约心脏协会分级和6分钟步行测试距离,心脏生物标志物(n端前b型利钠肽[NT-proBNP],高敏c反应蛋白),生活质量和激光斑点对比分析。在2023年3月至2023年12月期间,43名患者被随机分配,39名患者被纳入每个方案分析。该队列包括28名女性(72%),平均左室射血分数为59%,NT-proBNP中位数为238 ng/L。主要结局无显著差异;E / E”(-0.24 [-0.90 - -0.41],p = 0.46)和奥镁(-0.02 [-0.36 - -0.33],p = 0.92)。我们发现bsa调整后的ERPF (-29.62[-57.52;1.71], p = 0.038)和RBF (-50.20 [-95.80;-4.61], p = 0.032)。在安全结果方面没有显著差异。结论香叶酮是一种在临床前研究中对心肌舒张和内皮功能有良好影响的药物,但对HFpEF患者的舒张功能、内皮功能和运动能力没有影响。GGA降低有效肾血浆流量和肾血流量。GGA和安慰剂在安全性结果上没有差异。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
European Journal of Heart Failure
European Journal of Heart Failure 医学-心血管系统
CiteScore
27.30
自引率
11.50%
发文量
365
审稿时长
1 months
期刊介绍: European Journal of Heart Failure is an international journal dedicated to advancing knowledge in the field of heart failure management. The journal publishes reviews and editorials aimed at improving understanding, prevention, investigation, and treatment of heart failure. It covers various disciplines such as molecular and cellular biology, pathology, physiology, electrophysiology, pharmacology, clinical sciences, social sciences, and population sciences. The journal welcomes submissions of manuscripts on basic, clinical, and population sciences, as well as original contributions on nursing, care of the elderly, primary care, health economics, and other related specialist fields. It is published monthly and has a readership that includes cardiologists, emergency room physicians, intensivists, internists, general physicians, cardiac nurses, diabetologists, epidemiologists, basic scientists focusing on cardiovascular research, and those working in rehabilitation. The journal is abstracted and indexed in various databases such as Academic Search, Embase, MEDLINE/PubMed, and Science Citation Index.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信