Skeletal Muscle Plasticity Following LVAD Support

描述（由申请人提供）：慢性心力衰竭（CHF）是美国医疗保险患者的主要出院诊断。虽然药物治疗已导致心力衰竭患者的死亡率显著降低，但运动不耐受仍然是残疾、发病和生活质量下降的主要原因。疲劳通常会妨碍规律的体力活动，这可能导致几种共病和CHF的不良结局。CHF患者运动耐量受限的机制尚不完全清楚。心力衰竭运动不耐受的标志性特征是与骨骼肌肌病相关的早期乳酸产生。许多问题仍然没有答案。也许这些问题中最基本的是心脏和骨骼肌之间是否有直接联系？该建议的中心假设是，CHF中的中枢血流动力学和外周骨骼肌之间存在直接相互作用，并且这种相互作用将通过中枢血流动力学异常的持续正常化而变得明显。我们将研究心力衰竭患者，其中通过放置左心室辅助装置（LVAD）来纠正中心血流动力学异常。患者将在LVAD置入前和置入后的时间点接受研究。中心假设的预测将在杜克大学医学中心接受LVAD置入的至少60例患者中进行检验。将相同数量的目前住院接受非口服药物治疗CHF的患者作为比较（对照）组。具体目标是：一。确定中心血流动力学的改变足以诱导CHF患者外周骨骼肌的变化。二.确定从入组至LVAD支持或药物治疗后9周外周骨骼肌可塑性的程度、类型和时程。确定LVAD置入后2周至9周外周骨骼肌的哪些变化以及在多大程度上导致运动耐量的变化？三. A）在LVAD放置之前和之后的连续时间点检查骨骼肌肌病的潜在循环介质（即肿瘤坏死因子-Q）。B）使用特定目标1中选定的测量值，检查LVAD至心脏移植前腹直肌的变化，并将其与可比时间段内腿部（股外侧肌）肌肉的变化进行比较。

DESCRIPTION (provided by applicant): Chronic heart failure (CHF) is the leading discharge diagnosis among Medicare patients in the United States. Although pharmacologic therapies have resulted in dramatic reductions in mortality in patients with heart failure, exercise intolerance remains a major cause of disability, morbidity, and decreased quality of life. Exertional fatigue often prevents regular physical activity and this may contribute to several co-morbid diseases and the poor outcome from CHF. The mechanisms that account for limitations in exercise tolerance in CHF are not completely understood. The hallmark feature of exercise intolerance in heart failure is early lactate production that is linked with a skeletal muscle myopathy. A large number of questions remain unanswered. Perhaps the most basic of these questions is whether there is a direct link between the heart and skeletal muscle? The central hypothesis in this proposal is that there is a direct interplay between central hemodynamics and peripheral skeletal muscle in CHF, and that this interaction will be evident through a sustained normalization of central hemodynamic abnormalities. We will study humans with heart failure where abnormalities in central hemodynamics are corrected by the placement of a left ventricular assist device (LVAD). Patients will be studied before, and at time points following LVAD placement. Predictions of the central hypothesis will be tested in a minimum of 60 patients undergoing LVAD placement at Duke University Medical Center. An equal number of patients, currently in the hospital for non-oral pharmacological management of CHF will serve as the comparison (control) group. The Specific Aims are: I. Establish that alterations in central hemodynamics are sufficient to induce changes in peripheral skeletal muscle in patients with CHF. II. Establish the extent, type, and time course, of peripheral skeletal muscle plasticity from entry to 9-weeks post, LVAD support or, medical therapy. Determine which, and to what extent, changes in peripheral skeletal muscle contribute to changes in exercise tolerance from 2-weeks to 9-weeks following LVAD placement? III. A) Examine potential circulating mediators (i.e. tumor necrosis factor-Q) of the skeletal muscle myopathy before, and at serial time points after, LVAD placement. B) Examine changes in rectus abdominus muscle pre-LVAD to heart transplantation, using selected measures from Specific Aim 1, and compare those to changes in leg (vastus lateralus) muscle over a comparable time period.