Exercise Therapy to Reduce Heart Failure Symptoms; Sorting Mechanisms of Benefit

运动疗法可减轻心力衰竭症状；

• 批准号: 8976084
• 负责人: Daniel E. Forman
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8976084
• 关键词: Activities of Daily Living; Aerobic; Affect; Age; Biology; Blood Vessels; Body Composition; Breathing; Cardiac; Clinical; Complex; Cross-Sectional Studies; Data; Disease; Dyspnea; Elderly; Exercise; Female; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Goals; Guidelines; Heart failure; Histology; Incidence; Inflammation; Insulin-Like Growth Factor I; Intervention Trial; Investigation; Left Ventricular Ejection Fraction; Measurement; Measures; Mediating; Modality; Morbidity - disease rate; Muscle; Myocardial dysfunction; Myopathy; Outcome; Patients; Pattern; Performance; Perfusion; Peripheral; Pharmaceutical Preparations; Physical therapy exercises; Physiological; Physiology; Population; Prevalence; Process; Proteolysis; Quality of life; Questionnaires; Randomized; Regimen; Relative (related person); Relaxation; Research; Respiratory Diaphragm; Roentgen Rays; Scanning; Serological; Serum; Signal Transduction; Skeletal Muscle; Sleep; Sorting - Cell Movement; Stimulus; Symptoms; Systolic heart failure; Therapeutic; Therapeutic exercise; Training; Ubiquitin; Ubiquitin-mediated Proteolysis Pathway; Veterans; Work; adipokines; aged; clinical effect; comparative efficacy; cytokine; functional gain; functional outcomes; gene function; improved; indexing; insight; male; mortality; muscle form; nutrition; outcome forecast; prognostic; response; skeletal; strength training

DESCRIPTION (provided by applicant): The population of senior Veterans prone to heart failure (HF) is expanding rapidly. Exercise intolerance and dyspnea are common symptoms that detract from independence and quality of life and also predispose to increased mortality and morbidity. Peripheral pathophysiology, particularly involving skeletal muscle (SkMx) and vascular perfusion, likely exacerbates limitations such that HF symptoms and poor outcomes relate to combined effects of central and peripheral mechanisms. While HF therapeutic guidelines emphasize cardiac therapeutic parameters, goals to modify HF SkMx function may provide vital complementary gains. This proposal focuses on benefits of exercise training for HF and evolves from a pilot analysis we began three years ago. Preliminary data show reduced functional capacity (both aerobic and strength) in older HF patients (mean age 66�10 yrs) compared to age-matched healthy controls. SkMx expression of certain genes controlling ubiquitin-mediated proteolysis in muscle correspond to the decreased aerobic and strength indices; lean muscle mass also correlates inversely to reduced strength. We now propose to compare four different exercise regimens (i.e., aerobic, strength, combined aerobic-strength, and inspiratory training) to explore how each modality changes function/symptoms in relation to specific peripheral training effects, i.e., exercise effects on SkMx biology (histology, gene expression), peripheral perfusion, and body composition. Male and female (N=200) systolic HF patients (LVEF d40%) aged e50 years will be studied. Patients will be randomized into one of four 12-week, three weekly training regimens. A comprehensive battery of functional assessments (aerobic, strength, and integrated performance), symptoms, and physiological indices (SkMx histology, gene expression, and perfusion, body composition, and serological measures of inflammation, cytokines, and adipokines) will be assessed before and after training. Specific aims are: (1) To assess differences in functional outcomes relative to the different training regimens (aerobic vs. strength vs. aerobic-strength vs. inspiratory). We hypothesize that aerobic-strength will be superior to aerobic or strength alone. We also hypothesize that inspiratory training will match the affects of traditional aerobic-strength as it imparts aerobic and strengthening physiology to the diaphragm. (2) To assess gene expression and SkMx perfusion in relation to the different training regimens. We hypothesize that proteolytic genes (FoxO, Ubiquitin) will be over-expressed in relation to diminished function and that the genes counteracting SkMx proteolysis (IGF-1, PGC-1�) will increase in relation to functional gains. Consistently, we will compare how different training regimens modulate gene expression patterns. We hypothesize that exercise modes that directly stimulate SkMx function (strength and inspiratory) will best decrease proteolytic and in- crease anabolic gene expression patterns, and exercise modes that stimulate central cardiac performance and vascular relaxation (aerobic and inspiratory training) will induce relatively greater changes in SkMx perfusion.

描述（由申请人提供）： 容易患心力衰竭（HF）的老年退伍军人人数正在迅速增加。运动不耐受和呼吸困难是损害独立性和生活质量的常见症状，也容易增加死亡率和发病率。外周病理生理学，特别是涉及骨骼肌 (SkMx) 和血管灌注的外周病理生理学，可能会加剧局限性，例如心力衰竭症状和不良结果与中枢和外周机制的综合作用有关。虽然心力衰竭治疗指南强调心脏治疗参数，但改变心力衰竭 SkMx 功能的目标可能会提供重要的补充收益。 该提案重点关注心力衰竭运动训练的益处，并从我们三年前开始的试点分析演变而来。初步数据显示，与年龄匹配的健康对照相比，老年心力衰竭患者（平均年龄 66±10 岁）的功能能力（有氧运动和力量）降低。控制肌肉中泛素介导的蛋白水解作用的某些基因的 SkMx 表达与有氧指数和力量指数的降低相对应；瘦肌肉质量也与力量下降成反比。我们现在建议比较四种不同的运动方案（即有氧运动、力量训练、有氧力量联合训练和吸气训练），以探索每种方式如何改变与特定外周训练效果相关的功能/症状，即运动对 SkMx 生物学（组织学、基因表达）、外周灌注和身体成分的影响。 将研究年龄 50 岁左右的男性和女性 (N=200) 收缩性心力衰竭患者 (LVEF d40%)。患者将被随机分配到四种为期 12 周、每周三周的训练方案中的一种。将在训练前后评估一系列全面的功能评估（有氧、力量和综合表现）、症状和生理指标（SkMx 组织学、基因表达和灌注、身体成分以及炎症、细胞因子和脂肪因子的血清学测量）。 具体目标是：(1) 评估相对于不同训练方案（有氧训练、力量训练、有氧力量训练、吸气训练）的功能结果差异。我们假设有氧力量将优于有氧运动或单独的力量。我们还假设吸气训练将与传统有氧力量的效果相匹配，因为它可以向膈肌传递有氧和强化生理学。 (2) 评估与不同训练方案相关的基因表达和 SkMx 灌注。我们假设蛋白水解基因（FoxO、泛素）会因功能减弱而过度表达，而对抗 SkMx 蛋白水解的基因（IGF-1、PGC-1�）会因功能增强而增加。我们将始终如一地比较不同的训练方案如何调节基因表达模式。我们假设直接刺激 SkMx 功能（力量和吸气）的运动模式将最好地减少蛋白水解并增加合成代谢基因表达模式，而刺激中枢心脏功能和血管松弛的运动模式（有氧和吸气训练）将引起 SkMx 灌注相对较大的变化。