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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.

心力衰竭伴保留射血分数（HFpEF）被认为是一种老年综合征，几乎是老年人，尤其是女性所特有的。它影响到250万人，其患病率正在增加，其预后正在恶化，药理学试验一直是阴性的。我们和其他人的研究表明，HFpEF是由全身性炎症引发和促进的，这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，这是慢性HFpEF的主要表现，生活质量下降（QOL），住院，丧失独立性和死亡。全身性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。我们的临床前研究表明，老年肠道中的屏障，包括粘蛋白的产生，减少了，导致“漏肠”，这使得细菌和抗原从肠道扩散到循环系统，从而引起全身炎症。我们的临床研究表明：a)老年HFpEF患者的微生物群多样性明显减少，肠道微生物群不良，减少了有助于维持肠壁完整性和整体健康的有益代谢物的产生；b)这些异常与他们严重的运动不耐受有关，并且是可以改变的。二甲双胍是一种通用的、耐受性良好的抗糖尿病药物，可能是治疗HFpEF的理想候选药物。它对与HFpEF相关的多种衰老机制具有多效性作用。我们令人信服的初步数据表明，二甲双胍强烈促进有利的肠道细菌群产生有益的代谢物，增加粘蛋白的产生，并减少肠道渗漏和全身炎症。我们假设，在老年HFpEF患者中，二甲双胍会恢复肠道微生物群多样性，增加肠壁粘蛋白，从而减少漏肠和全身炎症，改善身体功能。我们将通过一项随机、盲法、安慰剂对照试验来检验这一假设，在80名年龄60岁的老年HFpEF患者中进行为期20周的二甲双胍试验，并在基线和随访中测量身体功能、生活质量、微生物群多样性、漏肠标志物和全身炎症，以满足三个特定目标：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)确定二甲双胍是否会增加微生物群多样性、粪便中的粘蛋白、降低血清中的肠漏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群多样性、黏液蛋白的增加以及肠道和全身炎症标志物渗漏的减少有关。这项研究与RFA-AG-22-011的目标和许多其他NIA优先事项非常一致，并将由一个具有互补专业知识的多元化，有凝聚力的多学科团队进行。拟议的项目可以通过确定第一个药物治疗来改善大量，不断增长的，脆弱的，服务不足的老年HFpEF患者的症状和运动不耐受，从而产生重大影响。