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.

Project Narrative Pulmonary vascular disease commonly occurs in chronic obstructive pulmonary disease (COPD), and despite the increased morbidity associated with severe pulmonary vascular disease, there is limited understanding of the clinical implications of less severe pulmonary vascular disease. Understanding the contribution of early pulmonary vascular disease to COPD morbidity will define opportunities for targeted interventions of the pulmonary vasculature that could improve outcomes in COPD patients. As a necessary first step, this proposal will address key limitations in characterizing less severe PVD with multi-modal noninvasive approaches and apply these approaches to evaluate the contribution of pulmonary vascular disease to COPD morbidity across its observed spectrum of severity.