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

骨骼肌萎缩作为治疗射血分数降低的心力衰竭患者的可修改目标

• 批准号: 10567792
• 负责人: Amanda Ruth Vest
• 金额: $ 43.05万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10567792
• 关键词: Activins; Adult; Affect; Aging; American; Antibodies; Automobile Driving; Blood; Body Weight decreased; Catabolism; Chronic; Clinical; Clinical Trials; Counseling; Data; Development; Devices; Diagnosis; Dietary Proteins; EFRAC; Effectiveness; Eligibility Determination; Enrollment; FSTL3 gene; Fatty acid glycerol esters; Fc Receptor; Follistatin; Future; GDF15 gene; Goals; Heart Diseases; Heart failure; Impairment; Inflammatory; Intervention; Knowledge; Left; Ligands; Literature; Medical; Metabolic; Metabolism; Molecular; Muscle; Muscular Atrophy; Myocardium; N-terminal; National Heart, Lung, and Blood Institute; Natriuretic Peptides; Natural experiment; Nutritional; Nutritional Requirements; Oral; Organ failure; Outcome; Pathway interactions; Patient Care; Patient-Focused Outcomes; Patients; Pharmacology; Pharmacotherapy; Phase; Physical Function; Physical Performance; Physical assessment; Proteins; Public Health; Publishing; Pump; Randomized, Controlled Trials; Receptor Inhibition; Recovery; Roentgen Rays; Skeletal Muscle; Source; Supplementation; Syndrome; Testing; Therapeutic; Therapeutic Clinical Trial; Therapeutic Intervention; Thinness; Translating; United States; Ventricular; Walking; activin A; cancer cachexia; clinical care; heart metabolism; implantation; improved; innovation; left ventricular assist device; mortality; muscle form; muscle strength; novel therapeutic intervention; novel therapeutics; nutrition; nutritional supplementation; pharmacologic; prevent; pro-brain natriuretic peptide (1-76); protein intake; receptor; response; skeletal; skeletal muscle wasting; therapeutic target; wasting

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.

项目概要 骨骼肌萎缩和分解代谢性体重减轻在心力衰竭患者中非常普遍 射血分数（HFrEF）降低，与多达一半的死亡率增加独立相关。 的晚期 HFrEF 患者有双 X 射线吸收测定法 (DXA) 证据表明肌肉质量显着 目前尚不清楚补充蛋白质是否可以逆转肌肉损失并改善体质。 受影响患者的功能或生存被认为伴随骨骼的全身代谢紊乱。 HFrEF 患者的肌肉萎缩也可能是改善其潜在治疗干预的一个来源 我们观察到在前 3-6 天内骨骼肌质量显着增加。 植入左心室辅助装置几个月后，该装置可治疗晚期 HFrEF 综合征 有助于使紊乱的全身代谢正常化在拟议的项目中，我们将进行随机试验。 口服蛋白质补充剂的对照试验以确定其在实现临床意义方面的有效性 我们还计划扩展有关 HFrEF 的两个主要知识。 分解代谢途径被认为会驱动生长分化因子 15 (GDF-15) 下游的肌肉萎缩 和激活素IIA/IIB型受体（ActRII）的成功完成将有助于我们的目标。 开发预防或逆转骨骼肌的营养和药物干预措施的长期目标 根据我们的研究，减少消耗，从而改善 HFrEF 患者的身体机能和生存率。 根据初步和已发表的数据，我们建议测试骨骼肌萎缩的创新假设 HFrEF 由分解代谢的神经体液激活促进，包括 GDF-15 和 ActRII 途径，并且可以通过增加饮食蛋白质摄入至少部分逆转。 通过招募 140 名患有 HFrEF 的成年人对 GDF-15 和 ActRII 进行横断面评估来提出假设 机制临床试验中蛋白质补充的途径（目标 1）和骨骼质量反应（目标 2）。 目标 1 将确定 ActRII 抑制的 GDF-15 是否可以作为重症患者的未来疗法 无法通过营养策略克服的肌肉萎缩将定义是否每天 30 克。 补充膳食蛋白质 6 个月可增加双 X 射线吸收测定 (DXA) 阑尾瘦肉 maa (ALM) 成功完成这些目标将确定是否需要补充膳食蛋白质。 参与 HFrEF 和分解代谢减肥患者的临床护理，并为未来的研究提供平台 GDF-15 中和或激活素 A 抑制的辅助疗法开发创新干预措施。 促进 HFrEF 患者的骨骼肌质量和身体功能，与 NHLBI 的要求非常一致 目标是开发治疗心脏病和改善患者预后的新治疗方法。