Diastolic Dysfunction and Pauci-inflammatory Acute Exacerbations of Chronic Obstructive Pulmonary Disease

慢性阻塞性肺疾病的舒张功能障碍和少发性炎症急性加重

• 批准号: 9753343
• 负责人: Surya P. Bhatt
• 金额: $ 19.48万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753343
• 关键词: Acute; Admission activity; Adrenal Cortex Hormones; Algorithms; Antibiotics; Arrhythmia; Atherosclerosis; Bacterial Infections; Biological Markers; Biometry; Bronchodilator Agents; C-reactive protein; Cardiac; Cardiopulmonary; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Chronic Obstructive Airway Disease; Clinical; Clinical Markers; Clinical Research; Clinical Sciences; Clinical Trials Design; Collaborations; Comorbidity; Complement; Complex; Congestive; Cost of Illness; Coughing; Development; Development Plans; Disease; Dyspnea; EKG P Wave; Echocardiography; Electrocardiogram; Enrollment; Environmental Pollutants; Epidemiology; Etiology; Evaluation; Event; Exhalation; Exposure to; Fostering; Frequencies; Functional disorder; Funding; Future; Glycine; Goals; Health Care Costs; Heart; Heart Atrium; Heart Injuries; Hospitalization; Infection; Inflammation; Inflammatory; Inspiratory Capacity; Interleukin-6; Intervention; K-Series Research Career Programs; Lead; Left; Length of Stay; Lung; Lung Inflammation; Mass Spectrum Analysis; Master' s Degree; Measures; Morbidity - disease rate; Myocardial Ischemia; Outcome; Pathogenicity; Pathway interactions; Patients; Phase; Phenotype; Pollution; Prevalence; Production; Proline; Prospective Studies; Proteomics; Pulmonary Edema; Pulmonary Inflammation; Recovery; Research; Research Personnel; Research Proposals; Respiratory Tract Infections; Risk Factors; Serum; Serum Markers; Spirometry; Sputum; Steroids; Stretching; Supraventricular Arrhythmia; Techniques; Testing; Therapeutic Intervention; Time; Training; Translational Research; Ultrasonography; United States; Ventricular; Ventricular Arrhythmia; Virus Diseases; base; career; career development; cost; heart imaging; hospital readmission; indexing; inflammatory marker; insight; mortality; neutrophil; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; patient population; pollutant; prospective; readmission rates; skills; targeted treatment

Project Summary/ Abstract Acute exacerbations account for the majority of the chronic obstructive pulmonary disease (COPD)- related morbidity, mortality and costs. Though many exacerbations are triggered by bacterial or viral infections or exposure to airborne pollutants and result in marked lung inflammation, a significant number occur without a clear precipitating cause and in the absence of pulmonary or systemic inflammation (pauci-inflammatory), suggesting an alternative pathophysiology. This may in part explain why current therapies targeting lung inflammation have only a modest effect on the rate of exacerbations and their outcomes even when used in combination. We and others have shown significant interactions between the lung and the heart in COPD, with accelerated atherosclerosis, arrhythmias, and a high frequency of diastolic dysfunction which may each cause or contribute to the development of acute exacerbations. This may be particularly relevant for diastolic dysfunction which may not only lead to overt pulmonary edema but can also cause subtle pulmonary congestion leading to bronchial hyper-reactivity. The prevalence, risk factors, mechanisms and consequences of diastolic dysfunction in this patient population remain unknown. We hypothesize that a subset of pauci- inflammatory acute exacerbations are due to diastolic dysfunction resulting from cardiac ischemia, cardiac arrhythmias and/or lung hyperinflation. These “congestive” exacerbations have a different clinical and inflammatory profile compared with episodes triggered by airway infection or exposure to pollution, and would therefore be expected to respond to a very different treatment algorithm. It is further hypothesized that that diastolic dysfunction in acute exacerbations is caused by subclinical coronary ischemia, cardiac arrhythmias, and/or dynamic lung hyperinflation. We propose a prospective study to answer these high impact questions by determining the frequency of diastolic dysfunction in acute pauci-inflammatory exacerbations of COPD, its clinical implications and underlying mechanisms. We will prospectively enroll patients hospitalized for acute exacerbations of COPD and test our hypothesis with the following three specific aims. Aim 1 of this application will be to assess whether diastolic dysfunction is the primary cause of the pauci-inflammatory phenotype of exacerbations of COPD by evaluation of diastolic dysfunction and pulmonary and systemic inflammation during acute exacerbation, as well as in stable phase after recovery. The goal of Aim 2 is to evaluate the clinical implications of diastolic dysfunction by comparing the length of hospital stay, time to next exacerbation and overall frequency of exacerbations in patients with and without diastolic dysfunction in the year following their index admission. In Aim 3, we will evaluate potential mechanisms underlying diastolic dysfunction by assessing coronary ischemia and surrogates for cardiac arrhythmias, as well as lung hyperinflation during the acute event and after recovery. The results of our study will potentially identify a novel mechanism of exacerbations by defining a congestive phenotype. I will utilize this proposal to acquire additional skills in advanced echocardiographic techniques to further study the complex heart-lung interrelationships in COPD; gain a fundamental understanding of the most up-to-date mass spectrometry techniques and their applications to proteomics of the lung in COPD; as well as obtain a Master’s degree in Clinical and Translational Sciences to foster an independent career in translational research and clinical trial design. The aims of this research proposal and career development plan are possible through the active collaboration of Dr. Edwin Blalock, a leader in neutrophilic inflammation in COPD and Dr. Mark Dransfield, a leading investigator in COPD with a special focus on exacerbations and cardiovascular comorbidity. The opportunities created by this Career Development Award will provide me with a clearly delineated path to acquire expertise and develop a research niche, compete successfully for independent funding for translational and clinical research in the field of COPD and cardiovascular disease, especially as it pertains to acute exacerbations. My ultimate goal is to identify novel etio-pathogenic mechanisms and new therapies for acute exacerbations, with a special focus on the complex heart-lung interactions in this disease.

