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

心力衰竭(HF)伴射血分数保留(HFpEF)是目前最常见的心力衰竭表型 影响到约310万美国人1与非退伍军人相比，退伍军人的痛苦不成比例2 尽管退伍军人管理局优先考虑了这一资深患者组的研究，但HFpEF仍然是导致 退伍军人保健系统内的住院3人和死亡率4人。不幸的是，HFpEF的治疗是 具有挑战性，因为传统的HF药物疗法在提高这一患者组的存活率方面失败，部分原因是 显然，这种未得到满足的需求需要进行新的研究。 提高我们对HFpEF的认识，并寻找替代的治疗方法来更好地恢复这种情况 患者组。HFpEF的一个主要症状是严重的运动耐受，这是一个重要的质量预测指标 生命、功能能力和死亡率。6在这些患者中，严重的运动不耐受可归因于一种疾病- 相关的“外周血管控制”的丧失，表现为骨骼肌运动的显著减弱 失去对周围血管的控制表现为自主神经系统功能障碍。 (ANS)和微血管系统的血管扩张能力，从而抑制骨骼肌血流量和氧气 8确实，微血管血流不足。 通过6分钟的测试，我们可以发现，腿部的氧气输送与功能能力下降有关 步行试验(6MWT)，从而加剧了身体缺乏活动和运动耐量。 ANS和血管功能障碍与疾病相关的功能能力和运动肢体血液变化的关系 退伍军人在接受HFpEF治疗时的心流尚未得到评估，拟议的研究旨在解决这一重大问题 知识鸿沟。有一些迹象表明，有氧运动训练可以改善周围血管功能 在HFpEF10中，尽管其作用机制尚不清楚。我们小组特别感兴趣的是它的功效 膝关节伸肌(KE)训练以改善HFpEF的功能和血管结果，因为它提供了 有机会研究对运动训练的外周反应，并将心脏损害降至最低。我们的团队已经 利用这个运动模型来研究外周血管控制，7尽管到目前为止还没有研究 在患有HFpEF的退伍军人中利用这一独特的运动训练模式。因此，CDA-2的目的是 建议确定ANS功能障碍(特定目标1)和血管功能障碍(特定目标1)的作用 目的2)退伍军人HFpEF(急性期)运动骨骼肌血流量和运动耐量的研究 以及KE训练对改善HFpEF病理生理学(慢性期)这些方面的疗效。这些 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管理局内未得到满足的需求 通过(A)提高我们对HFpEF病理生理学的了解和(B)确定 一种独特的运动训练模式对恢复退伍军人功能能力和运动耐量的效果 使用HFpEF。预计所获得的知识将提供新的见解，最终将推动临床 在康复医学方面的实践，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退伍军人管理局科学家，拥有神经血管和运动方面的专业知识 退伍军人高频肺功能的生理学研究。为了实现这一长期的职业目标，这项CDA-2申请将提供 通过额外的指导和科学/专业培训直接获得独特的技能和专业知识(即， 知识、技术研究和可移植技能)在康复医学和临床领域 神经血管和运动生理学的背景知识。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 HFpEF退伍军人的最佳运动康复和随后的VA优秀奖和 NIH R01应用程序。

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.