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影响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)和血管灌流，可能会加剧局限性，导致心力衰竭症状和不良预后与中枢和外周机制的综合作用有关。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。这项建议侧重于运动训练对心力衰竭的好处，并从我们三年前开始的试点分析中演变而来。初步数据显示，与年龄匹配的健康对照组相比，老年心力衰竭患者(平均年龄66�，10岁)的功能能力(有氧和力量)都有所降低。肌肉中控制泛素介导的蛋白分解的某些基因SkMx的表达与有氧指数和力量指数的下降相对应；瘦肌肉质量也与力量下降负相关。我们现在建议比较四种不同的运动方案(即有氧运动、力量运动、有氧-力量联合运动和吸气训练)，以探索每种运动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)、外周血流灌注和身体成分的影响。年龄为50岁的男性和女性(N=200)收缩期心衰患者(LVEF D40%)将被纳入研究。患者将被随机分为四个为期12周、每周三次的训练方案之一。训练前后将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、基因表达和血流、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)评估与不同训练方案(有氧与力量、有氧力量与吸气)相关的机能结果的差异。我们假设有氧力量将优于有氧或单独的力量。我们还假设吸气训练将与传统有氧力量的效果相匹配，因为它将有氧和加强生理学传授给横隔膜。(2)评估不同训练方案对基因表达和SkMx灌注的影响。我们假设蛋白降解基因(fox0，泛素)将随着功能的减弱而过度表达，而对抗Skmx蛋白降解的基因(IGF1，pgc-1�)将随着功能的增加而增加。我们将一如既往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分解和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(有氧和吸气训练)的运动模式将导致SkMx血流相对更大的变化。

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.