Central Limitations to Exercise Performance in HFpEF

项目摘要/摘要 具有保留射血分数的心力衰竭(HFpEF)已被证明对以下疗法具有众所周知的耐药性 降低射血分数的心力衰竭标准(HFrEF)。高血压性肺功能衰竭患者的主要症状 是劳力性呼吸困难(DOE)，导致有限的运动耐量，与HFrEF患者一样严重。 然而，导致DOE和运动耐量受损的机制令人惊讶地不清楚。一个万能的 发现在运动过程中肺毛细血管楔压(PCW)升高，即使在那些患有 静息时PCW正常。然而，目前尚不清楚这种充盈压力的上升是否是导致 运动停止，或者更确切地说，是与呼吸困难有关但不是导致呼吸困难的继发性发现 运动不耐受。确定检验这一假设的唯一方法是大幅降低心脏充盈压，并且 看看运动量是否会随着氧气摄取和心率的增加而增加。这样做的全球目标是 因此，该项目将直接测试HFpEF中运动不耐受的“核心机制”。假设1/ 具体目标1：检验HFpEF患者存在DOE并因以下原因而功能受损的假设 运动中PCW的过度上升，我们将直接测量PCW，以及全面的侵袭性和 持续直立次极量和最大强度运动前的无创心血管血流动力学 在用有机硝酸盐(硝化甘油)降低灌装压力后。肺部超声将被用于识别 “彗星尾巴”与胸阻抗的急性变化一起评估亚临床肺病的发展 浮肿。假设2/特定目标2：我们假设具有“中心表型”的HFpEF患者 (降低充盈压力会增加运动能力，增加心率和a-v O2差) 最好是在每次训练期间通过急剧降低文件压力来促进训练 学位而不是只专注于改善骨骼肌代谢的训练计划(小肌群 锻炼)。我们将随机将HFpEF患者分为“中枢表型”和“外周表型”。 (运动能力没有变化或随着PCW的降低而持续降低a-v O2 diff)到基于中枢的 运动干预(每次训练期间用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，在此之后将重复所有基线测量。这个项目将得到极大的加强 通过与项目2-4的紧密结合加上成像核心，其中对骨骼进行全面评估 肌肉对氧的利用、自主神经功能和对运动的肺限制将与 呼吸困难的高分辨率评估。当这些目标实现之后，我们就达到了最大的成就。 在HFpEF中对运动耐量和DOE机制进行了全面评估，这将 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， 为改善此类患者的运动耐量而采取的创造性策略。

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.