Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States. COPD will overtake stroke as the third leading cause of death within 7 years. Deaths attributable to heart failure (HF) have also increased over this period, particularly from HF with preserved ejection fraction (EF). The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study recruited 3,965 participants and confirmed its primary hypotheses that endothelial dysfunction measured by flow-mediated dilation (FMD) and neutrophil adhesion, measured by plasma ICAM, was associated with lower lung function. A corollary of the endothelial hypothesis of COPD is that damage to the pulmonary endothelium occurs early in subclinical emphysema and that such damage may reduce blood flow to the left ventricle (LV). We found highly significant associations of airflow obstruction and emphysema on CT scan with reduced LV end-diastolic volume, LV stroke volume and cardiac output but not LV-EF on magnetic resonance imaging, particularly among smokers. Furthermore, CT emphysema independently predicted incident HF over 4 years. Together, these findings suggest a "pulmonary" subtype of HF with preserved EF. Our findings to date are limited, however, by an inability to assess directly the pulmonary circulation, lack of full-lung CT scans and post-bronchodilator spirometry, and mostly cross-sectional findings. Since the pulmonary arterioles and arteries in COPD respond to small increases in resistance at the level of the pulmonary capillaries by marked vasodilation, we recently developed a measure of the total pulmonary vascular volume (TPVV) on non-contrast, full-lung CT scans. We propose to measure TPVV on full-lung CT scans, pre- and post-bronchodilator spirometry, oxymetry and biomarkers among active participants in the MESA-Lung Study to test the following hypotheses: 1) Pulmonary vascular structure, measured by increased TPVV, is linearly associated with lower LV end-diastolic volume, airflow obstruction and increased emphysema. These associations are modified by smoking status but persist in never-smokers and across race/ethnic groups. 2) Endothelium-dependent hypercoagulation, measured by PAI-1, and plasma viscosity is associated with greater TPVV, lower LV end-diastolic volume, greater emphysema and airflow obstruction. 3) Impaired FMD of the brachial artery and elevated PAI-1 and fibrinogen predict accelerated decline in lung function, increased emphysema and decreased LV end-diastolic volume over 6-10 years. Innovative aspects include the evaluation of cardiopulmonary structure and function in a large, well-characterized multiethnic cohort, use of a novel non-invasive measure of the pulmonary vasculature, and longitudinal testing of these hypotheses. Confirmation of the hypotheses would define shared mechanisms of COPD and HF with preserved EF and help justify testing of therapies targeting cardiopulmonary function. PHS 398 (Rev. 5/01) Page Number pages consecutively at the bottom throughout the application. Do not use suffixes such as 3a, 3b.

Public Health Relevance

Chronic obstructive pulmonary disease (COPD) is currently the fourth leading cause of death in the United States. COPD will overtake stroke as the third leading cause of death less than 10 years. The prevalence of heart failure prevalence has similarly increased. Historically, heart and lung disease was investigated as one entity. This study will examine if a particular kind of heart failure (with preserved ejection fraction or diastolic heart failure) is caused in part by and may share pathogenesis with subclinical lung disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular and Sleep Epidemiology (CASE)
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Croxton, Thomas
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Columbia University (N.Y.)
Internal Medicine/Medicine
Schools of Medicine
New York
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