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

项目总结 心力衰竭伴保留射血分数(HFpEF)是心力衰竭中增长最快的形式，几乎 仅见于老年人，并与高发病率和死亡率有关。初级阶段 HFpEF患者的慢性症状是严重的运动耐量，客观测量为峰值降低 运动摄氧量(最大摄氧量)。按照惯例，到目前为止，大部分工作都集中在中央 然而，针对心脏功能的药物治疗并不能改善HFpEF的VO2峰值或存活率。 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， 氧化能力和肌肉血流受损)是HFpEF中VO2峰值降低的重要原因。 运动训练是唯一被证实可以增加老年HFpEF患者峰值VO2的治疗方法，然而 导致这种情况的外周机制(骨骼肌氧输送/提取、氧化能力) 改进是未知的。以前的运动训练研究的局限性是主要关注全身 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--就像在HFpEF中发生的那样--可能不是这些患者的最佳训练形式。运动训练 医疗模式侧重于消除运动的中心限制(就像动感的单腿膝盖一样 推广[可]练习)可能被证明更有效。因此，目前的项目致力于界定：a) 运动耐量增加的具体“外周机制(S)”，和b)特异性 对运动训练的“外围”适应。为了实现这一目标，我们将进行有史以来第一次直接 ≥ 使用有创血管内技术测量腿部VO2、腿部O2(对流和扩散)的传输和提取 老年人(60岁)最大动态单腿KE运动中的测量和多普勒超声 具有“原发中心型”表型(A型，n=40)、“原发外周”表型(B型， N=40)和对照组(n=20)。我们的计划授予成像核心，我们还将在 静息和运动后骨骼肌代谢的活体评估(1H和31P核磁共振波谱) 动感运动。在基线测试后，A型和B型HFpEF患者将被随机分配到两组 不同的训练形式，每一种都专注于消除锻炼的中心限制 (第1组：单腿动态KE运动；第2组：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和 人们对体育锻炼的改善机制知之甚少，也没有药物治疗 事实证明，我们的结果是有效的，有可能改变范式，并对 高龄患者HFpEF的短期处理。

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.