Targeting skeletal muscle to improve exercise capacity in heart failure with preserved ejection fraction.

项目摘要 射血分数保留性心力衰竭（HFpEF）是心力衰竭中增长最快的一种，几乎是 这种疾病只发生在老年人身上，发病率和死亡率都很高。主 HFpEF患者的慢性症状是严重的运动不耐受，客观地测量为峰值降低 运动摄氧量（峰值VO 2）。按照惯例，迄今为止的大部分工作都集中在中央 然而，靶向心脏功能的药物治疗并不能改善HFpEF患者的峰值VO 2或生存率。 来自我们小组的新证据表明，外周“非心脏”因素（例如瘦体重减少， 受损的氧化能力和肌肉血流量）显著有助于HFpEF中峰值VO 2的降低。 运动训练是唯一经证实的增加老年HFpEF患者峰值VO 2的疗法，然而， 外周机制（骨骼肌O2输送/提取，氧化能力）负责此 改进是未知。以前的运动训练研究的局限性是主要集中在全身 在心脏充盈压显著增加和心输出量受损的情况下进行的运动 储备-发生在HFpEF-可能不是一个最佳的形式，这些患者的训练。运动训练 模式侧重于消除对运动的中心限制（如动态单腿膝关节 [2019 - 04 - 15][2019 - 04][2019 - 04]因此，本项目致力于定义：a） 导致HFpEF中运动不耐受的特定“外周机制”，和B）特定 “外围”适应运动训练。为了实现这一目标，我们将首次直接 ≥ 腿部VO 2、腿部O2（对流和扩散）运输和提取的测量，使用有创血管内 老年人（60岁）HFpEF最大动态单腿KE运动期间的测量和多普勒超声 具有“原发性中枢”表型的患者（A型，n=40），“原发性外周”表型的患者（B型， n=40）和对照组（n=20）。我们的计划授予成像核心，我们也将执行最全面的， 在静息时和对以下反应的骨骼肌代谢（1H和31 P NMR光谱）的体内评估 动态练习在基线测试后，“A”型和“B”型HFpEF患者将被随机分配到两个 不同形式的训练，每一种都专注于消除锻炼的中心限制 （第1组：单腿动力KE运动;或第2组：在周期前和周期中舌下含服硝酸甘油 运动训练以降低心脏充盈压）。鉴于运动不耐受的病理生理学， 体育训练的改善机制知之甚少，也没有药物治疗。 被证明是有效的，我们的研究结果有可能改变范式，并对 在短期内管理HFpEF老年患者。

PROJECT SUMMARY Heart failure with preserved ejection fraction (HFpEF) is the fastest growing form of heart failure, is almost exclusively found in older persons and is associated with a high morbidity and mortality rate. The primary chronic symptom in HFpEF patients is severe exercise intolerance measured objectively as decreased peak exercise oxygen uptake (peak VO2). By convention, the majority of work to date has focused on central limitations, however drug therapies targeting cardiac function do not improve peak VO2 or survival in HFpEF. Emerging evidence from our group suggests that peripheral `non-cardiac' factors (e.g. decreased lean mass, impaired oxidative capacity and muscle blood flow) contribute significantly to the reduced peak VO2 in HFpEF. Exercise training is the only proven therapy to increase peak VO2 in older HFpEF patients, however the peripheral mechanisms (skeletal muscle O2 delivery/extraction, oxidative capacity) responsible for this improvement are unknown. A limitation of prior exercise training studies was the primary focus on whole body exercise which in the setting of marked increases in cardiac filling pressures and impaired cardiac output reserve—as occurs in HFpEF—may not be an optimal form of training for these patients. Exercise training modalities focused on removing the central limitation to exercise (as occurs with dynamic single-leg knee extension [KE] exercise) may prove more effective. Accordingly, the current project is dedicated to defining: a) the specific “peripheral mechanism(s)” contributing to exercise intolerance in HFpEF, and b) specific “peripheral” adaptations to exercise training. To achieve this objective, we will perform the first ever-direct ≥ measure of leg VO2, leg O2 (convective and diffusive) transport and extraction, using invasive intravascular measures and Dopper ultrasound, during maximal dynamic single-leg KE exercise in older ( 60 years) HFpEF patients with a “primary central” phenotypye (Type A, n=40), “primary peripheral” phenotype (Type B, n=40) and controls (n=20). Our program grant Imaging Core we will also perform the most comprehensive in vivo assessment of skeletal muscle metabolism (1H and 31P NMR spectroscopy) at rest and in response to dynamic exercise. After baseline testing, Type “A” and “B” HFpEF patients will be randomly assigned to two different forms of training, each which are uniquely focused on removing the central limitation to exercise (Group 1: dynamic single-leg KE exercise; or Group 2: sublingual nitroglycerin given prior to and during cycle exercise training to lower cardiac filling pressures). Given the pathophysiology of exercise intolerance and mechanisms for improvement with physical training is poorly understood, and no medications have been proven effective, our results have the potential to shift paradigms, and have a major impact on the management of older patients with HFpEF in a short-time period.