Repurposing of Metormin for Older Patients with HFpEF

射血分数保留性心力衰竭（HFpEF）被认为是一种老年综合征，几乎是老年人所特有的，尤其是女性。它影响到250万人，其流行率正在增加，其预后正在恶化，药理学试验一直是阴性的。我们的工作和其他人的工作表明，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（QOL）受损，住院治疗，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，包括粘蛋白产生在内的屏障在老年肠道中减少，导致“肠漏”，这使得细菌和抗原从肠道扩散到循环中，从而引起全身炎症。我们的临床研究表明：a）老年HFpEF患者的微生物组多样性显著降低，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产物的产生;和B）这些异常与他们的严重运动不耐受相关，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HFpEF再利用的理想候选药物。它对HFpEF相关的多种衰老相关机制具有多效性作用。我们令人信服的初步数据表明，二甲双胍强烈促进产生有益代谢物的有利肠道细菌种群，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，从而减少肠道渗漏和全身炎症并改善身体功能。我们将通过在80名年龄> 60岁的老年HFpEF患者中进行20周二甲双胍的随机、盲法、安慰剂对照试验来检验这一假设，在基线和随访时测量身体功能、QOL、微生物组多样性、漏肠标志物和全身性炎症，以解决三个具体目的：1）确定二甲双胍治疗是否改善患有HFpEF的老年患者的身体功能和QOL; 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QOL的改善是否与微生物组多样性、粘蛋白的增加以及肠道和全身炎症标志物的泄漏减少相关。本研究与RFA-AG-22-011的目标和许多其他NIA优先事项保持一致，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很大的影响，通过确定第一个药物治疗，以改善症状和运动不耐受的大型，不断增长的，脆弱的，服务不足的老年HFpEF患者人群。

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.