The Pulmonary Vasculature and Platelets in Emphysema and COPD

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Rationale: Chronic obstructive pulmonary disease (COPD) and emphysema are the major components of chronic lower respiratory disease, the 4th leading cause of death in the United States and the world. Despite this, there are no disease-modifying pharmacologic therapies for COPD. Thus, there are opportunities to advance treatment of COPD by identifying and testing biological therapies that alter disease progression. Candidate: As a pulmonary-critical care-trained physician and Instructor at Brigham and Women's Hospital (BWH) and Harvard Medical School (HMS), the PI has conducted preliminary research identifying platelet activation as a potential risk factor for COPD and emphysema. The PI's long term goal is to become an independent clinical investigator with a focus on strategies that impact the development and progression of emphysema and COPD. Career Development: The PI's short term goals are to complete a Master's Degree in Epidemiology, to learn about imaging analysis, measures of platelet activation and clinical trial design and operations, which she will do with the guidance of the assembled multi-disciplinary mentorship team. Environment: BWH and HMS have a track-record of success in research career development and has committed significant resources to support this proposal including use of the BWH Center for Clinical Investigation. Research: The proposed research aims will evaluate the vascular hypothesis of emphysema and a specific related biological pathway (platelet activation) in sequential steps. Aim 1 will assess the association between pulmonary vascular morphology and the progression of percent emphysema on CT. Aim 2 will measure urinary 11-dehydro-thromboxane B2, a measure of in vivo platelet activation, in a sample of 1,537 participants in the Subpopulations and Intermediate Outcomes Measured in COPD Study (SPIROMICS) to test whether platelet activation is associated with emphysema and pulmonary vascular morphology in cross- sectional analyses, and whether it predicts longitudinal progression of emphysema. Aim 3 will recruit 20 novel participants with visual emphysema on CT and mild-moderate COPD for a crossover study to determine whether dual antiplatelet therapy improves pulmonary microvascular perfusion on dual-energy CT scan compared to placebo. Together, these aims link the pulmonary vasculature, platelet activation and emphysema progression, and will test whether inhibiting platelet activation impacts our measures of microvascular pulmonary perfusion. Improvement in pulmonary perfusion with dual antiplatelet therapy would suggest that these therapies may impact long-term progression of emphysema, a hypothesis I would propose to test in a future R01/phase IIb RCT. In completing these research objectives, the PI aims to identify a potential novel pathway related to emphysema and COPD, and gain the expertise to establish an independent research program that identifies and tests therapies that impact the progression of emphysema and COPD.