Novel Approaches for Improving Vascular Function in Veterans with HFpEF

改善 HFpEF 退伍军人血管功能的新方法

• 批准号: 10426039
• 负责人: D. Walter Wray
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2028-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10426039
• 关键词: Activities of Daily Living; Address; Area; Arginine; Biological Availability; Biological Markers; Blood Vessels; Cardiac; Chronic; Circulation; Citrulline; Clinical; Clinical Trials; Coupling; Crossover Design; Disease; Double-Blind Method; Dyspnea; EFRAC; Endothelium; Enteral; Exercise Tolerance; Exertion; Functional disorder; Goals; Health; Healthcare Systems; Heart failure; Hospitalization; Hospitals; Hydroxymethylglutaryl-CoA reductase; Impairment; Inflammation; Intervention; Knowledge; Link; Mechanics; Mediating; Medical Care Costs; Methodology; Mortality Decline; NOS3 gene; Nitric Oxide; Nitric Oxide Donors; Oxidative Stress; Pathway interactions; Patients; Peripheral; Peroxonitrite; Pharmacotherapy; Physical Capacity; Physical Function; Play; Prevalence; Production; Prognosis; Property; Quality of life; Randomized; Reactive Oxygen Species; Research; Risk; Role; Series; Signal Transduction; Symptoms; Testing; Therapeutic; Translating; Vascular Diseases; Veterans; Work; atorvastatin; cofactor; comorbidity; disease natural history; exercise intolerance; experimental study; hospital admission rate; improved; improved outcome; in vivo; inhibitor; novel; novel strategies; novel therapeutic intervention; oxidation; pharmacologic; preservation; readmission rates; stem; tetrahydrobiopterin; therapeutic target; vascular contributions; vascular inflammation

PROJECT SUMMARY: Heart failure with preserved ejection fraction (HFpEF) accounts for greater than 50% of the 6 million HF cases nationwide, and the prevalence relative to heart failure with reduced ejection fraction (HFrEF) continues to rise at a rate of 1% per year, presenting an imminent need for further research addressing the pathophysiology of this pervasive disease. The clinical presentation of HFpEF is defined by dyspnea upon exertion and severe exercise intolerance, symptoms that are likely due, at least in part, to disease-related changes in the peripheral circulation. While the mechanisms responsible for vascular dysfunction in HFpEF have not been established, chronic inflammation and associated production of reactive oxygen species (ROS), stemming from HFpEF-associated comorbidities and inactivity, appear to play a crucial role. The peripheral vasculature of this patient group represents an area that is particularly vulnerable to the harmful effects of ROS, which interact with, and reduce bioavailability of, nitric oxide (NO). The proposed work thus seeks to examine the mechanisms linking inflammation, vascular health, and exercise tolerance in Veterans with HFpEF, and identifying which aspects of this cascade could be targeted to improve physical capacity and vascular function in this patient group. Using a randomized, double-blind, crossover design, a series of experiments are proposed that will combine novel methodology with targeted pharmacologic interventions to selectively determine the importance of NO substrate, enzymatic cofactor bioavailability, and inflammation/ROS to disease-related changes in NO signalling in HFpEF. Specific Aim 1 will test the hypothesis that chronic enteral L-Citrulline administration (100mg/kg) will increase NO substrate, leading to an increase in NO bioavailability and a subsequent improvement in vascular function. Specific Aim 2 will explore whether administration of tetrahydrobiopterin (BH4), an essential cofactor for endothelial NO synthase, can improve enzymatic coupling and therefore restore vascular function in patients with HFpEF. Specific Aim 3 will evaluate the potential pleiotropic properties of atorvastatin, a HMG CoA reductase inhibitor, to reduce inflammation and oxidative stress, leading to improvement in physical capacity and vascular function. Each Specific Aim will combine in vivo and ex vivo assessments to comprehensively determine the impact of the proposed interventions on the cascade of inflammation, oxidative stress and exercise intolerance in this patient group. Upon completion, it is anticipated that the proposed work focused on developing a better understanding of the mechanisms that contribute to impaired peripheral vascular function in HFpEF, and pinpointing novel strategies to alleviate vascular dysfunction and promote physical cpacity, will translate directly into an improved ability to perform activities of daily living, which is likely to lead to improved quality of life and a better prognosis in this Veteran patient group.

项目摘要：射血分数保留的心力衰竭 (HFpEF) 占所有患者的 50% 以上 全国 600 万例心力衰竭病例，以及射血分数降低心力衰竭的患病率 (HFrEF) 继续以每年 1% 的速度增长，迫切需要进一步研究解决 这种普遍性疾病的病理生理学。 HFpEF 的临床表现是呼吸困难 劳累和严重的运动不耐受，这些症状可能至少部分是由疾病相关引起的 末梢循环的变化。虽然导致 HFpEF 血管功能障碍的机制有 尚未确定，慢性炎症和相关的活性氧（ROS）的产生， 由 HFpEF 相关合并症和不活动引起的，似乎起着至关重要的作用。周边 该患者组的脉管系统特别容易受到 ROS 有害影响的区域， 它与一氧化氮（NO）相互作用并降低其生物利用度。因此，拟议的工作旨在审查 患有 HFpEF 的退伍军人中炎症、血管健康和运动耐量之间的联系机制，以及 确定该级联的哪些方面可以针对改善身体能力和血管功能 在这个患者群体中。采用随机、双盲、交叉设计，提出了一系列实验 它将新颖的方法与有针对性的药理学干预措施相结合，以选择性地确定 NO 底物、酶辅因子生物利用度和炎症/ROS 对疾病相关的重要性 HFpEF 中 NO 信号传导的变化。具体目标 1 将检验以下假设：慢性肠内 L-瓜氨酸 给药（100mg/kg）会增加NO底物，导致NO生物利用度增加和 随后血管功能的改善。具体目标 2 将探讨是否管理 四氢生物蝶呤 (BH4) 是内皮 NO 合酶的重要辅助因子，可以改善酶促偶联 从而恢复 HFpEF 患者的血管功能。具体目标 3 将评估潜力 阿托伐他汀（一种 HMG CoA 还原酶抑制剂）具有多效性，可减少炎症和氧化 压力，从而改善身体能力和血管功能。每个具体目标都会在体内结合起来 和离体评估，以全面确定拟议干预措施对级联的影响 该患者组的炎症、氧化应激和运动不耐受的情况。预计完成后 拟议的工作重点是更好地了解有助于促进 HFpEF 中外周血管功能受损，并确定缓解血管功能障碍的新策略 并提高身体能力，将直接转化为日常生活活动能力的提高， 这可能会提高该退伍军人患者群体的生活质量和更好的预后。