Sympathetic Nerve Activity and the Skeletal Myopathy of Heart Failure

描述(申请人提供)：慢性心力衰竭(HF)患者的运动限制是由于运动中充盈压升高或心输出量不足直接导致的概念已被修订。现已认识到，心力衰竭的骨骼肌病是导致心力衰竭患者运动受限的重要因素。心力衰竭的骨骼肌病是慢性心功能不全的可预见的后遗症。氧运输是一个多步骤的途径，根据“协调适应”的概念，在一个多步骤的途径中，一个步骤的异常发展会启动途径中所有其他步骤的重新调整，以达到新的平衡，从而使所有的能力匹配。然而，“匹配能力”的机制(S)，在这种情况下，骨骼肌能力的下调和严重心脏病背景下骨骼肌病的发展，仍然未知。我们推测，肌肉交感神经的激活参与了心力衰竭骨骼肌病的发生。这可能在一定程度上解释了为什么心脏再同步疗法(CRT)，一种改善与运动功能障碍没有直接关系的心功能异常的疗法，仍然在运动能力方面产生无可辩驳的增加。我们有初步证据表明，CRT显著降低了肌肉交感神经活动(MSNA)。这个项目的总体目标是调查MSNA作为慢性心力衰竭骨骼肌病的促进者的作用。目的1.探讨慢性交感神经抑制联合CRT治疗心力衰竭的机制及其对骨骼肌病的影响。1.1晚期心力衰竭患者CRT是否慢性降低静息MSNA？1.2 CRT后MSNA降低的HF患者骨骼肌病是否逆转？1.3 CRT后MSNA下降是否源于压力感受器增益的增加？1.4 CRT后肌肉机械感受器敏感性增强的逆转是否导致CRT后MSNA的下降？目的2.确定另一种交感神经溶解疗法可乐定能否逆转心力衰竭的骨骼肌病。2.1可乐定的交感神经溶解是否与心力衰竭的骨骼肌病逆转有关？2.2改善的骨骼肌病对心力衰竭的肌力感受器敏感性有何影响？

DESCRIPTION (provided by applicant): The concept that exercise limitation in patients with chronic heart failure (HF) is directly due to elevated filling pressures or inadequate cardiac output during exercise has been revised. It is now recognized that the skeletal myopathy of HF is an important contributor exercise limitation in HF. The skeletal myopathy of HF is a predictable sequela to chronic cardiac dysfunction. Oxygen transport is a multi-step pathway, and according to the concept of "coordinated adaptation," the development of an abnormality in one step of a multi-step pathway initiates a readjustment of all other steps in the pathway to achieve a new equilibrium, so that all capacities are matched However, the mechanism(s) of "matching capacities," in this case the down- regulation of skeletal muscle capacity and the development of a skeletal myopathy in the setting of severe cardiac disease, remain unknown. We hypothesize that muscle sympathetic activation mediates the skeletal myopathy of HF. This may in part explain why cardiac resynchronization therapy (CRT), a therapy that improves abnormalities of cardiac function, which are not directly related to exercise dysfunction, nonetheless produces an irrefutable increase in exercise capacity. We have preliminary evidence that CRT significantly decreases muscle sympathetic nerve activity (MSNA). The overall goal of this project is to investigate the role of MSNA as the instigator of the skeletal myopathy of chronic HF. Aim 1. To determine the mechanisms of chronic sympathoinhibiton with CRT in HF, and the effect of this sympathoinhibition on the skeletal myopathy. 1.1 Does CRT reduce resting MSNA chronically in advanced HF? 1.2 Is the skeletal myopathy reversed in HF patients in whom MSNA is decreased following CRT? 1.3 Does an increase in baroreceptor gain underlie this decrease in MSNA following CRT? 1.4 Does reversal of the augmented muscle mechanoreceptor sensitivity in HF contribute to the decrease in MSNA following CRT? Aim 2. To determine if another sympatholytic therapy, clonidine, reverses the skeletal myopathy of HF. 2.1 Is the sympatholysis with clonidine associated with a reversal of the skeletal myopathy in HF? 2.2 What is the effect of the improved skeletal myopathy on muscle mechanoreceptor sensitivity in HF?