Pulmonary Limitations in Chronic Heart Failure

描述（由申请人提供）：我们提案的中心主题是了解慢性心力衰竭（CHF）中运动不耐受的机制，并最终使用这些信息来帮助指导这一不断增长的人群的康复和医疗管理。这一点很重要，因为在40至60岁的人群中，瑞士法郎的发病率增加了50倍，并且该疾病是该国增长最快的心血管疾病。将讨论两个专注于心脏和肺部相互作用的具体目标。首先，我们将验证运动时呼吸影响心功能的假设。我们将通过以下方法来验证这一点：a)使用持续气道正压、呼气阈负荷和自主动作来检查运动期间肺容量短暂和持续增加对心功能的影响；b)通过运动期间使用比例辅助通气来加载和卸载呼吸肌，确定胸内压力变化对心输出量的影响。c)通过运动后腿部缺血检查肌肉化学敏感反射是否比对照组更能刺激CHF患者的通气，d)通过释放呼吸肌和测量腿部血流量来确定运动过程中呼吸肌是否“窃取”运动肌肉的血流。其次，我们将通过检测一种关键调节酶血管紧张素转换酶（ACE，它以插入- il和缺失- dd等位基因两种形式存在）的多态性，研究肺系统结构变化和CHF运动耐量改变的神经体液基础。我们将对此进行测试，a)确定与对照组相比，CHF中激活的肾素-血管紧张素系统是否增强了ACE基因型相关的肺和心血管功能差异；b)确定CHF患者DD基因型肺功能改变是否与肺血管张力和通透性改变有关，是否独立于心功能；c)检查A-Il受体阻滞剂完全阻断血管紧张素- il （A-Il）是否会消除CHF患者的基因型差异。

DESCRIPTION (provided by applicant): The central theme of our proposal is to understand mechanisms of exercise intolerance in Chronic Heart Failure (CHF) and to ultimately use this information to help guide rehabilitation and medical management of this growing population. This is of importance because, the incidence of CHF increases 50-fold between the ages of 40 and 60 years and the disease is the nation's most rapidly growing cardiovascular disorder. Two specific aims focused on heart and lung interactions will be addressed. First, we will test the hypothesis that breathing during exercise influences cardiac function. We will test this by, a) examining the influence of transient and sustained increases in lung volume on cardiac function during exercise using continuous positive airway pressure, expiratory threshold loading and voluntary maneuvers, b) determining the effects of intra-thoracic pressure changes on cardiac output via loading and unloading the respiratory muscles using proportional assist ventilation during exercise, c) examine if a muscle chemosensitive reflex may stimulate ventilation in CHF greater than in controls by using post-exercise leg ischemia, and d) determining if the respiratory muscles "steal" blood flow from locomotor muscles during exercise by unloading respiratory muscles and measuring leg blood flow. Second, we will examine a neurohumoral basis for structural changes in the pulmonary system and altered exercise tolerance in CHF by examining a polymorphism of a key regulatory enzyme, angiotensin-converting enzyme (ACE, which exists in 2 forms, insertion-Il and deletion-DD alleles). We will test this by, a) determining if the activated renin-angiotensin system in CHF enhances ACE genotype related differences in pulmonary and cardiovascular function relative to controls, b) determining if the altered pulmonary function in the DD genotype of CHF patients is related to alterations in pulmonary vascular tone and permeability and independent of cardiac function c) examining if complete blockade of angiotensin-Il (A-Il) with A-Il receptor blockers will abolish genotype differences in the CHF subjects.