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Usefulness of the 6-minute walk test as a screening test for pulmonary arterial enlargement in COPD

Purpose Pulmonary hypertension and exercise-induced oxygen desaturation (EID) influence acute exacerbation of COPD. Computed tomography (CT)-detected pulmonary artery (PA) enlargement is independently associated with acute COPD exacerbations. Associations between PA to aorta (PA:A) ratio and EID in patients with COPD have not been reported. We hypothesized that the PA:A ratio correlated with EID and that results of the 6-minute walk test (6MWT) would be useful for predicting the risk associated with PA:A >1. Patients and methods We retrospectively measured lung function, 6MWT, emphysema area, and PA enlargement on CT in 64 patients with COPD. The patients were classified into groups with PA:A ≤1 and >1. Receiver-operating characteristic curves were used to determine the threshold values with the best cutoff points to predict patients with PA:A >1. Results The PA:A >1 group had lower forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1:FVC ratio, diffusion capacity of lung carbon monoxide, 6MW distance, and baseline peripheral oxygen saturation (SpO2), lowest SpO2, highest modified Borg scale results, percentage low-attenuation area, and history of acute COPD exacerbations ≤1 year, and worse BODE (Body mass index, airflow Obstruction, Dyspnea, and Exercise) index results (P<0.05). Predicted PA:A >1 was determined for SpO2 during 6MWT (best cutoff point 89%, area under the curve 0.94, 95% confidence interval 0.88–1). SpO2 <90% during 6MWT showed a sensitivity of 93.1, specificity of 94.3, positive predictive value of 93.1, negative predictive value of 94.3, positive likelihood ratio of 16.2, and negative likelihood ratio of 0.07. Conclusion Lowest SpO2 during 6MWT may predict CT-measured PA:A, and lowest SpO2 <89% during 6MWT is excellent for detecting pulmonary hypertension in COPD.


Introduction
Exacerbations of COPD are associated with accelerated loss of lung function, poor quality of life, and mortality. 1,2 These events can be predicted by numerous clinical factors, including prior exacerbations, airflow obstruction, symptom burden, gastroesophageal reflux, and leukocytosis. 3 It is important to detect COPD exacerbations early and minimize their severity.
Patients with COPD frequently experience significant decreases in oxygen saturation during exercise, attributed to the imbalance between oxygen delivery and exercise-induced demand. 4 Exercise-induced oxygen desaturation (EID) is reported to be associated with hospitalization and mortality in patients with COPD. 5 The 6-minute walking test (6MWT) has been suggested as the preferred measure to identify patients with COPD and EID. 6 EID occurs frequently during the 6MWT in patients with COPD. 7 EID has been related to forced expiratory volume in 1 second (FEV 1 ), diffusion capacity of lung carbon monoxide (D LCO ), amount of emphysema, and baseline oxygen saturation. [8][9][10] Pulmonary hypertension (PH) is an important factor contributing to acute exacerbation of COPD. 11 PH appears when airflow limitation is severe, and is associated with chronic hypoxemia. Pulmonary vascular remodeling in COPD is the main cause of increased pulmonary artery (PA) pressure, and is thought to result from the combined effects of hypoxia, inflammation, and capillary loss in severe emphysema. 12 The presence of PH has been shown to increase the hospitalization rate and mortality of patients with COPD. 13,14 Computed tomography (CT)-detected PA enlargement is independently associated with acute exacerbations of COPD. 15 The PA-to-aorta (PA:A) ratio measured by CT scan outperforms echocardiography for diagnosing resting PH in patients with severe COPD. 16 A PA:A .1 indicates lower oxygen saturation at rest than a PA:A ,1. 15 However, there are no reports on the association between PA:A and EID in patients with COPD.
We hypothesized that PA:A correlates with the presence of EID and that 6MWT results are useful for predicting the risk of having a PA:A .1. The present study aimed to examine the relationship between PA:A and EID and develop a simple screening tool by determining the appropriate cutoff score on the 6MWT to predict a PA:A .1 in patients with COPD.

