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中主要的出院诊断。尽管药物治疗显著降低了心力衰竭患者的死亡率，但运动不耐受仍然是导致残疾、发病率和生活质量下降的主要原因。劳累性疲劳常常妨碍有规律的身体活动，这可能导致几种合并症和慢性心力衰竭的不良预后。导致CHF患者运动耐量受限的机制尚不完全清楚。心力衰竭的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生成。许多问题仍未得到解答。也许这些问题中最基本的问题是心脏和骨骼肌之间是否有直接联系？本研究的中心假设是，心力衰竭患者的中枢性血流动力学和外周骨骼肌之间存在直接的相互作用，这种相互作用将通过中枢性血流动力学异常的持续正常化而变得明显。我们将研究通过放置左心室辅助装置（LVAD）纠正中央血流动力学异常的心力衰竭患者。患者将在LVAD放置之前和之后的时间点进行研究。中心假设的预测将在杜克大学医学中心接受LVAD安置的至少60名患者中进行测试。选取同等数量的目前在医院接受非口服药物治疗的CHF患者作为比较（对照组）。具体目的是：1 .确定中央血流动力学的改变足以诱导CHF患者外周骨骼肌的改变。2。确定周围骨骼肌可塑性的程度、类型和时间过程，从进入到9周后LVAD支持或药物治疗。确定在LVAD放置后2周至9周内，外周骨骼肌的变化对运动耐量的影响是什么，以及在多大程度上？3。A)在放置LVAD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Specific Aim 1中选定的测量方法，检查lvad前到心脏移植时腹直肌的变化，并将其与可比时间段内腿（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.