Pulmonary Vascular Disease as a Contributor to Respiratory Morbidity in Chronic Obstructive Pulmonary Disease

项目摘要/摘要 慢性阻塞性肺疾病(COPD)在美国有超过1500万成年人。多达 其中35%的患者发展为肺血管疾病(PVD)，但评估的建议 COPD患者PVD的治疗一直受到关键知识差距的限制。首先，评估 肺血管系统依赖于有创性右心导管术作为金标准，限制了研究 选择严重PVD的人群。非侵入性技术虽然广泛可用，但也已被 初步在患有严重PVD的人群中验证，应用可能反映终末期PVD的标记， 比如右心衰竭。因此，另一个关键的知识差距是PVD对 在其观察到的严重程度范围内，COPD的发病率。而严重的PVD的伴随存在是 与单纯COPD患者相比，观察到预示着发病率和死亡率的增加， 不那么严重的PVD，在疾病过程中可能更容易干预的时间点，人们对此了解较少。这 一项提案试图通过(SA1)测试诊断的准确性来解决三个目标的知识差距 三个对早期PVD(SA2)可能敏感的非侵入性标记及其应用 非侵入性标记物了解PVD在横断面和横断面中对呼吸道发病率的贡献 (SA3)纵向研究设计。这项应用将为一般的COPD队列增加非侵入性标记 未被选为PVD患者，并将进一步聚集COPD患者的前瞻性纵向队列 对PVD进行同样的无创检测。这项提议的结果将确定新的非侵入性方法 为了评估PVD，定义它们在PVD谱系中的临床相关性，并建立机会 在以肺为靶点的临床试验中，研究非侵入性标志物作为候选结果的使用 治疗慢性阻塞性肺疾病的血管系统。 巴拉苏布拉马尼安博士的提议是她职业发展的强大培训工具，为她提供了 具备实践队列研究设计和执行、先进的生物统计学和流行病学方法的技能， 通过包括右心在内的多种方法对COPD患者的PVD进行无创和有创评估 导管术、磁共振成像、斑点跟踪超声心动图和生理学检查 肺弥散能力的测量。巴拉苏布拉马尼安博士将得到强大的多方支持- 具有慢性阻塞性肺病、肺动脉高压、心脏病学、放射学和 生物统计学。她还将利用卓越的机构环境，通过其协作和 支持性文化，广泛的智力和体力资源，以及强大的支持青少年的历史 调查人员。这一奖项将使巴拉苏布拉马尼亚博士成为一名独立的研究员，具有独特的 研究利基，有别于她的指导团队，并为未来的研究评估和 慢性阻塞性肺疾病并发PVD的处理。

Project Summary/Abstract Chronic obstructive pulmonary disease (COPD) occurs in over 15 million adults in the US. As many as 35% of those patients develop pulmonary vascular disease (PVD), but the recommendations for assessment and management of PVD in COPD have been limited by key knowledge gaps. Firstly, assessment of the pulmonary vasculature has relied upon invasive right heart catheterization as the gold standard, limiting studies to select populations with severe PVD. Noninvasive techniques, though widely available, have also been primarily validated in populations with severe PVD applying markers that are likely to reflect end-stage PVD, such as right ventricular failure. As a result, another key knowledge gap is the unknown contribution of PVD to COPD morbidity across its observed spectrum of severity. While the concomitant presence of severe PVD is observed to portend increased morbidity and mortality compared to those with COPD alone, the contribution of less severe PVD, at potentially more intervenable points in the disease course is less well-understood. This proposal seeks to address these knowledge gaps in three aims by (SA1) testing the diagnostic accuracy of three noninvasive markers that are selected for plausible sensitivity to early PVD, (SA2) and applying these noninvasive markers to understand the contribution of PVD to respiratory morbidity in cross-sectional and (SA3) longitudinal study designs. This application will add noninvasive markers to a general COPD cohort unselected for PVD and will further assemble a prospective longitudinal cohort of COPD patients enriched for PVD with the same noninvasive testing. The results of this proposal will identify novel noninvasive approaches for assessing PVD, define their clinical relevance across the spectrum of PVD, and establish opportunities to study the use of noninvasive markers as candidate outcomes in clinical trials targeting the pulmonary vasculature to manage COPD. Dr. Balasubramanian’s proposal is a strong training vehicle for her career development, offering her skills in hands-on cohort study design and execution, advanced biostatistical and epidemiologic methodology, and noninvasive and invasive assessment of PVD in COPD through numerous modalities including right heart catheterization, magnetic resonance imaging, speckle-tracking echocardiography, and physiologic measurements of diffusing capacity of the lung. Dr. Balasubramanian will be supported by a strong multi- disciplinary mentorship team with expertise in COPD, pulmonary hypertension, cardiology, radiology, and biostatistics. She further will leverage an exceptional institutional environment with its collaborative and supportive culture, extensive intellectual and physical resources, and strong history of supporting junior investigators. This award will establish Dr. Balasubramanian as an independent investigator with a unique research niche, distinct from her mentorship team, and establish a foundation for future studies evaluating and managing PVD in COPD.