Novel Approaches for Improving Vascular Function in Veterans with HFpEF

项目摘要：心力衰竭保留射血分数(HFpEF)占50%以上 全国600万心力衰竭病例，以及与射血分数降低的心力衰竭相关的患病率 (HFrEF)继续以每年1%的速度增长，迫切需要进一步研究解决 这种广泛性疾病的病理生理学。HFpEF的临床表现是由呼吸困难定义的 劳累和严重的运动不耐受，这些症状很可能至少部分是由于与疾病有关的 外周循环的变化。而导致HFpEF血管功能障碍的机制有 慢性炎症和相关的活性氧物种(ROS)的产生， 由HFpEF相关的合并症和不活动引起的，似乎发挥了关键作用。外围设备 这组患者的血管系统代表了一个特别容易受到ROS有害影响的区域， 它们与一氧化氮(NO)相互作用，并降低其生物利用度。因此，拟议的工作试图审查 退伍军人的炎症、血管健康和运动耐量与HFpEF之间的联系机制 确定这一级联反应的哪些方面可以作为改善体能和血管功能的目标 在这组病人中。采用随机、双盲、交叉设计，设计了一系列实验。 这将结合新的方法学和有针对性的药物干预来选择性地确定 NO底物、酶辅助因子生物利用度和炎症/ROS对疾病相关的重要性 HFpEF中NO信号的变化。特定目标1将检验慢性肠内注射L-瓜氨酸钙的假设 给药(100 mg/kg)会增加NO底物，导致NO生物利用度增加 随后血管功能得到改善。具体目标2将探索管理是否 四氢生物蝶呤(BH4)是内皮型一氧化氮合酶的重要辅因子，可促进酶的偶联 从而恢复HFpEF患者的血管功能。具体目标3将评估潜力 HMG CoA还原酶抑制剂阿托伐他汀的多效性，以减少炎症和氧化 应激，导致体能和血管功能的改善。每个特定的目标都会在体内结合起来 和体外评估，以全面确定拟议干预措施对级联反应的影响 炎症、氧化应激和运动不耐受在这组患者中的发病率。建成后，预计 拟议工作的重点是更好地了解有助于 HFpEF患者的外周血管功能受损，并确定缓解血管功能障碍的新策略 并促进身体健康，将直接转化为执行日常生活活动的能力的提高， 这可能会改善这一资深患者的生活质量和预后。

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.