Chronic obstructive pulmonary disease (COPD) is very common, affecting up to 24 million people in the United States, and is associated with considerable and increasing morbidity and mortality. Cardiac comorbidities are prevalent in patients with COPD and contribute significantly to worse health outcomes. In fact, studies have shown that, in patients with COPD, cardiac causes of death are even more common than COPD-related causes. While COPD and cardiovascular disease share a common risk factor, smoking, it is clear that their association is multifactorial, going beyond this shared risk. One o the factors influencing the relationship is the shared position of the heart and lungs in a closed thoracic cage. It has been shown that many patients with COPD have increased lung volumes and that this hyperinflation impairs cardiac performance. In this career development proposal, the applicant hypothesizes that the abnormal cardiac performance in hyperinflated COPD patients is at least in part related to changes in the distribution of intrathoracic blood volume (.e. alterations in ventricular preload and afterload) that can be corrected with deflation. She proposes to use a novel noninvasive technique to develop a more detailed understanding of the relationship between hyperinflation and cardiac performance. Specifically, she will utilize computed tomographic vascular measurements to non-invasively estimate the distribution of blood within the thorax and assess how that distribution varies with changes in lung volumes and further, relates to cardiac chamber size and function at rest and during exercise in normals and in patients with different levels of COPD severity. In her first aim, she will explore the relationships between lung volumes, CT measurements of intrathoracic vessel caliber, and cardiac chamber size and function in a population based cohort (The Framingham Heart Study). This cohort will allow her to develop normative values for the size and relationships of extraparenchymal intrathoracic vessels and small pulmonary vessels. In her second aim, using data from the National Emphysema Treatment Trial, she will assess the effect of lung deflation (via lung volume reduction surgery) and transpulmonary pressure on intrathoracic vessel caliber. Use of this cohort will also allow her to correlate her CT vascular measurements with invasive measures of cardiac filling pressures and function. Finally, in her third aim, she will determine whether CT vascular measurements can predict cardiac performance during exercise. The results of this research may yield new insights into disease pathogenesis and suggest which patients would experience greatest benefit from pharmacologic or surgical deflation. This work will be performed in the Division of Pulmonary and Critical Care Medicine at Brigham and Women's Hospital, a core teaching hospital of Harvard Medical School. The division has an outstanding record of training physician scientists, one of the largest NIH grant portfolios of any pulmonary division in the country, and collaborations with multiple local and national institutions. There is abundant opportunity for intellectual stimulation with regular research meetings and seminars. Within the division, the candidate will work specifically in the Applied Chest Imaging Lab, where she will have access to all of the data bases and image analysis tools necessary to complete the proposed project. With the guidance of her mentors, Drs. George Washko, a leader in pulmonary research using quantitative chest imaging and director of ACIL, and Bartolome Celli, a world-renowned COPD clinical researcher, the principal investigator has formulated a comprehensive five-year training program to develop the skills necessary to become an independent physician-scientist conducting patient-oriented research on the association between COPD and cardiovascular disease. This curriculum includes advanced training in cardiac and respiratory pathophysiology, biostatistics, and clinical trial work, as well as in thoracic and cardiovascular imaging. In addition to her mentors, the candidate will have regular interactions with a committee of advisors with expertise relevant to the proposal. The candidate is dedicated to academic medicine and clinical research and hopes to build a career based on better understanding the heterogeneity and systemic manifestations of COPD. Her current proposal probes the mechanical nature of the heart-lung interaction;in future work, she would like to incorporate additional contributors including the important role of molecular and inflammatory mediators, more broadly considering COPD phenotypes through imaging- and biomolecular-based approaches. Ultimately, she would like to design and perform clinical and translational studies to assess therapies for patients with cardiopulmonary disease and in particular, understand how treatment of one condition (either through medical or surgical approaches) impacts the outcomes of another, and how therapies may be better targeted through improved diagnostic tools
COPD is an extremely prevalent disease with increasing morbidity and mortality, in part related to concurrent cardiovascular disease. This study aims to determine the effect of lung volumes on the distribution of blood within the thorax and, thereby, to better understand the mechanisms by which lung volumes affect cardiac performance. The results of this work have the potential to inform therapies for COPD patients.
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