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

射血分数正常的心力衰竭（HF）（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，退伍军人受到不成比例的影响。 尽管VA优先考虑了该退伍军人患者组的研究，但HFpEF仍然是 在VA医疗保健系统中，住院率3和死亡率4。不幸的是，HFpEF的治疗 具有挑战性，因为传统的HF药物治疗未能改善该患者组的生存率，部分原因是 5显然，这种未满足的需求需要进行新的研究， 提高我们对HFpEF的认识，并确定替代的治疗方法，以更好地恢复这一点 患者组。HFpEF的一个主要症状是严重的运动不耐受，这是HFpEF质量的一个重要预测因素。 在这些患者中，严重的运动不耐受可归因于一种疾病- 与“外周血管控制”相关的丧失，如运动骨骼肌的明显衰减所证明 血流。7外周血管控制的丧失表现为自主神经系统功能障碍 (ANS)和微血管系统的血管舒张能力，从而抑制骨骼肌血流和O2 输送和限制持续体力活动的能力。8事实上， 下肢的氧气输送与功能能力下降有关，这是通过6分钟的 步行试验（6 MWT），从而加剧身体活动不足和运动不耐症。 ANS和血管功能障碍的疾病相关的功能能力和运动肢体血液的变化 尚未对HFpEF退伍军人的血流进行评估，拟议的研究旨在解决这一重大问题。 知识差距。有迹象表明有氧运动训练可以改善外周血管功能 在HFpEF 10中，尽管机制尚未阐明。我们的研究小组特别关注 膝伸肌（KE）训练，以改善HFpEF的功能和血管结局，因为它提供了 有机会研究外周反应运动训练与最小的心脏参与。我们集团 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 在HFpEF退伍军人中利用这种独特的运动训练模式。因此，本CDA-2的目的 建议是确定ANS功能障碍（具体目标1）和血管功能障碍（具体目标2）的作用。 目的2）对HFpEF（急性期）退伍军人的运动骨骼肌血流量和运动耐量进行研究 以及KE训练改善HFpEF病理生理学（慢性期）这些方面的功效。这些 拟议的研究与退伍军人健康高度相关，因为它们试图解决退伍军人管理局内部未满足的需求 通过（a）提高我们对HFpEF病理生理学的理解和（B）确定 一种独特的运动训练方式对恢复退伍军人功能能力和运动耐量的有效性 HFpEF。预计所获得的知识将提供新的见解，最终推动临床 在康复医学实践中，提高对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，在神经血管和运动方面具有专业知识。 HFpEF退伍军人的生理学。为了实现这个长期的职业目标，这个CDA-2应用程序将提供 通过额外的指导和科学/专业培训（即， 知识，技术研究和可转移的技能），在康复医学和临床领域， 神经血管和运动生理学的背景。成功识别外周血管控制 完成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： HFpEF退伍军人的最佳运动康复和随后VA优异奖的初步数据， NIH R 01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.