Rationale and Objectives
Pulmonary vascular alteration is one of the characteristic features of chronic obstructive pulmonary disease (COPD). Recent studies suggest that vascular alteration is closely related to endothelial dysfunction and may be further influenced by emphysema. However, the relationship between morphological alteration of small pulmonary vessels and the extent of emphysema has not been assessed in vivo. The objectives of this study are: to evaluate the correlation of total cross-sectional area (CSA) of small pulmonary vessels with the extent of emphysema and airflow obstruction using CT scans and to assess the difference of total CSA between COPD phenotypes.
Materials and Methods
We measured CSA less than 5 mm 2 and 5–10 mm 2 , and calculated the percentage of the total CSA for the lung area (%CSA < 5, and %CSA5–10, respectively) using CT scans in 191 subjects. The extent of emphysema (%LAA-950) was calculated, and the correlations of %CSA < 5 and %CSA5–10 with %LAA-950 and results of pulmonary function tests (PFTs) were evaluated. The differences in %CSA between COPD phenotypes were also assessed.
Results
The %CSA < 5 had significant negative correlations with %LAA-950 ( r = -0.83, P < .0001). There was a weak but statistically significant correlation of %CSA < 5 with forced expiratory volume in 1 second (FEV1)% predicted ( r = 0.29, P < .0001) and FEV1/forced vital capacity ( r = 0.45, P < .0001). A %CSA 5–10 had weak correlations with %LAA-950 and results of PFTs. %CSA < 5 was significantly higher in bronchitis phenotype than in the emphysema phenotype ( P < .0001).
Conclusions
Total CSA of small pulmonary vessels at sub-subsegmental levels strongly correlates with the extent of emphysema (%LAA-950) and reflects differences between COPD phenotypes.
Pulmonary vascular alteration is a characteristic feature of chronic obstructive pulmonary disease (COPD). Early angiographic studies in patients with emphysema showed narrowing and reduction in the number of small pulmonary arteries at subsegmental or sub-subsegmental levels . Passive vascular compression by emphysema and hypoxic vasoconstriction has been considered the major pathogenesis of vascular alteration in COPD. Histologically, pulmonary vascular alterations are not exclusive to advanced COPD, however, because they are present in patients with mild COPD and even in smokers with normal pulmonary function . Recent studies suggest that both pulmonary and extrapulmonary vascular alterations in patients with COPD closely relate to endothelial dysfunction . Because of the important role played by the endothelium in regulating vascular tone and controlling cell growth, pulmonary arteries with endothelial dysfunction have a diminished ability to dilate . Consequently, the pulmonary vascular bed decreases, and structural vascular alterations lead to the functional impairments.
Recently, several researchers demonstrated the relationship between endothelial dysfunction and emphysema . Endothelial dysfunction results from changes in the expression and release of vasoactive mediators. In several vasoactive mediators, vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of both vascular alteration and emphysema . Kasahara et al demonstrated that the blockade of the VEGF receptor caused emphysema, and they simultaneously showed a pruning and decrease of the pulmonary arteries on angiography. More recently, Barr et al suggested that the extent of emphysema, rather than airway obstruction, is responsible for endothelial dysfunction in COPD. Considering these previous reports, we hypothesized that the vascular alteration, as estimated by the reduction in cross-sectional area (CSA) of small pulmonary vessels in patients with COPD, would be related to the extent of emphysema, and predicted a stronger correlation than that with decline of airflow obstruction. To test this hypothesis, we measured CSA of subsegmental and sub-subsegmental pulmonary vessels with CT images, and evaluated the correlation of total CSA with emphysema and airflow obstruction. In addition, previous studies showed the differences in the level of VEGF and vascular alteration between COPD phenotypes . We hypothesized that a difference in vascular alteration between COPD phenotypes existed and sought to measure it.
Methods
Subjects
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Multislice CT Scanning
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CT Measurement of Small Pulmonary Vessels
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Pulmonary Function Tests
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Statistical Analysis
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Results
Characteristics of the Study Subjects
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Table 1
Patient Characteristics and Results of Pulmonary Function Tests ( n = 191)
Mean ± SD Age (y) 62 ± 5 Age (y): female 61 ± 4 Age (y): male 63 ± 5 Pack-years 52 ± 29 Current smokers (%) 56.0 FEV 1 (L) 2.3 ± 0.8 FEV 1 % predicted (%) 74.2 ± 20.5 FVC (L) 3.7 ± 0.9 FEV 1 /FVC 0.63 ± 0.13
SD, standard deviation; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity.
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CSA Measurements and Correlation with %LAA-950 and results of PFTs
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Table 2
Cross-sectional Area of Pulmonary Vessels and Correlations with %LAA-950 and Pulmonary Function Tests ( n = 191)
Cross-sectional Area Mean ± SD (%) %LAA-950 FEV1% predicted FEV1/FVC_r__P__r__P__r__P_ %CSA < 5 0.43 ± 0.11 -0.83 <.0001 0.29 <.0001 0.45 <.0001 %CSA5–10 0.10 ± 0.04 -0.25 .0004 0.26 .0003 0.22 .0025
%LAA-950, the percentage of low attenuation area less than -950 HU (defined as emphysema); FEV 1 , forced expiratory volume in 1 second; FVC, forced vital capacity; SD, standard deviation; %CSA < 5, percentage total cross-sectional area calculated from pulmonary vessels less than 5 mm 2 ; %CSA5–10, percentage total cross-sectional area calculated from pulmonary vessel size between 5 and 10 mm 2 .
Correlations were assessed using Spearman’s rank correlation analysis.
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CSA Measurements and COPD Phenotypes
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Table 3
Cross-sectional Area of COPD Phenotypes ( n = 130)
GOLD Stage %CSA < 5 (%) Bronchitis Phenotype Emphysema Phenotype_P_ Value All Stage 0.53 ± 0.10 0.35 ± 0.08 <0.0001 GOLD 1 0.52 ± 0.08 0.36 ± 0.05 <0.0001 GOLD 2 0.53 ± 0.10 0.36 ± 0.09 <0.0001 GOLD 3 and 4 0.52 ± 0.11 0.33 ± 0.07 <0.0001
GOLD, Global Initiative for Chronic Obstructive Lung Disease; COPD, chronic obstructive pulmonary disease; %CSA < 5, percentage total cross-sectional area calculated from pulmonary vessels less than 5 mm 2 .
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Discussion
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