Patients and methods study design and patient selection
This study analyzed regularly treated outpatients with COPD between 2014 and 2015 at the Kobe City Medical Center West Hospital. A total of 64 patients with COPD were included after applying the exclusion criteria in this study ( Figure 1). The criteria for diagnosing COPD were a smoking history ($20 pack-years) and postbronchodilator FEV 1 /forced vital capacity (FVC) ,70%. Furthermore, we used the following inclusion criteria to define COPD clinically, all of which had to be fulfilled: symptoms, including cough, sputum production, wheezing, dyspnea, smoking history ($20 pack-years), existence of emphysema on chest CT, and a physician diagnosis of COPD. [17][18][19][20][21] Study-exclusion criteria were as follows: history of lung surgical procedures, exacerbation-related hospitalization 3 months before 6MWT, and patients on longterm oxygen therapy. This study was approved by the ethics committee of Kobe University (N287). All the participants provided written or oral informed consent.

Clinical characterization assessments
A chest physician performed the physical examination for all outpatients. This examination included an assessment of body weight, height, and medical history (eg, pulmonary embolism and sleep apnea syndrome), GOLD (Global initiative for chronic Obstructive Lung Disease) grade 0-4, history of acute exacerbations of COPD within the previous year, COPD Assessment Test, level of dyspnea (using the modified Medical Research Council dyspnea scale), postbronchodilator spirometry, D LCO , 6MWT (according to international recommendations), emphysema area, and PA enlargement on CT. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. GOLD 0 was defined as current and former smokers with a normal postbronchodilator ratio of FEV 1 :FVC exceeding 0.7 and an FEV 1 of at least 80%, symptoms, including cough, sputum production, wheezing, and dyspnea, smoking history ($20 pack-years), existence of emphysema on chest CT, and a physician diagnosis of COPD. [17][18][19][20][21] six-minute walking test The 6MWT was performed according to the 2002 American Thoracic Society guidelines. 22 Participants were asked to walk indoors on a flat, round, 25 m walking course supervised by a physician and physical therapist. A practice 6MWT was not undertaken. Subjects were encouraged using standard methodology every minute of the 6MWT. A pulse oximeter (WristOx 3150; Nonin Medical, Plymouth, MN, USA) with a finger probe measured peripheral oxygen saturation (SpO 2 ) during 6MWT, and 6MWT-analysis software (WristOx 2; Star Product, Tokyo, Japan) was used. In addition, a modified Borg scale was used to quantify

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6MWT as a screening test for Pae in COPD the levels of dyspnea perceived by subjects at each minute during the 6MWT. EID was defined as a nadir SpO 2 ,90%, SpO 2 #88%, and ΔSpO 2 $4%. [23][24][25] Measuring the Pa:a ratio One reviewer, blinded to hemodynamic information, analyzed CT scans (Optima CT 660 Discovery; GE Healthcare, Little Chalfont, UK). Measurements of the diameter of the main PA and the diameter of the aorta at the level of the bifurcation were used to calculate the PA:A ratio, as previously reported. [14][15][16] In cases where the aorta was not uniform in diameter, two measurements were taken 90° apart and the larger diameter used. PA was measured on the line that joins the origin of the left PA and the center of the adjacent ascending aorta on the axial section at the level of PA bifurcation. 26 CT-measured relative PA enlargement was defined as PA:A .1 ( Figure 2). 14-16

statistical analysis
Results are expressed as counts or median (interquartile range). Data are presented as means and standard deviation or as proportion, as appropriate. Cohen's κ-coefficient measured intraobserver and interobserver agreements for CT measurements of the PA:A ratio. Bivariate analyses were performed with the use of Pearson's χ 2 test for categorical data and the Mann-Whitney U-test for continuous data when appropriate. Spearman's rank-correlation coefficient was determined for relationships between the PA:A ratio, lungfunction parameters, 6MWT parameters, and CT parameters. Receiver operating characteristic (ROC) curves were used to determine the threshold values with the best sensitivity and specificity to predict PA:A .1, with the best being defined as the point on the ROC curve with the shortest distance from the upper-left corner. Sensitivity, specificity, positive/ negative predictive value, and positive/negative likelihood were calculated for lung-function parameters and 6MWT parameters of exacerbation-risk factors on the basis of a previous study. 6,27,28 All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for the R project (R Foundation for Statistical Computing, Vienna, Austria). 29 More precisely, it is a modified version of R Commander designed to add statistical functions frequently used in biostatistics, and P-values ,0.05 were considered statistically significant.

