Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally and in the United States. More than half of COPD patients have emphysema on computed tomography, which is associated with increased mortality, but medical therapies for COPD exclusively target the airways. The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited 327 participants to test the endothelial hypothesis of emphysema, which posits that smoking-related pulmonary endothelial damage contributes to emphysema. The MESA COPD Study confirmed its primary aims that: pulmonary microvascular blood flow (PMBF) on magnetic resonance imaging (MRI) is substantially reduced COPD and emphysema of all severities;endothelial microparticles are increased and endothelial progenitor cells are reduced;and gene expression in peripheral blood mononuclear cells is strongly linked to PMBF. Although supportive of the endothelial hypothesis, findings also may be due to newly described aberrant hypoxic pulmonary vasoconstriction (HPV) or residual HPV from impaired ventilation. We also found that right ventricular (RV) volumes were reduced in COPD and emphysema, a condition we have termed cor pulmonale parvus. This condition is associated with all-cause mortality in the general population and might result, pilot data suggest, from RV stiffness and subtle ventilatory impairment. The renewal is a longitudinal continuation of the MESA COPD Study in which we aim to use regional measures of oxygen tension, ventilation, PMBF and emphysema, along with interventions to reverse HPV and to treat hyperinflation, and innovative measures of RV function and venous blood flow on MRI to test the hypotheses that: emphysema is characterized by reduced PMBF independent of HPV and ventilatory impairment;cor pulmonale parvus is associated with RV stiffness and increased intrathoracic pressure;and reduced PMBF in non-emphysematous regions of the lung is associated with the local development of emphysema and tissue loss at five years. Innovative aspects of this proposal include the use of novel MRI imaging modalities of direct clinical relevance, examination of a new entity, cor pulmonale parvus, and the longitudinal testing of the vascular hypothesis of emphysema in humans. Confirmation of these aims would create a paradigm shift in COPD treatment to justify the testing of existing and novel (e.g., EPC/stem cell) therapies targeted to the pulmonary vasculature in emphysema, provide a potential imaging biomarker to facilitate early phase, short-term clinical trials of such therapies, and suggest mechanisms to approach and possibly treat cor pulmonale parvus.

Public Health Relevance

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally and in the United States;most patients with COPD and some without COPD have emphysema (destruction of lung tissue) yet no medical therapies target emphysema. We found evidence using advanced imaging, cellular and genomic measures of endothelial damage in emphysema, in addition to a new cardiovascular complication of emphysema. We propose longitudinal and interventional studies with advanced imaging to find out if endothelial damage may contribute to emphysema, establish an imaging biomarker for future trials, and examine reasons for the cardiovascular complication.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL093081-05
Application #
8632186
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Punturieri, Antonello
Project Start
2008-08-28
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10032
Manichaikul, Ani; Wang, Xin-Qun; Sun, Li et al. (2017) Genome-wide association study of subclinical interstitial lung disease in MESA. Respir Res 18:97
Sack, Coralynn S; Doney, Brent C; Podolanczuk, Anna J et al. (2017) Occupational Exposures and Subclinical Interstitial Lung Disease. The MESA (Multi-Ethnic Study of Atherosclerosis) Air and Lung Studies. Am J Respir Crit Care Med 196:1031-1039
Armstrong, Hilary F; Lovasi, Gina S; Soliman, Elsayed Z et al. (2017) Lung function, percent emphysema, and QT duration: The Multi-Ethnic Study of Atherosclerosis (MESA) lung study. Respir Med 123:1-7
Aaron, Carrie P; Hoffman, Eric A; Lima, Joao A C et al. (2017) Pulmonary vascular volume, impaired left ventricular filling and dyspnea: The MESA Lung Study. PLoS One 12:e0176180
Armstrong, Hilary F; Podolanczuk, Anna J; Barr, R Graham et al. (2017) Serum Matrix Metalloproteinase-7, Respiratory Symptoms, and Mortality in Community-Dwelling Adults. MESA (Multi-Ethnic Study of Atherosclerosis). Am J Respir Crit Care Med 196:1311-1317
Parikh, Megha A; Aaron, Carrie P; Hoffman, Eric A et al. (2017) Angiotensin-Converting Inhibitors and Angiotensin II Receptor Blockers and Longitudinal Change in Percent Emphysema on Computed Tomography. The Multi-Ethnic Study of Atherosclerosis Lung Study. Ann Am Thorac Soc 14:649-658
Restivo, Michaela D; Podolanczuk, Anna; Kawut, Steven M et al. (2017) Antacid use and subclinical interstitial lung disease: the MESA study. Eur Respir J 49:
Lo Cascio, Christian M; Quante, Mirja; Hoffman, Eric A et al. (2017) Percent Emphysema and Daily Motor Activity Levels in the General Population: Multi-Ethnic Study of Atherosclerosis. Chest 151:1039-1050
Doyle, Margaret F; Tracy, Russell P; Parikh, Megha A et al. (2017) Endothelial progenitor cells in chronic obstructive pulmonary disease and emphysema. PLoS One 12:e0173446
Hobbs, Brian D; de Jong, Kim; Lamontagne, Maxime et al. (2017) Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis. Nat Genet 49:426-432

Showing the most recent 10 out of 58 publications