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）： 容易发生心力衰竭的资深退伍军人人口（HF）正在迅速扩大。运动摄入症和呼吸困难是损害独立性和生活质量的常见症状，并且倾向于增加死亡率和发病率。外周病理生理学，尤其是涉及骨骼肌（SKMX）和血管灌注，可能会加剧局限性，以至于HF症状和不良结局与中央和外围机制的综合作用有关。尽管HF治疗指南强调心脏治疗参数，但修改HF SKMX功能的目标可能会带来重要的全部收益。该提案的重点是三年前开始的试点分析中对HF的运动培训的好处。与年龄匹配的健康对照相比，初步数据显示，年龄较大的HF患者（平均年龄66≥10岁）的功能能力（有氧和强度）降低。在肌肉中控制泛素介导的蛋白水解的某些基因的SKMX表达，对应于改善的有氧和强度指数；瘦肌肉质量也与降低强度相关。现在，我们建议比较四种不同的运动方案（即有氧，强度，有氧运动训练和灵感训练），以探讨每种方式与特定的外围训练效应有关的功能/症状如何改变功能/症状，即运动对SKMX生物学（组织学，基因表达），外围灌注和身体组合的影响。男性和女性（n = 200）收缩期HF患者（LVEF D40％）年龄为E50岁。患者将被随机分为四个12周，三个每周的训练方案之一。将在训练之前和之后评估全面的功能评估（有氧，力量和综合性能），症状和身体指标（SKMX组织学，基因表达和灌注，身体组成以及炎症，细胞因子和脂肪因子的血清学测量）的综合电池。具体目的是：（1）评估相对于不同训练方案的功能结果差异（有氧和强度与有氧运动与灵感的差异）。我们假设有氧运动长度将优于有氧或力量。我们还假设，吸气训练将与传统的有氧力量强度的影响相匹配，因为它意味着有氧和增强膜片的生理学。 （2）评估与不同训练方案有关的基因表达和SKMX灌注。我们假设蛋白水解基因（FOXO，泛素）将与功能下降有关，并且应对SKMX蛋白水解的基因（IGF-1，PGC-1。）将增加与功能增长的关系。一致地，我们将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功能的运动模式（强度和灵感）将最好地降低蛋白水解和折磨合成代谢基因表达模式，并且刺激中心心脏性能和血管松弛（有氧和灵感训练）的运动模式将在SKMX灌注中引起相对更大的变化。