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":"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","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":"{\"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}","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}
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.
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.
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.