Mechanisms of Impaired Skeletal Muscle Blood Flow and Exercise Intolerance in Veterans with Heart Failure with Preserved Ejection Fraction: Efficacy of Knee Extensor Training

射血分数保留的心力衰竭退伍军人骨骼肌血流受损和运动不耐受的机制：膝关节伸肌训练的功效

• 批准号: 10413604
• 负责人: Kanokwan Bunsawat
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10413604
• 关键词: Activities of Daily Living; Acute; Address; Aerobic Exercise; Affect; American; Attenuated; Autonomic Dysfunction; Autonomic nervous system; Award; Blood Vessels; Blood flow; Cardiac; Cardiopulmonary; Characteristics; Chronic Phase; Clinical; Complex; Complication; Data; Disease; Disease Progression; EFRAC; Educational Intervention; Exercise; Exercise Physiology; Exercise Tolerance; Exhibits; Extensor; Functional disorder; Goals; Health; Healthcare Systems; Heart failure; Hospitalization; Hospitals; Impairment; Knee; Knowledge; Lead; Limb structure; Link; Lower Extremity; Mediating; Mentorship; Metabolic; Modality; Modeling; Natural History; Nitric Oxide; Outcome; Patient Care; Patients; Peripheral; Pharmacotherapy; Phase; Phenotype; Physical Exercise; Physical Medicine; Physical activity; Quality of Care; Quality of life; Regulation; Rehabilitation therapy; Reporting; Research; Research Personnel; Research Proposals; Role; Scientist; Skeletal Muscle; Stress; Survival Rate; Symptoms; Testing; Therapeutic; Therapeutic exercise; Training; Transferable Skills; United States National Institutes of Health; Vascular Diseases; Vasodilation; Veterans; Walking; attenuation; base; career; clinical practice; efficacy evaluation; exercise intolerance; exercise rehabilitation; exercise training; experience; heart function; high risk; improved; improved outcome; insight; interest; mortality; mortality risk; muscle form; neurovascular; novel; physical inactivity; preservation; readmission rates; rehabilitation strategy; relating to nervous system; response; skeletal; skills; therapeutic target

Heart failure (HF) with preserved ejection fraction (HFpEF) is the most prevalent HF phenotype, currently affecting ~3.1 million Americans 1 and disproportionately afflicting Veterans compared to non-Veterans.2 Although the VA has prioritized studies in this Veteran patient group, HFpEF remains the leading cause of hospitalization 3 and mortality 4 within the VA Health Care System. Unfortunately, the treatment of HFpEF is challenging, as traditional HF pharmacotherapy has failed at improving survival in this patient group, in part, due to poor understanding of HFpEF pathophysiology.5 Clearly, this unmet need warrants new lines of research to improve our knowledge of HFpEF and to identify alternative, therapeutic approaches to better rehabilitate this patient group. One chief symptom of HFpEF is severe exercise intolerance, an important predictor of quality of life, functional capacity, and mortality.6 In these patients, severe exercise intolerance is attributable to a disease- related loss of “peripheral vascular control,” as evidenced by a marked attenuation in exercising skeletal muscle blood flow.7 Loss of peripheral vascular control is manifested as dysfunctions of the autonomic nervous system (ANS) and vasodilatory ability of the microvasculature, thereby restraining skeletal muscle blood flow and O2 delivery and limiting the capacity for sustained physical activity.8 Indeed, insufficient microvascular blood flow and O2 delivery of the lower limbs have been linked to reduced functional capacity, as determined via six-minute walk test (6MWT), thereby exacerbating physical inactivity and exercise intolerance.9 To date, the contribution of ANS and vascular dysfunction to disease-related changes in functional capacity and exercising limb blood flow has not been evaluated in Veterans with HFpEF, and the proposed research aims to address this significant knowledge gap. There is some indication that aerobic exercise training may improve peripheral vascular function in HFpEF10 , though the mechanisms have yet to be elucidated. Our group is particularly interested in the efficacy of knee extensor (KE) training to improve functional and vascular outcomes in HFpEF, as it provides the opportunity to study peripheral responses to exercise training with minimal cardiac involvement. Our group has utilized this exercise model to investigate peripheral vascular control,7 although no studies to date have capitalized on this unique exercise training modality in Veterans with HFpEF. Thus, the purpose of this CDA-2 proposal is to determine the role of ANS dysfunction (Specific Aim 1) and of vascular dysfunction (Specific Aim 2) on exercising skeletal muscle blood flow and exercise tolerance in Veterans with HFpEF (acute phase) and the efficacy of KE training to improve these aspects of HFpEF pathophysiology (chronic phase). These proposed studies are highly relevant to Veteran Health, as they seek to address an unmet need within the VA Health Care System by (a) improving our understanding of HFpEF pathophysiology and (b) determining the efficacy of a unique exercise training modality to restore functional capacity and exercise tolerance in Veterans with HFpEF. It is anticipated that knowledge gained will offer new insight that will ultimately advance clinical practice in rehabilitative medicine, improving quality of care for Veterans suffering from this pervasive disease. My long-term career goal is to become an independent VA scientist with expertise in neurovascular and exercise physiology in Veterans with HFpEF. To meet this long-term career goal, this CDA-2 application will provide immediate unique skills and expertise via additional mentorship and scientific/professional training (i.e., knowledge, technical research, and transferrable skills) in rehabilitative medicine and clinical domains in the context of neurovascular and exercise physiology. Successful identification of peripheral vascular control mechanisms behind exercise intolerance upon completion of this CDA-2 will provide critical information for optimal exercise rehabilitation in Veterans with HFpEF and preliminary data for subsequent VA Merit Award and NIH R01 applications.

