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）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CHF的发病率在40至60岁之间增加了50倍，并且该疾病是美国增长最快的心血管疾病。两个具体的目标集中在心脏和肺的相互作用将得到解决。首先，我们将检验运动时呼吸影响心脏功能的假设。我们将通过以下方式对此进行测试：a）在使用持续气道正压、呼气阈值负荷和自主动作的运动期间检查肺容量的瞬时和持续增加对心脏功能的影响，B）在运动期间使用比例辅助通气通过对呼吸肌进行负荷和卸载来确定胸内压变化对心输出量的影响，c）通过使用运动后腿部缺血检查肌肉化学敏感性反射是否可以刺激CHF中的通气大于对照，以及d）通过卸载呼吸肌并测量腿部血流来确定呼吸肌是否在运动期间从运动肌“窃取”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，以2种形式存在，插入-II和缺失-DD等位基因）的多态性，研究CHF中肺系统结构变化和运动耐量改变的神经体液基础。我们将通过以下方法进行检验：a）确定CHF中激活的肾素-血管紧张素系统是否增强ACE基因型相关的肺和心血管功能相对于对照的差异，B）确定CHF患者的DD基因型中改变的肺功能是否与肺血管张力和渗透性的改变相关并且独立于心脏功能II受体阻滞剂将消除CHF受试者的基因型差异。

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.