Central Limitations to Exercise Performance in HFpEF

项目概要/摘要 射血分数保留性心力衰竭（HFpEF）已被证明对以下治疗具有众所周知的抗性： 射血分数降低的心力衰竭（HFrEF）的标准。HFpEF患者的主要症状 是劳力性呼吸困难（DOE），导致与HFrEF患者一样严重的运动耐量受限。 然而，导致DOE和运动耐量受损的机制令人惊讶地不清楚。一个通用 研究发现，运动时肺毛细血管楔压（PCW）升高，即使是在那些患有肺动脉高压的患者中， 静息时PCW正常然而，尚不清楚这种填充压力的升高是否是导致以下症状的原因： 运动停止，或与呼吸困难相关但不是呼吸困难病因的继发性发现， 运动不耐受。检验这一假设的唯一方法是迅速降低心脏充盈压， 看看运动能力是否增加，沿着增加氧提取和HR。 因此，该项目是直接测试HFpEF中运动不耐受的“中心机制”。假设1/ 具体目的1：检验HFpEF患者因以下原因而发生DOE和功能受损的假设： 运动过程中PCW过度升高，我们将直接测量PCW，以及全面的侵入性和 在持续直立次极量和极量运动期间的无创心血管血流动力学， 以及在用有机硝酸盐（硝化甘油）降低填充压力之后。肺部超声将用于识别 “彗星尾”，沿着胸阻抗的急性变化，以评估亚临床肺动脉高压的发展 水肿假设2/特定目的2：我们假设具有“中枢表型”的HFpEF患者 （降低充盈压增加运动能力，HR和a-v O2差增加）将响应 最好的训练是在每次训练期间通过急剧降低归档压力来促进训练， 程度比训练计划专注于改善骨骼肌代谢单独（小肌肉质量 锻炼）。我们将HFpEF患者随机分为“中心表型”和“外周表型” (no运动能力的变化或持续低a-v O2差异与PCW的降低）， 运动干预（每次训练期间使用TNG急性降低PCW）或基于外周的 运动干预（单腿踢腿运动）。患者将接受包括耐力在内的16周训练 和高强度间隔，之后将重复所有基线测量。这个项目将大大提高 通过与项目2-4的紧密结合，加上影像学核心，其中骨骼的综合评估 肌肉氧利用率、自主神经功能和运动对肺部的限制将与以下内容一起进行沿着量化： 呼吸困难的高分辨率评估。在这些目标实现之后，我们将取得最大的成就。 在HFpEF中进行的运动不耐受和DOE机制的综合评估， 允许对这种复杂的多因素疾病进行详细的、“精确的”表型分析。我们还将测试特定的， 创造性的策略来提高这些患者的运动耐量。

Project Summary/Abstract Heart Failure with a Preserved Ejection Fraction (HFpEF) has proved notoriously resistant to therapies that are standard for heart failure with a reduced ejection fraction (HFrEF). The dominant symptom in patients with HFpEF is dyspnea on exertion (DOE), resulting in limited exercise tolerance that is as severe as patients with HFrEF. However the mechanisms leading to DOE and impaired exercise tolerance are surprisingly unclear. One universal finding is an elevated pulmonary capillary wedge pressure (PCW) during exercise, even in those patients with a normal PCW at rest. However it is not clear whether this rise in filling pressure is the cause of symptoms leading to exercise cessation, or rather a secondary finding which is associated with, but not causative of dyspnea and exercise intolerance. The only way to test this hypothesis for certain is to lower cardiac filling pressure acutely, and see if exercise capacity increases, along with increased oxygen extraction and HR. The global objective of this project therefore is to directly test the “central mechanism” of exercise intolerance in HFpEF. Hypothesis 1/ Specific Aim 1: To test the hypothesis that patients with HFpEF have DOE and impaired functional capacity due to an excessive rise in PCW during exercise, we will directly measure PCW, as well as comprehensive invasive and non-invasive cardiovascular hemodynamics during sustained upright submaximal and maximal exercise, before and after lowering of filling pressure with organic nitrates (nitroglycerin). Lung ultrasound will be used to identify “comet tails”, along with acute changes in thoracic impedance to assess for development of subclinical pulmonary edema. Hypothesis 2/Specific Aim 2: We hypothesize that patients with HFpEF who have a “central phenotype” (lowering filling pressure increases exercise capacity with an increase in HR and a-v O2 difference) will respond best to exercise training facilitated by the acute lowering of filing pressure during each training session to a greater degree than a training program focused on improving skeletal muscle metabolism alone (small muscle mass exercise). We will randomly assign HFpEF patients with both a “central phenotype” and a “peripheral phenotype” (no change in exercise capacity or persistently low a-v O2 diff with lowering of PCW) to either a centrally based exercise intervention (acute lowering of PCW with TNG during each training session) or a peripherally based exercise intervention (single leg kicking exercise). Patients will undergo 16 weeks of training including endurance and high intensity intervals, after which all baseline measures will be repeated. This project will be greatly enhanced by the tightly integrated link with projects 2-4 plus the imaging core in which comprehensive assessment of skeletal muscle oxygen utilization, autonomic function, and pulmonary limitations to exercise will be quantified along with high resolution assessment of dyspnea. After these aims are accomplished, we will have achieved the most comprehensive assessment of exercise intolerance and mechanisms of DOE ever performed in HFpEF, which will allow detailed, “precision” phenotyping of this complex and multifactorial disease. We also will have tested specific, creative strategies for improving exercise tolerance in such patients.