Sympathetic Nerve Activity and the Skeletal Myopathy of Heart Failure

描述（由申请人提供）：慢性心力衰竭（HF）患者的运动受限直接归因于充盈压升高或运动期间心输出量不足的概念已被修订。现在认识到HF的骨骼肌病变是HF运动受限的重要原因。心力衰竭的骨骼肌病变是慢性心功能不全的可预测后遗症。氧转运是一个多步骤的途径，根据"协调适应"的概念，多步骤途径中一个步骤的异常发展启动了该途径中所有其他步骤的重新调整，以实现新的平衡，使得所有能力都匹配。"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变的发展仍然未知。我们推测肌肉交感神经激活介导了HF骨骼肌病变。这可能部分解释了为什么心脏起搏治疗（CRT），一种改善心脏功能异常的治疗方法，与运动功能障碍没有直接关系，但却产生了无可辩驳的运动能力增加。我们有初步的证据表明，CRT显着降低肌肉交感神经活动（MSNA）。该项目的总体目标是研究MSNA作为慢性HF骨骼肌病变的诱发者的作用。目标1。探讨慢性交感神经抑制与CRT治疗心衰的机制，以及这种交感神经抑制对骨骼肌病变的影响。1.1 CRT是否能长期减少晚期HF患者的静息MSNA？1.2 CRT后MSNA降低的HF患者的骨骼肌病变是否逆转？1.3压力感受器增益的增加是否是CRT后MSNA降低的基础？1.4 HF患者增强的肌肉机械感受器敏感性的逆转是否有助于CRT后MSNA的降低？目标二。确定另一种交感神经阻滞疗法可乐定是否能逆转HF的骨骼肌病变。2.1可乐定的交感神经松解作用是否与HF骨骼肌病变的逆转有关？2.2改良骨骼肌病对心力衰竭患者肌肉机械感受器敏感性的影响是什么？

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?