Autonomic Circulatory Control in Patients with HFpEF

HFpEF 患者的自主循环控制

• 批准号: 10551305
• 负责人: QI FU
• 金额: $ 44.87万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-09 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551305
• 关键词: Acceleration; Activities of Daily Living; Affect; Attenuated; Baroreflex; Blood Pressure; Blood Vessels; Blood flow; Cardiac; Cardiac Output; Cardiovascular Diseases; Cardiovascular system; Clinical; Clinical Management; Data; Development; Disease; Doppler Ultrasound; EFRAC; Exercise; Exercise Tolerance; Feedback; Functional disorder; Heart; Heart failure; Homeostasis; Hypertension; Impairment; Knee; Left ventricular structure; Leg; Measures; Mediating; Metabolic; Morbidity - disease rate; Muscle; Muscle Fibers; Nerve; Nitroglycerin; Organ; Outcome; Patients; Peripheral; Pharmaceutical Preparations; Physical activity; Play; Precision therapeutics; Prognosis; Quality of life; Randomized; Reflex action; Regimen; Relaxation; Research; Rest; Role; Series; Skeletal Muscle; Sterile coverings; Sympathetic Nervous System; Testing; Training; Treatment Protocols; Visceral; Walking; design; effective therapy; exercise capacity; exercise intolerance; exercise training; functional disability; heart function; improved; insight; mode of exercise; mortality; muscle form; neuromechanism; neuroregulation; peripheral blood; preservation; pressure; targeted treatment; therapeutic target; therapeutically effective; vasoconstriction

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.

项目概要 射血分数保留的心力衰竭 (HFpEF) 是增长最快的 HF 形式，与 发病率和死亡率高。 HFpEF 的一个主要问题是严重的运动不耐受，导致运动能力下降 生活质量。尽管已知心输出量受损和明显的左心室舒张异常 目前，针对心脏功能的药物治疗并不能改善运动耐量、生活质量或生存率 HFpEF 患者。因此，有必要对 HFpEF 患者在休息时和治疗期间进行更好的表征。 体力活动。交感神经过度活跃存在于几种心血管疾病状态中，除了 交感神经活动 (SNA) 的增加会加速高血压 (BP) 终末器官损伤的进展与血压的升高无关。尽管存在这些关键问题， 目前尚不清楚静息交感神经过度活跃是否与该病的发生和进展有关 HFpEF。同样，SNA 控制的损害以及由此导致的外周脉管系统的变化是否会导致 休息和运动肌肉会导致 HFpEF 出现严重的运动不耐受和不良预后 未知。我们将检查骨骼肌代谢反射，这是增加 SNA 的关键神经机制 锻炼。此外，非运动和运动肌肉中交感神经介导的血管收缩将 研究以确定活跃肌肉（即功能性肌肉）的血管收缩是否正常减弱 HFpEF 中交感神经功能受损。所有措施将在运动训练方案之前和之后进行 旨在最大限度地减少已知的全身运动期间心脏充盈压的显着增加 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 静息和运动期间 HFpEF 的机制，以寻求 HFpEF 患者的有效治疗方法。目标1将 确定 HFpEF 患者静息时 SNA 是否增强，以及 HFpEF 中的运动不耐受是否与 与交感神经反应性增强和交感功能受损有关。我们将直接执行 使用显微神经造影和双工多普勒超声测量对骨骼肌进行 SNA 测量 外周血流量，在一系列实验测试中评估静息和运动期间的 SNA 控制 患有和不患有 HFpEF 的患者。目标2将决定是全身训练还是单腿膝盖训练 伸展对静息 SNA、交感反应性、功能性交感神经和肌肉的影响不同 HFpEF 患者的代谢反射激活。患者将被随机分配接受 16 周的单腿治疗 在心脏不受限制的情况下进行膝关节伸展，或使用硝酸甘油治疗进行全身训练以减弱 前后进行完整交感神经评估后心脏充盈压升高（1:1 比例） 训练。从这项研究中获得的信息将有助于全面了解交感神经 HFpEF 患者的机制，并将为潜在的治疗靶点提供重要的见解 改善 HFpEF 患者的生活质量和生存率。