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

基本信息

批准号：
10597119
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
项目类别：
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

项目摘要

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.

心力衰竭（HF）具有保留的射血分数（HFPEF）是最普遍的HF表型，目前与非退伍军人相比，影响约310万美国人1，对退伍军人的影响不成比例。2 尽管VA已在此资深患者组中进行了优先研究，但HFPEF仍然是 VA医疗保健系统中的住院3和死亡率4。不幸的是，HFPEF的治疗是具有挑战性，因为传统的HF药物治疗未能改善该患者组的生存，部分原因是对HFPEF病理生理学的了解不足。5显然，这种未满足的需求需要新的研究线来提高我们对HFPEF的了解，并确定替代的治疗方法，以更好地修复这种情况患者组。 HFPEF的一个主要症状是严重的运动，这是质量的重要预测指标生命，功能能力和死亡率。6在这些患者中，严重的运动摄入症归因于疾病 - 相关的“周围血管控制”的相关损失，锻炼骨骼肌的明显衰减证明了血流7失去外周血管控制表现为自主神经系统功能障碍（ANS）微脉管系统的血管舒张能力，从而限制骨骼肌肉血流和O2 8的确，微血管血流不足下肢的O2递送已与降低的功能能力相关，如六分钟确定步行测试（6MWT），从而加剧了身体上的不活动和锻炼。9迄今为止，贡献与疾病相关的功能能力变化和肢体血液的变化的ANS和血管功能障碍尚未在HFPEF的退伍军人中评估流量，拟议的研究旨在解决这一重要的知识差距。有一些迹象表明有氧运动训练可能会改善周围血管功能在HFPEF10中，尽管这些机制尚未阐明。我们的小组在效率方面特别有趣膝关节扩展器（KE）训练以改善HFPEF的功能和血管结果，因为它提供了通过最少的心脏参与来研究对锻炼训练的周围反应的机会。我们的小组有利用这种运动模型来研究周围血管控制，7虽然迄今为止尚无研究使用HFPEF的退伍军人使用这种独特的运动训练方式。那是这个CDA-2的目的建议是确定ANS功能障碍（特定目标1）和血管功能障碍的作用（特定目标2）与HFPEF的退伍军人（急性期）的骨骼骨骼肌肉血流和运动耐受性以及KE培训提高HFPEF病理生理学（慢性期）的效率。这些拟议的研究与退伍军人健康高度相关，因为他们试图满足VA中未满足的需求通过（a）提高我们对HFPEF病理生理学的理解和（b）确定的医疗保健系统独特的运动训练方式的功效，以恢复退伍军人的功能能力和锻炼能力与HFPEF。预计获得的知识将提供新的见解，最终将推进临床康复医学的实践，改善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具有神经血管和运动专业知识的独立VA科学家 HFPEF的退伍军人的生理学。为了满足这个长期职业目标，该CDA-2应用程序将提供通过额外的心态和科学/专业培训（即，知识，技术研究和转移技能）在康复医学和临床领域神经血管和运动生理的背景。成功识别周围血管控制 CDA-2完成后锻炼的机制将为关键信息提供具有HFPEF的退伍军人的最佳运动康复和随后的VA优异奖和初步数据 NIH R01应用程序。