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

描述（由申请人提供）： 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降低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，可能会加剧局限性，使HF症状和不良结局与中枢和外周机制的联合作用有关。虽然HF治疗指南强调心脏治疗参数，但修改HF SkMx功能的目标可能会提供重要的补充收益。 该建议侧重于运动训练对HF的益处，并从我们三年前开始的试点分析发展而来。初步数据显示，与年龄匹配的健康对照组相比，老年HF患者（平均年龄66 - 10岁）的功能能力（有氧和力量）降低。某些基因的SkMx表达控制肌肉中的泛素介导的蛋白水解，对应于有氧和力量指数的下降;瘦肌肉质量也与力量下降呈负相关。我们现在建议比较四种不同的运动方案（即，有氧、力量、组合有氧-力量和吸气训练）来探索每种形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岁的男性和女性（N=200）收缩期HF患者（LVEF d40%）。患者将被随机分配到四个12周，每周三次的训练方案中的一个。在训练前后，将评估一系列综合功能评估（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指标）。 具体目标是：（1）评估不同训练方案（有氧与力量与有氧力量与吸气）的功能结果差异。我们假设有氧强度将优于有氧或强度单独上级。我们还假设，吸气训练将匹配传统的有氧力量的影响，因为它赋予有氧和加强横膈膜的生理。(2)评估基因表达和SkMx灌注与不同训练方案的关系。我们假设，蛋白水解基因（FoxO，泛素）将过度表达与功能减弱有关，而抵消SkMx蛋白水解的基因（IGF-1，PGC-1 β）将增加与功能获得有关。因此，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（强度和吸气）将最好地减少蛋白水解和增加合成代谢基因表达模式，刺激中枢心脏功能和血管舒张的运动模式（有氧和吸气训练）将诱导SkMx灌注的相对较大的变化。

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.