In this study, we performed a quantitative analysis of pulmonary vessel changes according to GOLD grade and CT subtype. As the GOLD grade based on PFT and the emphysema severity based on volumetric chest CT increased, the number of pulmonary vessels consistently decreased. In addition, quantitative longitudinal analysis up to 6 years demonstrated that the number of vessels decreased more significantly in the normal and SAD subtypes than in the emphysema subtypes, while no significant differences were observed according to GOLD grades.
Pulmonary vascular alteration is an important complication in the natural history of COPD, but its pathophysiologic mechanisms are still poorly understood. Endothelial dysfunction is a major cause of vascular remodeling and emphysema[2, 8, 19]. Chest CT could quantitatively assess macroscopic pulmonary vascular alterations in subjects with COPD. The ratio of the main pulmonary artery to the ascending aorta diameter has been suggested as an important marker for pulmonary vascular disease. Approximately 66 % of subjects with COPD have some degree of pulmonary hypertension, and a pulmonary artery-to-ascending-aorta ratio > 1 was associated with acute exacerbation (AE) and mortality in patients with COPD[20–22]. Our previous study showed that the pulmonary artery-to-ascending aorta ratio was correlated with FEV1 in patients with mild to moderate COPD. In addition, a study using CT and cardiac magnetic resonance imaging reported that pulmonary artery enlargement is associated with the loss of blood volume in the distal pulmonary vessels in patients with COPD.
The CSAs of the small pulmonary vessels can be evaluated quantitatively on CT to identify pulmonary vascular alterations in patients with COPD[18, 25]. Several studies found the CSAs of small pulmonary vessels to be associated with symptoms, pulmonary artery pressure, pulmonary function, exercise capacity, AE of COPD, and mortality[5, 26, 27]. In our study, similar to other studies, Ntotal/LSA and N< 5mm/LSA showed a distinct decrease as the GOLD grades progressed. Histological studies have shown that a greater degree of emphysema and SAD are associated with pulmonary vascular alteration[28, 29]. Downregulation of lung vascular endothelial growth factor (VEGF) and upregulation of inducible nitric oxide synthase (iNOS), which can lead to endothelial dysfunction, play crucial roles in the development of vascular alteration and emphysema[6, 19, 30]. Previous studies have found a relationship between quantitative CT vascular parameters and emphysema[8, 17]. Likewise, the current study showed that Ntotal/LSA and N< 5mm/LSA were negatively correlated with LAA-950. In addition, the quantitative assessment of pulmonary vascular alterations may be more strongly associated with the extent of emphysema than the PFT results.
COPD is a heterogeneous disease with various clinical and pathologic characteristics, and can traditionally be distinguished into two phenotypes: emphysema and airway disease[31, 32]. VEGF is a potential mediator of pulmonary vascular remodeling, and its expression increases in the airway of bronchitis-type patients, leading to abnormal proliferation of endothelial and vascular smooth muscle cells in pulmonary vessels. A study reported that pulmonary vascular alteration was more strongly associated to the emphysema phenotype than to the bronchitis phenotype in patients with COPD. In our study, the analysis was conducted by dividing the patients into five subtypes based on quantitative CT analysis. Compared with the emphysema phenotype, Ntotal/LSA and N< 5mm/LSA were significantly higher in the SAD phenotype. Therefore, the results of our study confirmed that pulmonary vascular alteration was more severe in the emphysema phenotype than in the airway phenotype.
In the past, pulmonary vascular disease was considered an end-stage feature of COPD, and pulmonary hypertension was observed in 90 % of patients with GOLD grade 4 COPD[17, 34]. However, recent studies have shown that pulmonary vascular alteration occurs in the setting of subclinical and early stage COPD by an impairment of endothelial function in pulmonary vessels[4, 18, 25, 35, 36]. Emphysema and air trapping progressed over time in smokers. Some studies reported that emphysema increased over 2–3 years, whereas the CSAs of small pulmonary vessels did not decrease[9, 37]. In our study, there were no changes in each GOLD grade, but the number of vessels decreased in the normal and SAD CT subtype over the follow-up period of up to 6 years. This suggests that vessel changes over time were more prominent in the normal and SAD phenotype than in the emphysema phenotype. However, various factors could have affected this result, because the pulmonary hemodynamics affecting quantitative CSA assessment can be changed by breath-holding, circulating blood volume, and treatment[9, 37, 38].
This study has several limitations. First, we quantitatively measured the pulmonary vessel count change based on volumetric chest CT, but could not distinguish between the pulmonary artery and vein. Second, the gold standard for assessing pulmonary vascular abnormality and pulmonary hypertension is right heart catheterization, but this was not done in our study because of the invasiveness of the method. Third, a longitudinal analysis was performed over the 6-year follow-up period, but the baseline values of the subjects were not uniform. Over the entire observation period, the number of observed subjects gradually decreased, leading to lack of statistical power to detect statistical significance in the longitudinal observation of pulmonary vascular changes. Therefore, validation of our results in a large cohort study is necessary.