Mechanisms of Exercise Intolerance in Heart Failure With Preserved Ejection Fraction: Precision Therapy Based on Patient Specific Pathophysiology

项目摘要/摘要 心力衰竭伴保留射血分数(HFpEF)可能是中国最常见的无法治愈的疾病 整个世界。它占所有心力衰竭病例的50%以上，与其他心血管疾病形成对比 除了疾病，其流行率正在增加，导致大量的发病率、死亡率和成本。HFpEF已经被 对“一刀切”疗法的抵抗力，这些疗法已经成为心力衰竭的标准治疗方法，但减少了 射血分数(HFrEF)；因此，有越来越大的压力来改善这一复杂和 多因素疾病，以指导“个性化”病理生理学为基础的治疗。主要症状 HFpEF患者多为运动耐量不足和劳力性呼吸困难(DOE)。这样的呼吸困难可能是- 发现，发生在非常低的外部工作水平，从而限制了导致向下的体力活动 不活动和解除条件的螺旋上升，加剧了潜在的心脏和血管疾病。2012年 国家心肺血液研究所召集了一个工作组，以确定在以下方面的关键知识差距 并为今后关于运动不耐受的研究提出战略建议，并将运动训练作为一种治疗-- 治疗心力衰竭。(2015年)我们建议通过一个 独特的PPG，将4个项目和3个核心联系起来，以解决确定以下机制的全球目标 HFpEF患者的运动耐量和呼吸困难，并在此基础上设计了运动耐量和呼吸困难的治疗方案。 积极的运动干预，提高生活质量。尽管几乎所有的计划项目赠款都与 通过一个共同的主题，这个PPG将是独一无二的，因为各个项目将更加紧密地联系在一起 通过共同治疗普通病人来密切合作。所有患者将由一名专科医生招募参加该计划- ED招募核心；然后每个患者将接受所有4个项目的高分辨率生理表型分析 然后是量身定做的干预措施，旨在测试表型策略的临床相关性。这 这种方法将使我们能够实现以下具体目标：具体目标1：确定机甲-- 有创与无创超声心动图对高血压性充血性心力衰竭患者运动耐量及运动耐量的影响 肺运动试验。患者将被分为主要有“中枢”限制的患者和 根据这一初步评估，主要是“外围限制”。具体目标2：确定 基于高分辨率表型的“精确”运动干预将带来临床意义 功能能力的改善和呼吸困难的减少。所有患者将随机接受一次治疗。 两种量身定制的运动干预措施，为期16周：a)小肌群，单腿踢腿运动，以允许 高强度肌肉运动而不会挑战心血管储备；b)降低心脏充盈压 在运动期间，急性摄入TNG，以允许更高的全身工作量和改进的训练。通过 通过跨多个平台研究相同的患者，我们的团队将各种努力整合为一个PPG 在改善HFpEF患者的生活质量方面取得非常新的进展的潜力。

Project Summary/Abstract Heart failure with preserved ejection fraction (HFpEF) is perhaps the most common “untreatable” disease in the world. It makes up more than 50% of all heart failure cases and in contrast to other cardiovascular diseases, its prevalence is increasing resulting in substantial morbidity, mortality, and cost. HFpEF has been resistant to “one-size-fits-all” therapies that have become standard treatment of heart failure with a reduced ejection fraction (HFrEF); therefore there has been increasing pressure to better phenotype this complex and multifactorial disease in order to direct “personalized” pathophysiology based therapy. The dominant symptom of patients with HFpEF is exercise intolerance and dyspnea on exertion (DOE). Such dyspnea can be pro- found, occur at very low levels of external work, and thereby limits physical activity leading to a downward spiral of inactivity and deconditioning which compounds the underlying cardiac and vascular disease. In 2012 The National Heart, Lung, and Blood Institute convened a working group to identify the key knowledge gaps in this field and to suggest strategies for future research on exercise intolerance, and exercise training as a treat- ment for heart failure.(Fleg 2015) We propose to address each of the working group recommendations through a unique PPG that links 4 projects and 3 cores to address the global objective of determining the mechanisms of exercise intolerance and dyspnea in patients with HFpEF and based on this pathophysiology, designing cre- ative exercise interventions that improve quality of life. Although virtually all Program Project Grants are linked together by a common theme, this PPG will be unique in that the individual projects will be linked even more closely by working together on common patients. All patients will be recruited into the Program by a specializ- ed Recruitment Core; each patient will then undergo high resolution physiological phenotyping by all 4 projects followed by a tailored intervention designed to test the clinical relevance of the phenotyping strategy. This approach will allow us to accomplish the following specific aims: Specific Aim 1: To determine the mechan- ism(s) of exercise intolerance and DOE in patients with HFpEF using invasive and non-invasive cardio- pulmonary exercise testing. Patients will be divided into those with a primarily “central” limitation and those with a primarily “peripheral limitation” based on this initial assessment. Specific Aim #2: to determine whether a “precision” exercise intervention based on the high resolution phenotyping will lead to clinically meaningful improvements in functional capacity and reduction in dyspnea. All patients will be randomized to undergo one of two tailored exercise interventions for 16 weeks: a) small muscle mass, single leg kicking exercise to allow high intensity muscle exercise without challenging cardiovascular reserve; b) reduce cardiac filling pressure during exercise with acute ingestion of TNG to allow higher systemic workloads and improved training. By combining efforts into a PPG integrated by studying the same patients across multiple platforms, our team has the potential to make highly novel advances towards improving the quality of life for patients with HFpEF.