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.

项目摘要/摘要 急性加重占慢性阻塞性肺疾病(COPD)的大部分- 相关的发病率、死亡率和费用。尽管许多恶化是由细菌或病毒感染引发的 或暴露在空气中的污染物，并导致明显的肺部炎症，相当多的发生在没有 明确的诱因，在没有肺部或全身炎症(少见炎症)的情况下， 暗示了另一种病理生理学。这可能在一定程度上解释了为什么目前针对肺的治疗方法 炎症对恶化的速度和结果只有轻微的影响，即使在 组合。 我们和其他人已经证明了COPD患者的肺和心脏之间存在显著的相互作用， 动脉粥样硬化加速、心律失常和高频率的舒张期功能障碍，每一种都可能导致 或导致急性加重的发展。这可能与舒张压特别相关 功能障碍，不仅可能导致显性肺水肿，还可能导致隐蔽的肺 充血导致支气管高反应性。流行率、危险因素、机制和后果 这一患者群体中的舒张期功能障碍仍不清楚。我们假设有一组稀疏的- 炎症性急性加重是由于心脏缺血引起的舒张期功能障碍 心律失常和/或肺过度膨胀。这些“充血性”恶化具有不同的临床和 炎症情况与由呼吸道感染或暴露于污染引发的发作进行比较，并将 因此，预计会对一种截然不同的治疗算法做出反应。进一步的假设是 急性加重期的舒张期功能障碍是由亚临床冠脉缺血、心律失常、 和/或动态肺过度膨胀。我们提出了一项前瞻性研究，通过以下方式回答这些高影响力的问题 测定慢性阻塞性肺疾病急性发作期患者舒张期功能障碍的发生率，其 临床意义和潜在机制。 我们将前瞻性地招募因COPD急性加重而住院的患者，并测试我们的 假设有以下三个具体目标。此应用程序的目标1将评估舒张压 功能障碍是COPD急性加重期少炎性表型的主要原因 急性加重期间的舒张期功能障碍以及肺部和全身炎症，以及 恢复后为稳定相。目标2的目标是评估舒张期功能障碍的临床意义 比较住院时间、下一次病情恶化的时间和总的病情恶化频率 有和没有舒张期功能障碍的患者在他们的指数入院后的一年内。在《目标3》中，我们将 通过评估冠脉缺血和心肌梗死评估舒张期功能障碍的潜在机制 对于心律失常以及急性事件期间和恢复后的肺过度膨胀的替代物。 我们的研究结果可能会通过定义充血性疾病来识别一种新的恶化机制 表型。 我将利用这项建议获得更多高级超声心动图技术方面的技能，以 进一步研究慢性阻塞性肺疾病复杂的心肺相互关系；对大多数 最新的质谱学技术及其在慢性阻塞性肺疾病肺蛋白质组学中的应用 获得临床和翻译科学硕士学位，培养独立的翻译职业生涯 研究和临床试验设计。本研究方案和职业发展计划的目标是可能的。 通过埃德温·布拉洛克博士的积极合作，他是慢性阻塞性肺疾病中性粒细胞炎症领域的领军人物。 马克·德兰斯菲尔德，慢性阻塞性肺病的主要研究员，特别关注病情恶化和心血管疾病 合并症。这个职业发展奖创造的机会将为我提供一个明确的 勾勒出获取专业知识和开发研究利基、成功竞争独立的路径 资助慢性阻塞性肺病和心血管疾病领域的翻译和临床研究，特别是 与急性加重有关。我的最终目标是识别新的病因致病机制和新的 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。