项目概要/摘要 急性加重占慢性阻塞性肺病 (COPD) 的大部分 - 尽管许多病情恶化是由细菌或病毒感染引起的，但相关的发病率、死亡率和费用。 或暴露于空气污染物并导致明显的肺部炎症，其中大量发生而没有 明确的诱发原因并且在没有肺部或全身炎症（少炎症）的情况下， 这可能部分解释了当前针对肺的治疗的原因。 即使用于炎症，炎症对恶化率及其结果也只有适度的影响。 组合。 我们和其他人已经证明了慢性阻塞性肺病中肺和心脏之间的显着相互作用， 加速动脉粥样硬化、心律失常和频繁的舒张功能障碍，这些都可能导致 或导致急性加重的发生，这可能与舒张期特别相关。 功能障碍不仅可能导致明显的肺水肿，还可能导致微妙的肺水肿 充血导致支气管高反应性的患病率、危险因素、机制和后果。 该患者群体舒张功能障碍的发生率仍不清楚。 炎症急性加重是由于心脏缺血、心脏舒张功能障碍导致的 心律失常和/或肺部过度充气具有不同的临床和症状。 与气道感染或接触污染引发的炎症相比，炎症特征 因此预计会对非常不同的治疗算法做出反应。 急性加重时的舒张功能障碍是由亚临床冠状动脉缺血、心律失常、 我们提出了一项前瞻性研究来回答这些具有重大影响的问题。 确定 COPD 急性少炎症恶化时舒张功能障碍的频率，其 临床意义和潜在机制。 我们将前瞻性地招募因慢性阻塞性肺病急性加重住院的患者，并测试我们的 该应用的目标 1 是评估舒张期是否正常。 通过评估，功能障碍是 COPD 恶化的少炎症表型的主要原因 急性加重期间的舒张功能障碍以及肺部和全身炎症的影响，以及 目标 2 的目标是通过以下方式评估舒张功能障碍的临床影响。 比较住院时间、距下一次恶化的时间以及总体恶化频率 在目标 3 中，我们将针对入院后一年内患有或不患有舒张功能障碍的患者进行评估。 通过评估冠状动脉缺血来评估舒张功能障碍的潜在机制 替代心律失常，以及急性事件期间和恢复后的肺部过度充气。 我们的研究结果将有可能通过定义充血性来确定一种新的恶化机制。 表型。 我将利用这个建议来获得高级超声心动图技术的额外技能 进一步研究 COPD 中复杂的心肺相互关系，获得最根本的了解； 最新的质谱技术及其在慢性阻塞性肺病（COPD）肺部蛋白质组学中的应用； 获得临床和转化科学硕士学位，以培养独立的转化职业生涯 研究和临床试验设计的目的是可能的。 通过慢阻肺中性粒细胞炎症领域的领导者 Edwin Blalock 博士和 Dr. Edwin Blalock 的积极合作。 Mark Dransfield，慢性阻塞性肺病领域的首席研究员，特别关注急性加重和心血管疾病 该职业发展奖所创造的机会将为我提供一个明确的机会。 描绘获得专业知识和发展研究领域、成功争取独立的路径 资助慢性阻塞性肺病和心血管疾病领域的转化和临床研究，特别是因为 我的最终目标是确定新的致病机制和新的发病机制。 针对急性加重的治疗，特别关注这种疾病中复杂的心肺相互作用。