Results
The current analysis comprised 64 patients who were separated into groups on the basis of PA:A .1 (n=29) and #1 (n=35). Participants had a mean age of 73 (68-79) years.   Figure 3). The performance data on the 6MWT and lung function for predicting PA enlargement are depicted in

Discussion
We were able to reveal three main findings in the present study. First, we found a strong association between the PA:A ratio and lowest SpO 2 during the 6MWT. For this reason, a consistent finding in patients with COPD is the close relationship between severity of hypoxemia and PA pressure or pulmonary vascular resistance, supporting a major role for alveolar hypoxia. 30 Alveolar hypoxia causes constriction of the resistance PAs, and sustained alveolar hypoxia induces pulmonary vascular remodeling. 28 Pathological studies of lung specimens from patients with COPD have shown extensive pulmonary vascular remodeling, with prominent intimal thickening and medial hypertrophy. For this reason, chronic alveolar hypoxia plays an important role in pulmonary vascular remodeling. 28 In a previous study, patients with PA:A .1 showed lower resting SpO 2 , higher usage rates of supplemental oxygen, and an indirect association with EID. 15 In the present study, the lowest SpO 2 during the 6MWT to predict PA:A .1 was considered to be a beneficial result based on the ROC curves. Lowest SpO 2 ,89% during the 6MWT is excellent in the detection of PH. These results suggest that the lowest SpO 2 during the 6MWT is a very helpful measure and screening test for the PA:A ratio. For example, it might be possible to easily screen for pulmonary artery expansion by means of the six-minute walking test in a home-care situation, where it would be difficult to perform CT imaging. Second, with regard to the relationship between PA:A ratio and lung function, correlations were observed among FEV 1 , D LCO , and LAA. One of the factors that may play a role in causing PH to advance in patients with COPD is the destruction of lung parenchyma, leading to loss of part of the pulmonary vascular bed, 30,31 and the burden of airway remodeling influencing PA-pressure increase. 28 A previous study included patients with airflow-obstruction severity greater than moderate, and our study included mild airflow obstruction and smokers with normal spirometry. 15 Therefore, regardless of the severity of airflow obstruction, PA enlargement may be progressing. Undiagnosed COPD is a problem worldwide. 18 GOLD 0 has been reported to be an exacerbation risk; therefore, 18 early detection and not just spirometry evaluation is important from multiple perspectives. 18,32 From the viewpoint of early detection of PA enlargement, a definition of EID as SpO 2 ,90% may be a good start.
Third, there are many causes for acute COPD exacerbations. However, these findings may imply that PA:A .1 is one of the multiple risk factors for acute COPD exacerbations. One reason for this is that PA:A is associated with PH 16 and PH is also a risk factor for acute COPD exacerbations. 33 Furthermore, a previous study reported an association between the PA:A ratio and acute COPD exacerbation. 15 These results suggest that screening for the PA:A ratio without CT using the 6MWT may indicate the risk of acute COPD exacerbations at an early stage.

Limitations
This study had some limitations, including small size, singlecenter experience, and retrospective design. In addition, this study also included COPD subjects who did not fit the    GOLD criteria. Furthermore, because healthy controls do not have respiratory symptoms and there are no control data for the measurement items pertaining to such individuals, healthy controls were not included in the present study. However, it has been reported that the presence of clinical symptoms and low D LCO in smokers, even with normal spirometry, increases the risk of progression to airflow obstruction in COPD. [17][18][19][20] Therefore, the present study's results during the 6MWT could be useful to screen for PH at an early COPD stage, even in GOLD 0 patients. Finally, according to a previous study, left ventricular dysfunction causes PA enlargement. However, echocardiography was not performed in all subjects, and this information could not be included because it was unavailable from the medical history, although we observed clinically relevant associations between CT-measured PA:A ratios and 6MWT results.

Conclusion
The current study's findings suggest that there is a strong association between PA:A ratio and lowest SpO 2 during the 6MWT. The 6MWT is a simple, noninvasive, and reproducible measurement tool. Lowest SpO 2 during the 6MWT is a very helpful measurement to predict PA:A ratios on CT, and lowest SpO 2 of ,89% during the 6MWT is excellent to screen for PH in COPD.