Repurposing of Metormin for 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，特别是女性所特有的。它影响着250万人，其患病率正在上升，其预后正在恶化，而且药理试验一直是阴性的。我们的工作和其他人的研究表明，HFpEF是由全身性炎症启动和促进的，全身性炎症导致全球器官功能受损，包括心脏、动脉、肺和骨骼肌，最终导致严重的运动不耐受，慢性HFpEF的主要表现，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，肠道异常是一个关键作用。我们的临床前研究表明，包括粘蛋白产生在内的屏障在较老的肠道中减少，导致“渗漏的肠道”，这允许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患者的微生物群多样性显著减少，肠道微生物区系不利，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耐受有关，并且是可以改变的。二甲双胍是一种耐受性良好的非专利抗糖尿病药物，可能是重新用于HFpEF的理想候选药物。它对多种与HFpEF相关的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，二甲双胍有力地促进了有利的肠道细菌群，这些细菌产生有益的代谢物，增加粘蛋白的产生，并减少肠道渗漏和全身炎症。我们推测，在老年HFpEF患者中，二甲双胍将恢复肠道微生物群多样性，增加肠壁粘蛋白，这反过来将减少肠道渗漏和全身炎症，并改善身体功能。我们将通过一项随机、盲目、安慰剂对照的试验来验证这一假设，该试验对80名60岁的老年HFpEF患者服用二甲双胍20周，测量基线并随访身体功能、生活质量、微生物多样性、渗漏肠道标志物和全身炎症，以解决三个具体目标：1)确定二甲双胍治疗是否改善了老年HFpEF患者的身体功能和生活质量；2)确定二甲双胍是否增加了微生物群多样性、粪便粘液，并减少了血清中渗漏肠道的标志物以及肠道和血液中的炎症；3)确定二甲双胍对身体功能和生活质量的改善是否与微生物组多样性增加、粘蛋白增加以及肠道和全身炎症标志物渗漏减少有关。这项研究与RFA-AG-22-011和许多其他NIA优先事项的目标非常一致，并将由一个具有互补专业知识的多样化、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，因为它确定了第一种药物疗法，以改善大量、不断增长的、脆弱的、服务不足的HFpEF老年患者的症状和运动不耐受。

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.