Skeletal Muscle Wasting as a Modifiable Target for Treating Patients with Heart Failure with Reduced Ejection Fraction

项目摘要 骨骼肌萎缩和分解代谢体重减轻在心力衰竭患者中非常普遍， 射血分数（HFrEF）降低，并与死亡率增加独立相关。多达一半 的晚期HFrEF患者有双重X线吸收测定法（DXA）证据表明肌肉质量显著 损失目前尚不清楚补充蛋白质是否可以逆转肌肉损失并改善身体状况。 影响患者的功能或生存。全身代谢紊乱被认为伴随着骨骼 HFrEF患者的肌肉萎缩也可能是潜在的治疗干预的来源， 肌肉质量和存活率。我们已经观察到在前3-6个月骨骼肌质量的显著增加， 左心室辅助装置植入后3个月，治疗晚期HFrEF综合征， 有助于恢复紊乱的全身新陈代谢在这个项目中，我们将进行一个随机的 口服蛋白质补充剂的对照试验，以确定其在实现临床意义 增加肌肉质量肌肉。我们还计划扩展两个主要的HFrEF特定知识 被认为是生长分化因子15（GDF-15）下游驱动肌肉萎缩的分解代谢途径 和激活素IIA/IIB型受体（ActRII）。成功完成拟议目标将有助于我们 长期目标是开发预防或逆转骨骼肌的营养和药理干预措施 从而改善HFrEF患者的身体功能和生存率。基于我们 初步和发表的数据，我们建议测试的创新假设，骨骼肌萎缩， HFrEF由分解代谢的神经体液激活促进，包括GDF-15和ActRII 途径，并且可以通过增加膳食蛋白质摄入至少部分逆转。我们将测试这个 通过招募140名患有HFrEF的成人进行GDF-15和ActRII的横断面评估 途径（目的1）和骨骼质量反应的蛋白质补充剂的机制临床试验（目的2）。 目的1将确定ActRII抑制的GDF-15是否可能是严重急性胰腺炎患者的未来疗法。 营养策略无法克服的肌肉萎缩。目标2将定义是否30克/天 连续6个月补充膳食蛋白质可提高双能X线吸收法（DXA）测定的瘦度 maa（ALM）。成功完成这些目标将确定是否需要补充膳食蛋白质 在HFrEF和分解代谢体重减轻患者的临床护理中，并为未来的研究提供平台， GDF-15中和或激活素A抑制的连续疗法。制定创新的干预措施， 促进HFrEF患者的骨骼肌质量和身体功能与NHLBI的 目的开发新的治疗心脏病的方法，改善患者的预后。

PROJECT SUMMARY Skeletal muscle wasting and catabolic weight loss are highly prevalent among patients with heart failure with reduced ejection fraction (HFrEF) and are independently associated with increased mortality. As many as half of patients with advanced HFrEF have dual X-ray absorptiometry (DXA) evidence of significant muscle mass loss. It currently unknown whether protein supplementation can reverse muscle loss and improve physical function or survival for affected patients. The deranged systemic metabolism thought to accompany skeletal muscle wasting in patients with HFrEF may also be a source of potential therapeutic intervention to improve both muscle mass and survival. We have observed significant gains in skeletal muscle mass in the first 3-6 months after implantation of a left ventricular assist device, which treats the advanced HFrEF syndrome and helps to normalize the deranged systemic metabolism. In the proposed project, we will perform a randomized controlled trial of oral protein supplementation to determine its effectiveness in achieving clinically meaningful increases in muscle mass muscle. We also plan to expand knowledge specific to HFrEF of two of the main catabolic pathways thought to drive muscle wasting downstream from growth-differentiation factor 15 (GDF-15) and the activin type IIA/IIB receptor (ActRII). Successful completion of the proposed Aims will facilitate our long-term goal to develop nutritional and pharmacological interventions that prevent or reverse skeletal muscle wasting and consequently improve physical functioning and survival for patients with HFrEF. Based on our preliminary and published data, we propose to test the innovative hypothesis that skeletal muscle wasting in HFrEF is promoted by neurohumoral activation of catabolic metabolism, including GDF-15 and ActRII pathways, and can be at least partially reversed by enhanced dietary protein intake. We will test this hypothesis by enrolling 140 adults with HFrEF for a cross-sectional assessment of GDF-15 and ActRII pathways (Aim 1) and skeletal mass response to protein supplementation in a mechanistic clinical trial (Aim 2). Aim 1 will determine whether GDF-15 of ActRII inhibition may be future therapies for patients with severe muscle wasting that cannot be overcome by nutritional strategies. Aim 2 will define whether 30 gram/day supplemental dietary protein for 6 months can increase dual X-ray absorptiometry (DXA) appendicular lean maa (ALM). Successful completion of these aims will establish if dietary protein supplementation is indicated in the clinical care of patients with HFrEF and catabolic weight loss and provide a platform for future studies of adjunctive therapies of GDF-15 neutralization or activin A inhibition. Developing innovative interventions to promote skeletal muscle mass and physical function for patients with HFrEF aligns well with the NHLBI’s objective to develop novel therapeutic approaches for treating heart diseases and improving patient outcomes.