Administraive Core

项目概要/摘要 射血分数正常的心力衰竭（HFpEF）可能是最常见的“无法治疗”的疾病， 世界它占所有心力衰竭病例的50%以上，与其他心血管疾病相比， 随着疾病的流行，其发病率、死亡率和成本越来越高。HFpEF已被 对已成为心力衰竭标准治疗的“一刀切”疗法具有抗性， 射血分数（HFrEF）;因此，越来越多的压力，以更好地表型这种复合物， 多因素疾病，以指导“个性化”的病理生理学为基础的治疗。主要症状 HFpEF患者的主要危险因素是运动不耐受和劳力性呼吸困难（DOE）。这种呼吸困难可能是前- 发现，发生在非常低的外部工作水平，从而限制了身体活动，导致下降 不活动和失调的螺旋式上升，加剧了潜在的心脏和血管疾病。2012年 国家心脏、肺和血液研究所召集了一个工作组，以确定 这一领域，并建议战略，为未来的研究运动不耐症，运动训练作为一种治疗- 心脏衰竭的症状(Fleg 2015年）我们建议通过一个 一个独特的项目编制补助金，将4个项目和3个核心联系起来，以实现确定 HFpEF患者的运动不耐受和呼吸困难，并基于此病理生理学，设计cre- 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相互关联 通过在普通病人身上的合作。所有患者都将被招募到该计划的专家- 艾德招募核心;然后每例患者将通过所有4个项目进行高分辨率生理表型分析 随后进行定制的干预，旨在测试表型分析策略的临床相关性。这 方法将使我们能够实现以下具体目标：具体目标1：确定机制， 使用有创和无创心脏起搏器评估HFpEF患者的运动不耐受和呼吸困难。 肺运动试验患者将被分为主要为“中枢”受限的患者和 基于该初步评估，主要具有“外周限制”。具体目标#2：确定是否 基于高分辨率表型的“精确”运动干预将导致临床意义 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项 两个量身定制的运动干预16周：a）小肌肉质量，单腿踢运动，让 不挑战心血管储备高强度肌肉锻炼; 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负荷和改善训练。通过 通过在多个平台上研究相同的患者，我们的团队将这些努力结合到PPG中， 在改善HFpEF患者生活质量方面取得高度新颖进展的潜力。

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 increasingly 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 dyspnea 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.