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运动期间充盈压升高或心输出量不足的概念已得到修订。现在人们认识到，心力衰竭的骨骼肌病是心力衰竭运动受限的一个重要原因。心力衰竭的骨骼肌病是慢性心功能障碍的可预测后遗症。氧运输是一个多步途径，根据“协调适应”的概念，多步途径中一个步骤的异常发展会引发该途径中所有其他步骤的重新调整，以达到新的平衡，从而使所有能力相匹配。然而，“能力匹配”的机制，在这种情况下，在严重心脏病的情况下，骨骼肌能力的下调和骨骼肌病的发展仍然未知。我们假设肌肉交感神经激活介导心力衰竭的骨骼肌病。这可能部分解释了为什么心脏再同步治疗（CRT）这种改善心脏功能异常的疗法，虽然与运动功能障碍没有直接关系，但却能无可辩驳地提高运动能力。我们有初步证据表明 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 作为慢性心力衰竭骨骼肌病诱发因素的作用。目的 1. 确定 HF 中 CRT 慢性交感抑制的机制，以及这种交感抑制对骨骼肌病的影响。 1.1 CRT 是否会长期降低晚期心力衰竭患者的静息 MSNA？ 1.2 CRT 后 MSNA 降低的心力衰竭患者的骨骼肌病是否会逆转？ 1.3 CRT 后压力感受器增益的增加是否是 MSNA 下降的原因？ 1.4 HF 中增强的肌肉机械感受器敏感性的逆转是否会导致 CRT 后 MSNA 的降低？目标 2. 确定另一种抗交感神经疗法可乐定是否可以逆转心衰引起的骨骼肌病。 2.1 可乐定的交感作用与心力衰竭骨骼肌病的逆转有关吗？ 2.2 改善的骨骼肌病对心衰时肌肉机械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?