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.

项目摘要 心力衰竭，保留的射血分数（HFPEF）是HF的最快生长形式，与 高发病和死亡率。 HFPEF的一个主要问题是严重的运动不耐受，导致减少 生活质量。尽管已知心脏输出受损和明显的左心室松弛异常 存在，靶向心脏功能的药物疗法不能提高运动耐受性，生活质量或生存 在HFPEF患者中。因此，在休息和期间，保证HFPEF患者的更好表征 体育活动。几种心血管疾病状态中存在交感神经过度活动，除了 有助于高血压（BP），交感神经活动（SNA）的这种增加加速了 最终器官损伤的进展与BP的任何升高无关。尽管存在这些关键问题 尚不清楚休息的同情过度活动是否涉及 HFPEF。同样，SNA控制中的损伤以及导致的外周脉管系统的变化是否 静止和锻炼肌肉有助于HFPEF中严重的运动不耐症和预后不良 是未知的。我们将检查骨骼肌代谢反射，这是一种关键的神经机制，用于增加SNA 锻炼。同样，在非运动和锻炼肌肉中的同情介导的血管收缩将是 研究以确定活性肌肉血管收缩的正常钝化（即功能性） HFPEF中的交感神经解析）。所有措施将在运动训练方案之前和之后执行 设计以最大程度地减少全身运动中心脏填充压力的明显增加 存在于HFPEF中。总体而言，项目3的全球目标是全面研究同情神经 HFPEF的机制在休息和运动过程中为HFPEF患者寻求有效的疗法。目标1意志 确定HFPEF患者是否在休息时增强了SNA，以及HFPEF中的运动不耐受是 与更大的交感神经反应性和功能交感神经能力受损相关。我们将直接执行 使用微功能学的SNA度量到骨骼肌，以及双工多普勒超声措施 外周血流量，在一系列实验测试中，以评估静止和锻炼过程中的SNA控制 在患有和没有HFPEF的患者中。 AIM 2将确定全身训练还是单腿膝关节 伸展对静止的SNA，交感反应性，功能性交感解和肌肉的差异影响 HFPEF患者的代谢反射激活。患者将被随机分配到任一条腿的16周 膝盖伸展，心脏不限制，或通过硝酸甘油治疗进行全身训练以减弱 心脏填充压力的升高（1：1比率），并在 训练。从这项研究中获得的信息将导致对同情神经的全面理解 HFPEF患者的机制，将为潜在的治疗靶标提供重要的见解 改善HFPEF患者的生活质量和生存质量。