Pulmonary Mechanisms of Dyspnea in HFpEF: Impact of Obesity

HFpEF 呼吸困难的肺部机制：肥胖的影响

• 批准号: 10551308
• 负责人: TONY G BABB
• 金额: $ 38.15万
• 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/10551308
• 关键词: 3-Dimensional; Activities of Daily Living; Adult; Affect; Affective; Attenuated; Blood Vessels; Blood flow; Body Composition; Body Weight decreased; Breathing; Cardiac; Cardiac Output; Cardiovascular system; Cell Respiration; Coupled; Diffusion; Disease; Distress; Dyspnea; EFRAC; Exercise; Exercise Tolerance; Exertion; Feeling; Functional disorder; Goals; Heart; Heart failure; Image; Leg; Lung; Magnetic Resonance Imaging; Measurement; Muscle; Nitroglycerin; Non obese; Obesity; Patients; Peripheral; Phenotype; Physiological; Precision therapeutics; Pulmonary Capillary Wedge Pressure; Resolution; Rest; Risk; Sensory; Symptoms; Thinking; Water; Work of Breathing; abdominal fat; adult obesity; age related; clinically relevant; density; design; emotional distress; endurance exercise; exercise intolerance; exercise training; experience; heart function; improved; lung imaging; lung volume; neural; novel; obese patients; preservation; pulmonary body; pulmonary function; pulmonary vascular disorder; respiratory; response; uptake

Dyspnea on exertion (DOE) and exercise intolerance are hallmark symptoms of heart failure with preserved ejection fraction (HFpEF). The mechanisms of these two symptoms are unknown. Potential mechanisms for DOE are numerous and multifactorial, including pulmonary limitations, exercise ventilatory limitations, central cardiovascular limitations, peripheral vascular/muscle limitations, autonomic control alterations, and lastly obesity. Obesity decreases lung volume subdivisions and exaggerates the age-related decline in maximal expiratory flow increasing the risk of expiratory flow limitation and dynamic hyperinflation during exercise, both responses associated with DOE. Obesity also increases the energy requirement of exercise, ventilatory demand, the work of breathing, and exercise intolerance; all these alterations can also influence DOE. Indeed, one third of obese adults experience DOE and many HFpEF patients are obese. DOE can be attenuated in adults by exercise training due to ‘sensory adaptation. However, the effect of obesity in HFpEF patients is underappreciated, in contrast to conventional thinking, which assumes that increased pulmonary capillary wedge pressure (PCW) is responsible. The overall objective of Project 4 is to investigate the mechanisms of DOE and exercise intolerance in obese and nonobese HFpEF patients. Aim 1) We will examine the interaction of obesity (obesity-related alterations in pulmonary function & body composition including abdominal fat) and HFpEF (underlying changes in lung function) on ventilatory reserves at rest and during submaximal cycling exercise, and their associations (if any) with DOE and exercise intolerance in obese HFpEF patients as compared with nonobese HFpEF patients, and obese and nonobese patients without HFpEF. We hypothesize that breathing limitations due to obesity and HFpEF will combine to limit ventilatory reserves during exercise, which will provoke greater DOE and exercise intolerance in the obese HFpEF patients; Aim 2) We will investigate the effects of pulmonary vascular function (including the effects of decreased PCW via sublingual nitroglycerin, SL TNG, treatment,) on DOE and exercise tolerance during submaximal constant load cycling exercise (& during MR imaging for lung water content). We hypothesize that DOE may not be decreased as much by SL TNG treatment in obese HFpEF patients as in nonobese HFpEF patients since obesity-related respiratory limitations will not be altered by decreased PCW via SL TNG treatment; and Aim 3) We will examine the effects of central and peripheral exercise limitations via endurance exercise training coupled with SL TNG treatment (improved central cardiac function) and single leg kicking exercise training (improved peripheral muscle/vascular function) on DOE and exercise tolerance in HFpEF patients during constant load submaximal cycling exercise. We hypothesize that both central and peripheral exercise training will decrease DOE to a greater extent in obese HFpEF patients due to sensory adaptation (i.e., vs nonobese patients). Our long term goal is to understand the mechanisms of DOE and exercise intolerance in patients with HFpEF, and provide novel results that could alter conventional approaches for treating DOE in patients with HFpEF.

劳动呼吸困难（DOE）和运动摄入术是心力衰竭的标志性症状，保留了射血 分数（HFPEF）。这两种症状的机制尚不清楚。 DOE的潜在机制是 许多和多因素，包括肺部限制，运动通风限制，中央心血管 局限性，周围血管/肌肉局限性，自主控制改变以及最后的肥胖症。肥胖 减少肺部体积细分，并夸大与年龄有关的最大呼气流量下降 在运动过程中，到期流量限制和动态过度充电的风险，这两个反应与 母鹿。肥胖还增加了运动的能量需求，通风需求，呼吸工作以及 锻炼；所有这些变化也会影响能源部。确实，三分之一的肥胖成年人经历 DOE和许多HFPEF患者肥胖。由于“感觉” 适应。但是，与常规的相比，肥胖对HFPEF患者的影响不足 认为肺毛细血管楔压（PCW）是负责的思维。总体 项目4的目的是调查肥胖和肠道和运动的机制 非肥胖HFPEF患者。目的1）我们将检查肥胖的相互作用（与肥胖相关的改变 肺功能和身体成分，包括腹部脂肪）和HFPEF（肺功能的潜在变化） 在静止和次最大骑自行车运动中进行通风储备，及其与DOE的关联（如果有） 与非肥胖HFPEF患者以及肥胖和肥胖和肥胖患者相比 没有HFPEF的非肥胖患者。我们假设由于肥胖和HFPEF引起的呼吸限制 结合限制运动过程中的通气储备 肥胖的HFPEF患者；目标2）我们将研究肺血管功能的影响（包括 PCW通过舌下硝酸甘油，SL TNG，治疗，DOE和运动耐受性降低的影响 次最大的恒定载荷循环运动（及其在肺水含量的MR成像期间）。我们假设这一点 肥胖HFPEF患者的SL TNG治疗可能不会像非肥胖HFPEF那样改善DOE 患者由于与肥胖相关的呼吸局限性不会通过SL TNG治疗减少而改变。 目标3）我们将通过耐力运动研究中心和外围运动限制的影响 训练与SL TNG治疗（改善中心功能）和单腿踢运动训练相结合 （改善外周肌/血管功能）在恒定过程中，HFPEF患者的DOE和运动耐受性 负载次最大骑自行车运动。我们假设中央和外围运动训练都会减少 由于感觉适应的肥胖HFPEF患者（即与非肥胖患者），DOE在更大程度上。我们的漫长 术语目标是了解HFPEF患者的DOE和运动含量的机制，并提供 新的结果可能会改变HFPEF患者治疗DOE的常规方法。