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：保留的射血分数（HFPEF）的心力衰竭占50％以上 全国600万例HF病例，相对于心力衰竭的患病率减少了 （HFREF）继续以每年1％的速度上升，这迫在眉睫，需要进一步研究 这种普遍疾病的病理生理学。 HFPEF的临床表现由呼吸困难定义 劳累和严重的运动不宽容，至少部分归因于疾病有关的症状 周围循环的变化。虽然HFPEF中负责血管功能障碍的机制具有 未建立，活性氧（ROS），慢性炎症和相关的产生 由HFPEF相关的合并症和不活动的原因似乎起着至关重要的作用。外围 该患者组的脉管系统代表一个特别容易受到ROS有害影响的区域 与一氧化氮相互作用并减少生物利用度（NO）。因此，拟议的工作试图检查 与HFPEF的退伍军人相关的机制，与HFPEF的退伍军人相关联 确定可以针对该级联的哪个方面来提高身体能力和血管功能 在这个患者组中。使用随机的双盲，跨界设计，提出了一系列实验 这将结合新方法与有针对性的药理干预措施，以选择性地确定 无底物，酶辅因子生物利用度和与疾病相关的炎症/ROS的重要性 HFPEF中无信号的变化。特定目标1将检验慢性肠内L-库氨酸的假设 管理（100mg/kg）不会增加底物，导致无生物利用度和 随后的血管功能改善。具体目标2将探讨管理是否 四氢无菌蛋白酶（BH4）是内皮NO合酶的必需辅助因子，可以改善酶促耦合 因此，HFPEF患者恢复血管功能。特定目标3将评估潜力 HMG COA还原酶抑制剂Atorvastatin的多效特性，以减少炎症和氧化 压力，导致身体能力和血管功能的提高。每个特定目标都将在体内结合 并在体内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症。完成后，预计 提议的工作着重于对有助于有助于的机制有更好的理解 HFPEF中的外周血管功能受损，并指出了减轻血管功能障碍的新型策略 并促进身体上的能力，将直接转化为进行日常生活活动的提高能力， 这可能会导致改善的生活质量和在这个退伍军人群体中的预后更好。