Pulmonary Mechanisms of Dyspnea in HFpEF: Impact of Obesity

劳力性呼吸困难和运动不耐受是射血功能保留性心力衰竭的标志性症状 分数（HFpEF）。这两种症状的机制尚不清楚。DOE的潜在机制包括 众多且多因素，包括肺部限制、运动限制、中枢心血管 限制，外周血管/肌肉限制，自主控制改变，最后是肥胖。肥胖 减少肺容量细分，并夸大最大呼气流量增加的年龄相关性下降 运动期间呼气流量限制和动态过度充气的风险，这两种反应与 能源部肥胖还增加了运动的能量需求、排泄需求、呼吸功， 运动不耐受;所有这些改变也会影响DOE。事实上，三分之一的肥胖成年人 DOE和许多HFpEF患者肥胖。由于“感觉”，运动训练可以减弱成年人的DOE 适应然而，与传统的HFpEF患者相比， 认为肺毛细血管楔压（PCW）增加是原因。整体 项目4的目的是研究肥胖和肥胖症患者DOE和运动不耐受的机制， 非肥胖HFpEF患者。目的1）我们将研究肥胖的相互作用（肥胖相关的改变， 肺功能和身体组成，包括腹部脂肪）和HFpEF（肺功能的潜在变化） 在休息时和次极量自行车运动期间，以及它们与DOE的关联（如果有的话）， 与非肥胖HFpEF患者相比，肥胖HFpEF患者的运动不耐受， 无HFpEF的非肥胖患者。我们假设由于肥胖和HFpEF引起的呼吸限制 联合收割机限制运动过程中的能量储备，这将引起更大的DOE和运动不耐受， 目的2）探讨肥胖HFpEF患者肺血管功能（包括肺动脉收缩功能）的影响。 舌下含服硝酸甘油（SL TNG）治疗降低PCW对DOE和运动耐量的影响 次最大恒定负荷循环运动（&在肺水含量的MR成像期间）。我们假设 SL TNG治疗肥胖HFpEF患者的DOE降低程度可能不及非肥胖HFpEF患者 患者，因为通过SL TNG治疗减少PCW不会改变肥胖相关的呼吸限制; 和目的3）我们将通过耐力运动来检查中枢和外周运动限制的影响 训练结合SL TNG治疗（改善中心心脏功能）和单腿踢腿运动训练 （改善外周肌肉/血管功能）对HFpEF患者在恒定 负荷次极量自行车运动。我们假设中枢和外周运动训练都会减少 由于感觉适应，肥胖HFpEF患者的DOE程度更大（即，与非肥胖患者相比）。我们漫长 长期目标是了解HFpEF患者DOE和运动不耐受的机制，并提供 新的结果可能会改变HFpEF患者治疗DOE的传统方法。

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.