Autonomic Circulatory Control in Patients with HFpEF

项目摘要 射血分数保留性心力衰竭（HFpEF）是发展最快的HF形式， 发病率和死亡率高。HFpEF的一个主要问题是严重的运动不耐症， 生活质量尽管已知受损的心输出量和显著的左心室舒张异常， 目前，靶向心脏功能的药物治疗不能改善运动耐量、生活质量或生存率 在HFpEF患者中。因此，HFpEF患者在静息时和静息时的更好表征是必要的。 身体活动。交感神经过度活跃存在于几种心血管疾病状态中， 交感神经活动（SNA）的增加加速了高血压（BP）的发生， 终末器官损伤的进展与血压的任何升高无关。尽管存在这些严重问题， 目前尚不清楚静息交感神经过度活跃是否参与了 HFpEF。同样，SNA控制中的损伤和由此引起的外周血管系统的变化是否会影响患者的预后。 静息和运动肌肉导致HFpEF患者出现严重的运动不耐受和预后不良 不明我们将研究骨骼肌代谢反射，一个关键的神经机制，增加SNA与 锻炼的此外，交感神经介导的血管收缩在非运动和运动的肌肉将是 研究以确定活动肌肉中血管收缩的正常钝化（即，功能 交感神经溶解）在HFpEF中受损。所有的测量将在运动训练方案前后进行 旨在最大限度地减少全身运动期间心脏充盈压的显著增加， 存在于HFpEF中。总体而言，项目3的总体目标是全面研究交感神经系统 研究HFpEF患者静息状态和运动状态下的发病机制，为HFpEF患者寻求有效的治疗方法。目标1将 确定HFpEF患者是否在休息时SNA增强，以及HFpEF患者的运动不耐受是否 与更大的交感神经反应性和受损的功能性交感神经溶解有关。我们将直接执行 使用显微神经造影术测量SNA至骨骼肌，沿着多普勒超声测量 外周血流量，在一系列实验测试，以评估SNA控制在休息和运动期间， 在有和没有HFpEF的患者中。目标2将决定是否全身训练或单腿膝关节 伸展不同地影响静息SNA、交感神经反应性、功能性交感神经溶解和肌肉 HFpEF患者的代谢反射激活。患者将被随机分配到16周的单腿 膝盖伸展，心脏不受限制，或全身训练与硝酸甘油治疗，以减弱 心脏充盈压升高（1：1比率），在术前和术后进行完整的交感神经评估 训练从本研究中获得的信息将导致对交感神经系统的全面了解。 HFpEF患者的机制，并将提供重要的洞察潜在的治疗靶点， 提高HFpEF患者生活质量和生存率。

PROJECT SUMMARY Heart failure with preserved ejection fraction (HFpEF) is the fastest growing form of HF and is associated with high morbidity and mortality. A major problem with HFpEF is severe exercise intolerance that leads to reduced quality of life. Although impaired cardiac output and marked left ventricle relaxation abnormalities are known to be present, drug therapies targeting cardiac function do not improve exercise tolerance, quality of life, or survival in HFpEF patients. Thus, a better characterization of HFpEF patients is warranted both at rest and during physical activities. Sympathetic overactivity is present in several cardiovascular disease states, and aside from contributing to high blood pressure (BP), this increase in sympathetic nerve activity (SNA) accelerates the progression of end organ damage that is independent of any rise in BP. Despite these critical problems, it remains unknown whether resting sympathetic overactivity is involved in the development and progression of HFpEF. Likewise, whether impairments in SNA control and resultant changes in the peripheral vasculature in resting and exercising muscle contribute to the severe exercise intolerance and poor prognosis present in HFpEF is unknown. We will examine the skeletal muscle metaboreflex, a key neural mechanism for increasing SNA with exercise. Also, sympathetically mediated vasoconstriction in non-exercising and exercising muscles will be investigated to determine whether the normal blunting of vasoconstriction in active muscle (i.e., functional sympatholysis) is impaired in HFpEF. All measures will be performed before and after exercise training regimens designed to minimize the marked increase in cardiac filling pressure during whole-body exercise known to be present in HFpEF. Overall, the global objective of Project 3 is to comprehensively investigate sympathetic neural mechanisms in HFpEF at rest and during exercise to seek an effective therapy for HFpEF patients. Aim 1 will determine whether HFpEF patients have enhanced SNA at rest, and whether exercise intolerance in HFpEF is associated with greater sympathetic reactivity and impaired functional sympatholysis. We will perform direct measures of SNA to skeletal muscle using microneurography, along with duplex Doppler ultrasound measures of peripheral blood flow, during a series of experimental tests to assess SNA control at rest and during exercise in patients with and without HFpEF. Aim 2 will determine whether whole-body training or single-leg knee extension differentially effects resting SNA, sympathetic reactivity, functional sympatholysis, and muscle metaboreflex activation in HFpEF patients. Patients will be randomly assigned to 16 weeks of either single-leg knee extension, where the heart is not limiting, or whole-body training with nitroglycerin treatment to attenuate the rise in cardiac filling pressure (1:1 ratio) with complete sympathetic assessments performed before and after training. Information gained from this research will lead to a comprehensive understanding of sympathetic neural mechanisms in patients with HFpEF and will provide important insight into potential therapeutic targets to improve quality of life and survival in HFpEF patients.