Evidence suggests that lung injury, inflammation and extracellular matrix remodeling precede lung fibrosis in interstitial lung disease (ILD). We examined whether a quantitative measure of increased lung attenuation on computed tomography (CT) detects lung injury, inflammation and extracellular matrix remodeling in community-dwelling adults sampled without regard to respiratory symptoms or smoking. We measured high attenuation areas (HAA; percentage of lung voxels between -600 and -250 Hounsfield Units) on cardiac CT scans of adults enrolled in the Multi-Ethnic Study of Atherosclerosis. HAA was associated with higher serum matrix metalloproteinase-7 (mean adjusted difference 6.3% per HAA doubling, 95% CI 1.3 to 11.5), higher interleukin-6 (mean adjusted difference 8.8%, 95% CI 4.8 to 13.0), lower forced vital capacity (mean adjusted difference -82 mL, 95% CI -119 to -44), lower 6-minute walk distance (mean adjusted difference -40 m, 95% CI -1 to -80), higher odds of interstitial lung abnormalities at 9.5 years (adjusted OR 1.95, 95% CI 1.43 to 2.65), and higher all cause-mortality rate over 12.2 years (HR 1.58, 95% CI 1.39 to 1.79). High attenuation areas are associated with biomarkers of inflammation and extracellular matrix remodeling, reduced lung function, interstitial lung abnormalities, and a higher risk of death among community-dwelling adults.

Rationale: Smoking-related microvascular loss causes end-organ damage in the kidneys, heart, and brain. Basic research suggests a similar process in the lungs, but no large studies have assessed pulmonary microvascular blood flow (PMBF) in early chronic lung disease.Objectives: To investigate whether PMBF is reduced in mild as well as more severe chronic obstructive pulmonary disease (COPD) and emphysema.Methods: PMBF was measured using gadolinium-enhanced magnetic resonance imaging (MRI) among smokers with COPD and control subjects age 50 to 79 years without clinical cardiovascular disease. COPD severity was defined by standard criteria. Emphysema on computed tomography (CT) was defined by the percentage of lung regions below 2950 Hounsfield units (2950 HU) and by radiologists using a standard protocol. We adjusted for potential confounders, including smoking, oxygenation, and left ventricular cardiac output.Measurements and Main Results: Among 144 participants, PMBF was reduced by 30% in mild COPD, by 29% in moderate COPD, and by 52% in severe COPD (all P , 0.01 vs. control subjects). PMBF was reduced with greater percentage emphysema 2950HU and radiologist-defined emphysema, particularly panlobular and centrilobular emphysema (all P < 0.01). Registration of MRI and CT images revealed that PMBF was reduced in mild COPD in both nonemphysematous and emphysematous lung regions. Associations for PMBF were independent of measures of small airways disease on CT and gas trapping largely because emphysema and small airways disease occurred in different smokers.Conclusions: PMBF was reduced in mild COPD, including in regions of lung without frank emphysema, and may represent a distinct pathological process from small airways disease. PMBF may provide an imaging biomarker for therapeutic strategies targeting the pulmonary microvasculature.

Background COPD is characterized by reduced airway lumen dimensions and fewer peripheral airways. Most studies of airway properties sample airways based upon lumen dimension or at random, which may bias comparisons given reduced airway lumen dimensions and number in COPD. We sought to compare central airway wall dimensions on computed tomography (CT) in COPD and controls using spatially matched airways, thereby avoiding selection bias of airways in the lung. Methods The MESA COPD Study and SPIROMICS recruited smokers with COPD and controls aged 50–79 years and 40–80 years, respectively. COPD was defined by current guidelines. Using CT image data, airway dimensions were measured for all central airway segments (generations 0–6) following 5 standardized paths into the lungs. Case-control airway comparisons were spatially matched by generation and adjusted for demographics, body size, smoking, CT dose, percent emphysema, airway length, and lung volume. Results Among 311 MESA COPD participants, airway wall areas at generations 3–6 were smaller in COPD compared to controls(all p<0.001). Among 1248 SPIROMICS participants, airway wall areas at generations 1–6 were smaller(all p<0.001), and this reduction was monotonic with increasing COPD severity(P<0.001). In both studies, sampling airways by lumen diameter or randomly resulted in a comparison of more proximal airways in COPD to more peripheral airways in controls(p<0.001) resulting in the appearance of thicker walls in COPD(p<0.02). Conclusions Airway walls are thinner in COPD when comparing spatially matched central airways. Other approaches to airway sampling result in comparisons of more proximal to more distal airways and potentially biased assessment of airway properties in COPD.

Our results suggest that some genes previously identified as influencing lung function are independently associated with emphysema rather than lung function, and that genes related to α-mannosidase may influence risk of emphysema.

1143C hronic lower respiratory disease is the third-leading cause of death in the United States. 1 The most morbid components of chronic lower respiratory dis ease are COPD, defi ned by spirometry as airfl ow obstruction that is not fully reversible, and pulmonary emphysema, defi ned by morphology as permanent enlargement of airspaces accompanied by destruction of their walls. 2,3 Emphysema on CT imaging is present in approximately one-half of patients with COPD, 4-7 and an estimated 2% of the general population aged . 50 years has emphysema without spirometry-defi ned COPD. 8 The number of Americans with a diagnosis of heart failure was 5.7 million in 2008, and approximately one-half of prevalent heart failure cases are characterized by preserved ejection fraction. 9,10 By comparison, 12 million Americans have a diagnosis of COPD and an additional 12 million may have undiagnosed COPD and emphysema. 11Background: COPD and heart failure with preserved ejection fraction overlap clinically, and impaired left ventricular (LV) fi lling is commonly reported in COPD. The mechanism underlying these observations is uncertain, but may include upstream pulmonary dysfunction causing low LV preload or intrinsic LV dysfunction causing high LV preload. The objective of this study is to determine if COPD and emphysema are associated with reduced pulmonary vein dimensions suggestive of low LV preload. Methods: The population-based Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited smokers aged 50 to 79 years who were free of clinical cardiovascular disease. COPD was defi ned by spirometry. Percent emphysema was defi ned as regions , 2 910 Hounsfi eld units on full-lung CT scan. Ostial pulmonary vein cross-sectional area was measured by contrast-enhanced cardiac magnetic resonance and expressed as the sum of all pulmonary vein areas. Linear regression was used to adjust for age, sex, race/ethnicity, body size, and smoking. Results: Among 165 participants, the mean ( Ϯ SD) total pulmonary vein area was 558 Ϯ 159 mm 2 in patients with COPD and 623 Ϯ 145 mm 2 in control subjects. Total pulmonary vein area was smaller in patients with COPD ( 2 57 mm 2 ; 95% CI, 2 106 to 2 7 mm 2 ; P 5 .03) and inversely associated with percent emphysema ( P , .001) in fully adjusted models. Signifi cant decrements in total pulmonary vein area were observed among participants with COPD alone, COPD with emphysema on CT scan, and emphysema without spirometrically defi ned COPD. Conclusions: Pulmonary vein dimensions were reduced in COPD and emphysema. These fi ndings support a mechanism of upstream pulmonary causes of underfi lling of the LV in COPD and in patients with emphysema on CT scan. CHEST 2013; 144(4):1143-1151Abbreviations: E/A ratio 5 ratio of peak fi lling rates during early phase diastole and atrial contraction; E/A ratioMR 5 ratio of peak fi lling rates during early phase diastole and atrial contraction estimated by magnetic resonance; EDV 5 end-diastolic volume; LV 5 left ventricle; MESA 5 Multi-Ethnic Study of Atherosclero...