Skeletal Muscle Plasticity Following LVAD Support

描述(申请人提供)：慢性心力衰竭(CHF)是美国联邦医疗保险患者的主要出院诊断。虽然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。疲劳性疲劳经常妨碍有规律的体力活动，这可能会导致几种共病疾病和充血性心力衰竭的不良结局。CHF患者运动耐量受限的机制尚不完全清楚。心力衰竭患者运动耐受的显著特征是早期产生乳酸，这与骨骼肌病有关。大量的问题仍然没有得到回答。也许这些问题中最基本的是，心脏和骨骼肌之间是否存在直接联系？这一建议的中心假设是，在CHF中，中枢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血流动力学异常的持续正常化而明显。我们将研究患有心力衰竭的人类，在那里，中心血流动力学的异常可以通过放置左心室辅助装置(LVAD)来纠正。患者将在放置LVAD之前和之后的时间点进行研究。中心假说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。同样数量的患者，目前在医院进行非口服药物治疗的CHF将作为对照(对照)组。具体目标是：1.确定中枢血流动力学的改变足以引起CHF患者外周骨骼肌的改变。确定外周骨骼肌可塑性的范围、类型和时间进程，从入院到接受左心功能支持或药物治疗后9周。确定外周骨骼肌的哪些变化以及在多大程度上影响了放置左冠状动脉后2周至9周的运动耐量的变化？在放置LVAD之前和之后的一系列时间点，检查骨骼肌病潜在的循环介质(即肿瘤坏死因子-Q)。B)使用特定目标1中选定的措施，检查左冠状动脉旁路移植术到心脏移植前腹直肌的变化，并将这些变化与腿部(股外侧肌)在可比时间段内的变化进行比较。

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.