Repurposing of Metormin for Older Patients with HFpEF

老年 HFpEF 患者重新使用美托明

基本信息

批准号：
10672897
负责人：
DALANE W KITZMAN
金额：
$ 73.91万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672897
关键词：
Address Affect Age Aging Antidiabetic Drugs Antigens Arteries Bacteria Blinded Blood Blood Circulation Body Weight decreased Butyrates CD14 gene Cardiomyopathies Cessation of life Circulation Cities Clinical Clinical Research Congestive Heart Failure Data Diffusion Dose EFRAC Elderly Environment Event Exercise FDA approved Feces Foundations Future Goals Health Heart Heart failure Hospitalization Human Impairment Individual Inflammation Interleukin-1 beta Interleukin-6 Intestines Intravenous Kansas LCN2 gene Leaky Gut Left Leukocyte L1 Antigen Complex Lung Measurement Measures Mediating Metformin Microbe Modeling Mucins Nematoda Oral Organ Oxygen Consumption Patients Persons Pharmaceutical Preparations Pharmacological Treatment Phase Physical Function Physical Performance Physiological Processes Population Positioning Attribute Prevalence Process Production Prognosis Property Quality of life Questionnaires Randomized Rodent Role SF-36 Serum Skeletal Muscle Source Symptoms Syndrome TNF gene Testing Underserved Population Ventricular Walking Woman Work adverse outcome anti aging cytokine dietary exercise capacity exercise intolerance exercise training follow-up gastrointestinal epithelium gut bacteria gut inflammation gut microbiome gut microbiota heart function improved improved outcome indexing inflammatory marker lipopolysaccharide-binding protein microbial microbiome microbiota mouse model multidisciplinary non-diabetic older patient older women optimal treatments pharmacologic placebo controlled trial preclinical study preservation symptomatic improvement systemic inflammatory response

项目摘要

Heart failure with preserved ejection fraction (HFpEF) is accepted as a geriatric syndrome and is nearly unique to older persons, particularly women. It affects 2.5 million persons, its prevalence is increasing, its prognosis is worsening, and pharmacologic trials have been negative. Our work and others’ suggest that HFpEF is initiated and promoted by systemic inflammation, which causes globally impaired organ function, including in the heart, arteries, lungs, and skeletal muscle, ultimately causing severe exercise intolerance, the primary manifestation of chronic HFpEF, impaired quality of life (QOL), hospitalization, loss of independence, and death. The source of the systemic inflammation has been unknown, but our preliminary data suggest a key role of abnormalities in the gut. Our preclinical studies show that barriers, including mucin production, are reduced in older gut causing ‘leaky gut’, which allows diffusion of bacteria and antigens from the gut into the circulation, thus causing systemic inflammation. Our clinical studies suggest that: a) older HFpEF patients have markedly reduced microbiome diversity with adverse gut microbiota that reduce production of beneficial metabolites that help maintain gut wall integrity and overall health; and b) that these abnormalities are associated with their severe exercise intolerance and are modifiable. Metformin, a generic, well-tolerated anti-diabetic medication may be an ideal candidate for repurposing for HFpEF. It has pleotropic effects against multiple aging-related mechanisms relevant to HFpEF. Our compelling preliminary data indicate that metformin strongly promotes favorable gut bacteria populations that produce beneficial metabolites, increases mucin production, and reduces leaky gut and systemic inflammation. We hypothesize that in older HFpEF patients, metformin will restore gut microbiome diversity and increase gut wall mucin, which in turn will reduce leaky gut and systemic inflammation and improve physical function. We will test this hypothesis with a randomized, blinded, placebo-controlled trial of 20 weeks of metformin in 80 older HFpEF patients > age 60 years with measurements at baseline and follow-up of physical function, QOL, microbiome diversity, markers of leaky gut, and systemic inflammation to address three Specific Aims: 1) Determine if metformin treatment improves physical function and QOL in older patients with HFpEF; 2) Determine if metformin increases microbiome diversity, mucin in the feces, and reduces markers of leaky gut in serum and inflammation in gut and blood; 3) Determine if metformin-mediated improvements in physical function and QOL are associated with increased microbiome diversity, mucin, and reduced leakiness in gut and systemic inflammatory markers. This study is well aligned with the goals of RFA-AG-22-011 and many other NIA priorities, and will be conducted by a diverse, cohesive multidisciplinary team with complementary expertise. The proposed project could have a large impact by identifying the first pharmacologic treatment to improve symptoms and exercise intolerance in the large, growing, vulnerable, under-served population of older patients with HFpEF.

射血分数保留的心力衰竭（HFpEF）被认为是一种老年综合征，几乎是老年人所特有的疾病，它影响着 250 万人，其患病率正在增加，其预后正在恶化，并且我们的药理学试验结果为阴性。工作和其他人表明，HFpEF 是由全身炎症引发和促进的，全身炎症会导致全身器官功能受损，包括心脏、动脉、肺和骨骼肌，最终导致严重的运动不耐受，这是运动不耐受的主要表现。慢性 HFpEF、生活质量 (QOL) 受损、住院、丧失独立性和死亡全身炎症的来源尚不清楚，但我们的初步数据表明肠道异常的关键作用。老年肠道中的微生物，包括粘蛋白的产生减少，导致“肠漏”，从而使细菌和抗原从肠道扩散到循环系统中，从而引起全身炎症：a) 老年 HFpEF 患者的微生物群明显减少。多样性b) 这些异常与严重的运动不耐受有关，并且可以通过二甲双胍（一种耐受性良好的抗糖尿病药物）进行改变。是重新利用 HFpEF 的理想候选者，它对与 HFpEF 相关的多种衰老相关机制具有多效作用。我们感兴趣的是，在老年 HFpEF 患者中，二甲双胍将恢复肠道微生物组多样性并增加肠壁粘蛋白，从而减少肠漏和全身炎症并改善身体功能。通过对 80 名年龄大于 60 岁的老年 HFpEF 患者进行 20 周二甲双胍治疗的随机、盲法、安慰剂对照试验来检验这一假设，并进行基线测量和身体功能、生活质量、生活质量、微生物组多样性、肠漏标志物和全身炎症，以解决三个具体目标：1) 确定二甲双胍治疗是否改善老年 HFpEF 患者的身体功能和生活质量；2) 确定二甲双胍是否增加微生物组多样性、粪便中的粘蛋白，并减少血清中肠漏的标志物以及肠道和血液中的炎症；3) 确定二甲双胍介导的身体功能和生活质量的改善是否与微生物组多样性的增加有关；这项研究与 RFA-AG-22-011 和许多其他 NIA 优先事项非常一致，并将由具有互补专业知识的多元化、有凝聚力的多学科团队进行。拟议的项目可能会产生巨大的影响，通过确定第一种药物治疗方法来改善大量、不断增长、脆弱、服务不足的老年 HFpEF 患者的症状和运动不耐受。