Pulmonary Limitations in Chronic Heart Failure

总结 HL-71478“慢性心力衰竭的肺限制”的长期目标是了解 心血管系统和肺系统之间的功能关系，特别是与慢性病相关 心力衰竭（HF）。此次更新的重点是更好地了解肺充血和肺液 心力衰竭的平衡及其对呼吸系统结构和功能的影响。这将被评估 通过两个主要目标。目标 1) 量化和定义人类肺充血及其影响 胸腔内液体室的变化对气道结构和功能的影响。这将在 HF 中确定 根据 NYHA 等级、体位和运动负荷的患者，以及使用快速盐水的健康受试者 输注作为急性充血模型。目标 2) 确定 β2 肾上腺素受体 (¿2AR) 的作用 与心力衰竭相关的肺充血。更具体地说，a) 我们将量化 ¿2AR 活动 肺相对于肺液平衡和疾病严重程度，b) 确定基因变异的作用 编码 ¿2AR 对心力衰竭患者肺液平衡的影响，并且 c) 检查急性治疗的潜在益处 ¿激动剂治疗心力衰竭人群的肺微血管通透性和肺水。的 该提案的中心假设是，心力衰竭患者的体液分布更加集中 （肺毛细血管床扩张、肺血容量和支气管循环），证据 通透性增加和液体清除减少，将对肺组织产生最大的改变 结构和功能，更严重的症状和预后较差的证据。 这些研究将结合独特的成像模式和方法来定义和量化胸部和 肺血容量、支气管和肺微血管血容量、气道管腔、气道壁和血液 给定气道生成的血管直径。此外，我们还将估计肺血管外肺水， 微血管通透性和AR密度。我们开发了许多新颖的可溶性气体技术 测量肺毛细血管血容量、肺泡毛细血管电导、肺和支气管血 流量以及支气管组织体积。这些措施结合起来将为 了解胸腔内液体变化对呼吸结构和最终生理的影响 功能。 这些研究很重要，因为，1）尽管肺充血是心力衰竭的主要特征，因此 入院的主要原因，其定义和理解不明确，2）肺力学的变化和 与充血相关的气体交换可能比心功能的静息测量更具预测性 并可提供对治疗优化的见解，3) 肺水肿的发生（肺水肿的组成部分） 肺充血）与心功能不全的程度没有紧密联系，导致不同的心功能不全 受试者之间的脆弱性，表明遗传因素可能影响易感性。因此提出的 研究将提供有关心力衰竭患者住院的主要原因的重要信息 并有可能影响治疗。

Summary The long term goal of HL-71478, "Pulmonary Limitations in Chronic Heart Failure", is to understand the functional relationships between the cardiovascular and pulmonary systems, particularly as it relates to chronic heart failure (HF). This renewal focuses on a better understanding of pulmonary congestion and lung fluid balance in heart failure and its impact on respiratory system structure and function. This will be assessed through two primary aims. Aim 1) To quantify and define pulmonary congestion in humans and the impact of changes in intrathoracic fluid compartments on airway structure and function. This will be determined in HF patients according to NYHA class, body position, and exercise load, and in healthy subjects using rapid saline infusion as a model of acute congestion. Aim 2) To determine the role of beta 2 adrenergic receptors (¿2AR) in the pulmonary congestion associated with heart failure. More specifically, a) we will quantify ¿2AR activity in the lungs relative to lung fluid balance and disease severity, b) determine the role of variation in the gene that encodes the ¿2AR on lung fluid balance in heart failure patients and c) examine the potential benefits of acute ¿-agonist therapy on lung microvascular permeability and lung water in the heart failure population. The central hypothesis of the proposal is that HF patients that have a more central distribution of fluid (expanded pulmonary capillary bed, pulmonary blood volume and bronchial circulation), evidence for increased permeability and reduced fluid removal, will have the greatest alterations in pulmonary structure and function, greater symptoms and evidence for poorer prognosis. These studies will incorporate unique imaging modalities and methods to define and quantify thoracic and pulmonary blood volume, bronchial and lung microvascular blood volume, airway lumen, airway wall and blood vessel diameters for a given airway generation. In addition we will estimate lung extravascular lung water, microvascular permeability and ¿AR density. We have developed a number of novel soluble gas techniques to measure pulmonary capillary blood volume, alveolar-capillary conductance, pulmonary and bronchial blood flow as well as bronchial tissue volume. These measures combined will provide an important framework for understanding the impact of intrathoracic fluid changes on respiratory structure and ultimately physiological function. These studies are important because, 1) although pulmonary congestion is a primary feature of HF and thus a major reason for hospital admissions, it is poorly defined and understood, 2) changes in lung mechanics and gas exchange associated with congestion may be more prognostic than resting measures of cardiac function and may provide insight into optimization of therapy, 3) development of pulmonary edema (component of pulmonary congestion) is not tightly linked to the degree of cardiac dysfunction resulting in variable vulnerability among subjects, suggesting genetic factors could influence susceptibility. Thus the proposed studies will provide important information regarding the central reason heart failure patients are hospitalized and have the potential to impact therapy.