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:
- 金额:$ 73.91万
- 依托单位:
- 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:
- 关键词:AddressAffectAgeAgingAntidiabetic DrugsAntigensArteriesBacteriaBlindedBloodBlood CirculationBody Weight decreasedButyratesCD14 geneCardiomyopathiesCessation of lifeCirculationCitiesClinicalClinical ResearchCongestive Heart FailureDataDiffusionDoseEFRACElderlyEnvironmentEventExerciseFDA approvedFecesFoundationsFutureGoalsHealthHeartHeart failureHospitalizationHumanImpairmentIndividualInflammationInterleukin-1 betaInterleukin-6IntestinesIntravenousKansasLCN2 geneLeaky GutLeftLeukocyte L1 Antigen ComplexLungMeasurementMeasuresMediatingMetforminMicrobeModelingMucinsNematodaOralOrganOxygen ConsumptionPatientsPersonsPharmaceutical PreparationsPharmacological TreatmentPhasePhysical FunctionPhysical PerformancePhysiological ProcessesPopulationPositioning AttributePrevalenceProcessProductionPrognosisPropertyQuality of lifeQuestionnairesRandomizedRodentRoleSF-36SerumSkeletal MuscleSourceSymptomsSyndromeTNF geneTestingUnderserved PopulationVentricularWalkingWomanWorkadverse outcomeanti agingcytokinedietaryexercise capacityexercise intoleranceexercise trainingfollow-upgastrointestinal epitheliumgut bacteriagut inflammationgut microbiomegut microbiotaheart functionimprovedimproved outcomeindexinginflammatory markerlipopolysaccharide-binding proteinmicrobialmicrobiomemicrobiotamouse modelmultidisciplinarynon-diabeticolder patientolder womenoptimal treatmentspharmacologicplacebo controlled trialpreclinical studypreservationsymptomatic improvementsystemic 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。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Geroprotective potential of microbiome modulators in the Caenorhabditis elegans model.
- DOI:10.1007/s11357-023-00901-7
- 发表时间:2024-02
- 期刊:
- 影响因子:5.6
- 作者:Miller, Brandi C.;Mathai, Megha;Yadav, Hariom;Jain, Shalini
- 通讯作者:Jain, Shalini
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DALANE W KITZMAN其他文献
DALANE W KITZMAN的其他文献
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{{ truncateString('DALANE W KITZMAN', 18)}}的其他基金
Repurposing of Metormin for Older Patients with HFpEF
老年 HFpEF 患者重新使用美托明
- 批准号:
10434271 - 财政年份:2022
- 资助金额:
$ 73.91万 - 项目类别:
Physical Rehabilitation for Older Patients with Acute HFpEF-The REHAB-HFpEF Trial
老年急性 HFpEF 患者的身体康复 - REHAB-HFpEF 试验
- 批准号:
10683332 - 财政年份:2022
- 资助金额:
$ 73.91万 - 项目类别:
Physical Rehabilitation for Older Patients with Acute HFpEF-The REHAB-HFpEF Trial
老年急性 HFpEF 患者的身体康复 - REHAB-HFpEF 试验
- 批准号:
10501900 - 财政年份:2022
- 资助金额:
$ 73.91万 - 项目类别:
Wake Forest Atrium HeartShare Clinical Center
维克森林中庭 HeartShare 临床中心
- 批准号:
10483210 - 财政年份:2021
- 资助金额:
$ 73.91万 - 项目类别:
Wake Forest Atrium HeartShare Clinical Center
维克森林中庭 HeartShare 临床中心
- 批准号:
10327453 - 财政年份:2021
- 资助金额:
$ 73.91万 - 项目类别:
Wake Forest Atrium HeartShare Clinical Center
维克森林中庭 HeartShare 临床中心
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10678972 - 财政年份:2021
- 资助金额:
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Improving the usage and impact of the Integrated Aging Studies Databank and Registry
改善综合老龄化研究数据库和登记处的使用和影响
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10408207 - 财政年份:2018
- 资助金额:
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Coordinating Center of the Claude D. Pepper Older Americans Independence Centers
克劳德·D·佩珀美国老年人独立中心协调中心
- 批准号:
10163762 - 财政年份:2018
- 资助金额:
$ 73.91万 - 项目类别:
Coordinating Center of the Claude D. Pepper Older Americans Independence Centers
克劳德·D·佩珀美国老年人独立中心协调中心
- 批准号:
10449365 - 财政年份:2018
- 资助金额:
$ 73.91万 - 项目类别:
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