射血分数保留的心力衰竭（HFpEF）是目前最常见的 HF 表型 影响约 310 万美国人1，与非退伍军人相比，退伍军人受到的影响更大。2 尽管 VA 已优先研究该退伍军人患者组，但 HFpEF 仍然是导致该病的主要原因 退伍军人管理局医疗保健系统内的住院 3 和死亡 4 不幸的是，HFpEF 的治疗是困难的。 具有挑战性，因为传统的心力衰竭药物治疗未能改善该患者组的生存，部分原因是 对 HFpEF 病理生理学了解甚少。5 显然，这种未满足的需求需要新的研究方向 提高我们对 HFpEF 的了解，并找到替代的治疗方法来更好地恢复这种情况 HFpEF 的主要症状之一是严重的运动不耐受，这是运动质量的重要预测指标。 寿命、功能能力和死亡率。6 在这些患者中，严重的运动不耐症可归因于以下疾病： 相关的“外周血管控制”丧失，骨骼肌运动明显减弱就证明了这一点 7 周围血管控制丧失表现为自主神经系统功能障碍 (ANS) 和微脉管系统的血管舒张能力，从而抑制骨骼肌血流量和 O2 输送并限制持续身体活动的能力。8 事实上，微血管血流量不足 下肢的 O2 输送与功能能力下降有关，通过六分钟运动确定 步行测试 (6MWT)，加剧身体不活动和锻炼，从而达到耐受性。9 迄今为止，贡献 ANS 和血管功能障碍对疾病相关的功能能力和运动肢体血液变化的影响 尚未对患有 HFpEF 的退伍军人进行流量评估，拟议的研究旨在解决这一重大问题 知识差距 有一些迹象表明有氧运动训练可以改善外周血管功能。 在 HFpEF10 中，尽管其机制尚未阐明，但我们的小组对其功效特别感兴趣。 膝关节伸肌 (KE) 训练可改善 HFpEF 的功能和血管结果，因为它提供了 我们小组有机会研究运动训练的外周反应，而心脏受累最少。 利用这种运动模型来研究外周血管控制，7尽管迄今为止还没有研究表明 利用这种独特的运动训练模式对患有 HFpEF 的退伍军人进行治疗，这就是 CDA-2 的目的。 提议是确定 ANS 功能障碍（具体目标 1）和血管功能障碍（具体目标 目标 2) 锻炼 HFpEF 退伍军人的骨骼肌血流量和运动耐量（急性期） 以及 KE 训练对改善 HFpEF 病理生理学（慢性期）这些方面的功效。 拟议的研究与退伍军人健康高度相关，因为它们寻求解决退伍军人事务部内未满足的需求 医疗保健系统通过 (a) 提高我们对 HFpEF 病理生理学的理解和 (b) 确定 独特的运动训练方式对恢复退伍军人的功能能力和运动耐量的功效 预计获得的知识将提供新的见解，最终推动临床发展。 康复医学实践，提高患有这种普遍疾病的退伍军人的护理质量。 我的长期职业目标是成为一名独立的 VA 科学家，拥有神经血管和运动方面的专业知识 为了实现这一长期职业目标，该 CDA-2 应用程序将提供 HFpEF 退伍军人的生理学信息。 通过额外的指导和科学/专业培训（即， 康复医学和临床领域的知识、技术研究和可转移技能） 神经血管和运动生理学的背景成功识别外周血管控制。 完成本 CDA-2 后，运动不耐受背后的机制将为以下方面提供关键信息： 患有 HFpEF 的退伍军人的最佳运动康复以及后续 VA 优异奖的初步数据和 NIH R01 应用。