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.

运动性呼吸困难(DOE)和运动不耐受是射血功能受损的心力衰竭的显著症状。 分数(HFpEF)。这两种症状的发病机制尚不清楚。DOE的潜在机制包括 多种因素，包括肺限制、运动呼吸限制、中枢心血管 限制，外周血管/肌肉限制，自主神经控制改变，最后是肥胖。肥胖 减少肺容量细分并夸大与年龄相关的最大呼气流量增加的下降 运动中呼气流速受限和动态过度充气的风险，这两种反应都与 无名氏。肥胖还会增加运动、呼吸需求、呼吸功的能量需求，以及 运动不耐受；所有这些变化也会影响DOE。事实上，三分之一的肥胖成年人经历了 DOE和许多HFpEF患者都很肥胖。成年人的无名氏可以通过运动训练来减弱，这是因为 适应。然而，与传统的治疗方法相比，肥胖症对HFpEF患者的影响被低估了。 认为是肺毛细血管楔压(PCW)升高所致。整体而言 项目4的目标是研究肥胖和运动耐量异常的机制。 非肥胖型HFpEF患者。目标1)我们将研究肥胖(肥胖相关的改变)之间的相互作用 肺功能和身体成分，包括腹部脂肪)和HFpEF(肺功能的潜在变化) 静息和次极量骑车运动时的肺活量储备及其与DOE和 肥胖型HFpEF患者与非肥胖型HFpEF患者运动耐量的比较，以及肥胖和 未使用HFpEF的非肥胖者。我们假设肥胖和HFpEF导致的呼吸受限将 联合起来限制运动期间的通风储备，这将引发更大的DOE和运动不耐受 目的2)我们将调查肺血管功能的影响(包括 舌下含服硝酸甘油降低PCW对运动耐量和DOE的影响 次极量恒定负荷自行车运动(&在磁共振肺水含量成像期间)。我们假设 SL TNG治疗肥胖型HFpEF对DOE的影响可能不如非肥胖型HFpEF 通过SL TNG治疗减少PCW不会改变肥胖相关呼吸受限的患者； 和目标3)我们将通过耐力训练来检验中央和外围运动限制的影响 训练结合SL TNG治疗(改善中心心功能)和单腿踢腿运动训练 (改善外周肌肉/血管功能)持续时间对HFpEF患者DOE和运动耐量的影响 负荷量低于极限的自行车运动。我们假设中枢和外周运动训练都会减少 在肥胖的HFpEF患者中，由于感觉适应(即与非肥胖患者相比)，DOE的影响程度更大。我们的龙 学期目标是了解HFpEF患者DOE和运动耐量障碍的机制，并提供 新的结果可能改变治疗HFpEF患者DOE的传统方法。