Pulmonary Limitations in Chronic Heart Failure

描述（由申请人提供）：HL-71478“慢性心力衰竭中的肺限制”的长期目标是了解心血管和肺系统之间的功能关系，特别是与慢性心力衰竭（HF）相关的功能关系。这次更新的重点是更好地了解心力衰竭中的肺充血和肺液平衡及其对呼吸系统结构和功能的影响。这将通过两个主要目标来评估。目的1)量化和定义人类肺充血以及胸内液室变化对气道结构和功能的影响。这将根据NYHA分级、体位和运动负荷来确定HF患者，并在健康受试者中使用快速生理盐水输注作为急性充血模型。目的2)确定β 2肾上腺素能受体（¿2AR）在心力衰竭相关肺充血中的作用。更具体地说，a)我们将量化肺中与肺液平衡和疾病严重程度相关的¿2AR活性，b)确定编码¿2AR的基因变异对心力衰竭患者肺液平衡的作用，c)检查急性激动剂治疗对心力衰竭患者肺微血管通透性和肺水的潜在益处。该建议的中心假设是，心衰患者的液体分布更集中（肺毛细血管床、肺血容量和支气管循环扩大），渗透性增加和液体清除减少的证据，将有最大的肺结构和功能改变，更大的症状和更差的预后证据。这些研究将结合独特的成像模式和方法来定义和量化给定气道生成的胸部和肺部血容量、支气管和肺部微血管血容量、气道管腔、气道壁和血管直径。此外，我们将估计肺血管外肺水，微血管通透性和¿AR密度。我们已经开发了许多新的可溶气体技术来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理解胸内液体变化对呼吸结构和最终生理功能的影响提供一个重要的框架。这些研究很重要，因为1)尽管肺充血是心衰的主要特征，因此是住院的主要原因，但它的定义和理解都很差；2)与充血相关的肺力学和气体交换的变化可能比心功能的静息测量更能预测预后，并可能为优化治疗提供见解。3)肺水肿（肺充血的组成部分）的发展与心功能障碍的程度没有紧密的联系，导致受试者的易感性不同，遗传因素可能影响易感性。因此，拟议的研究将提供关于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。公共卫生相关性：我们研究项目的长期目标是了解心血管和肺系统之间的功能关系，特别是与慢性心力衰竭有关的关系。这次更新的重点是更好地了解心力衰竭中的肺充血和肺液平衡及其对呼吸系统结构和功能的影响。更具体地说，我们将研究各种胸内液体室（如肺血容量、血管外肺水、支气管血容量）的变化如何影响气道管腔容量和直径、气道壁厚度和血管大小，进而影响肺功能、肺力学和气体交换。此外，我们将研究β 2肾上腺素能受体在调节心力衰竭人群肺液中的核心作用，受体刺激对微血管通透性的影响，以及受体功能和液体调节如何受到编码β 2肾上腺素能受体基因变异的影响。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The long term goal of our research program is to understand the functional relationships between the cardiovascular and pulmonary systems, particularly as it relates to chronic heart failure. 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. More specifically we will examine how changes in various intrathoracic fluid compartments (e.g., pulmonary blood volume, extravascular lung water, bronchial blood volume) impact airway luminal volumes and diameters, airway wall thickness and blood vessel size, and in turn how this influences pulmonary function, lung mechanics and gas exchange. In addition, we will examine the central role of the beta 2 adrenergic receptors in regulating lung fluid in the heart failure population, the impact of receptor stimulation on microvascular permeability and how receptor function and fluid regulation may be influenced by variation in the gene that encodes the beta 2 adrenergic receptor.