Comparison of Functional Capacity and Symptoms of COPD Patients with and without Pulmonary Hypertension

Objective: Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD) associated with a decrease in the survival rate of patients with COPD. Our aim was to investigate whether PH impairs the functional capacity and symptoms in patients with COPD. In addition, we aimed to evaluate the correlation between the functional capacity and symptoms score in patients with COPD. Materials and Methods: This prospective cross-sectional study enrolled 64 patients with moderate to severe COPD, prospectively. All patients underwent the pulmonary function test, echocardiography, 6-minute walk test (6MWT), and cardiopulmonary exercise testing (CPET). We applied the modified Medical Research Council (mMRC) dyspnea scale and COPD Assessment Test (CAT) to all patients. The mean pulmonary arterial pressure (mPAP) >30 mmHg with echocardiography was considered as PH. The patients were grouped according to the presence of PH as COPD-PH (n=30) and COPD-nonPH (n=34). Results: Hospitalization rate was higher in the COPD-PH group than in the COPD-nonPH group (p=0.006). The 6MWT results were lower in the COPD-PH group compared to the COPD-nonPH group (325±61 m vs. 354±46 m, respectively, p=0.025). In the COPD-PH group, the maximum oxygen consumption (VO 2max ) was lower, but the difference did not reach statistical significance (p=0.118). Although the maximum load and minute ventilation were lower in the COPD-PH group, the end-tidal pressure of CO 2 (PETCO 2 ) was higher (p=0.033, p=0.036, and p=0.009, respectively). However, the CAT score and mMRC were similar between the groups (p=0.405 and p=0.238, respectively). Conclusion: An elevated PAP in patients with COPD limits the exercise capacity. Using CPET in the functional evaluation of patients with COPD may be beneficial in the early detection of PH.


Introduction
Chronic obstructive pulmonary disease (COPD) is a common public health problem worldwide that is characterized by respiratory symptoms and persistent airflow limitation due to airway or alveolar abnormalities resulting from the exposure to smoke, noxious gases, and particles [1]. It is the currently the fourth most common cause of death and is estimated to become the third cause by the year 2020 [2,3]. Pulmonary hypertension (PH) is a common complication of COPD that is associated with a decrease in the survival rate of patients with COPD [4,5].
In patients with COPD, the PH progression correlates better with the degree of airflow obstruction and pulmonary gas exchange impairment [6,7]. Hypoxemia plays a major role in the development of PH [8]. Other factors that contribute to the development of PH are cigarette smoke, systemic inflammation, and oxidative stress [9]. The reported prevalence of PH in COPD patients is 20%-90% [6,10,11]. As the incidence of PH is correlated with disease severity, it is more common in patients with severe COPD.
Pulmonary hypertension is one of the causes of cor pulmonale, which is defined as a change in the structure and function of the right ventricle, secondary to underlying lung disease. The presence of PH and cor pulmonale is associated with increased mortality and a poorer clinical COPD course [12]. They also affect the quality of life [13].

Comparison of Functional Capacity and Symptoms of COPD Patients with and without Pulmonary Hypertension
In this study, we aimed to determine whether PH in COPD impairs the functional capacity and symptoms score and whether a correlation exists between the functional capacity and symptoms score.

Study Design
This prospective cross-sectional study was conducted at a single tertiary care hospital. The patients with COPD in our outpatient clinic were screened to enroll in the study for 12 months in 2015. The study was approved by the Ethics Council of Faculty of Medicine, and written informed consent was provided by all subjects.

Study Population
Seventy-nine patients with moderate to severe COPD were prospectively enrolled. Selection criteria were a clinical diagnosis of COPD according to the GOLD consensus [1] and having stable COPD, without exacerbation, during the examination for 4 weeks. The ones who could not perform exercise testing (n=12) or had systolic hypertension (>220 mmHg) during exercise testing (n=3) were excluded from the study. Also, patients with coronary artery disease and peripheral artery disease were excluded. A total of 64 patients with moderate to severe COPD were included in the study. The patients were divided into the COPD-PH (n=30) and COPD-nonPH (n=34) subgroups. The PH diagnosis was based on echocardiography. The mean pulmonary arterial pressure (mPAP) >30 mmHg on echocardiography was considered to indicate PH.

Diagnostic Testing
Medical records were reviewed. After a physical examination, all patients underwent electrocardiography, pulmonary function test, echocardiography, 6-minute walk test (6MWT), and cardiopulmonary exercise testing (CPET). The modified Medical Research Council (mMRC) dyspnea scale and COPD Assessment Test (CAT) were performed in all patients.

Pulmonary Function Test
Each patient underwent a pulmonary function test that was performed using the American Thoracic Society/European Respiratory Society guidelines [14] and European predictive values [15].

Echocardiography
All patients underwent conventional twodimensional and Doppler echocardiographic examination in addition to tissue Doppler imaging using a VIVID 7 (GE, NORWAY) echocardiography device with a 2.5 MHz transducer. In the left lateral decubitus position, echocardiograms were recorded on standard parasternal and apical images. The images were recorded at the end-inspiration and end-expiration on normal ventilation. The M-mode, B-mode, color-flow mapping, and pulse-wave Doppler records for each patient were obtained. The left ventricle diameter, left atrium diameter, right atrium diameter (RA), and right ventricle diameter were determined with a parasternal long-axis view. Left ventricular ejection fraction was calculated using a modified Simpson method [16]. Systolic pulmonary arterial pressure (sPAP) was calculated by adding estimated right atrial pressure onto the regurgitation gradient through the tricuspid valve. For calculating the mean pulmonary arterial pressure (mPAP), a pulmonary regurgitation (PR) signal was obtained in the parasternal short-axis view using a color Doppler. CW Doppler at a sweep speed of 100 mm/s was used to measure the peak PR velocity. The peak pressure difference (measured by the Bernoulli equation) is then added to the right atrial pressure. mPAP was calculated by the formula mPAP=4V (early peak pulmonary regurgitation velocity) 2+RA pressure [17,18].

6-Minute Walk Test
We performed the 6MWT in all patients according to the ATS guideline [19]. The patients were set to walk back and forth at their own pace in a 30-meters-long corridor to cover as much ground as possible in the given time. The test was observed by a supervisor, reminding the patient about the remaining exercise time every 2 minutes. The patients were permitted to halt and take a rest during the test but were instructed to re-start walking as quickly as possible. Dyspnea during the test was assessed with the modified Borg dyspnea score.

Cardiopulmonary Exercise Testing
A cycle ergometer (Ergoselect Ergoline Viasprint 150P) was used for the test. The symptomlimited exercise was applied to all subjects, who were wearing a facemask (Rudolph Face Mask for Exercise Testing; Hans Rudolph Inc., Kansas City, MO, USA). Following a 3-minute resting period, a 3-minute warm-up period (60 rpm was the maintenance pedaling rate) was started, then incremental work (10-15 W elevation for each minute) was applied [20]. An automated exercise testing system (Desktop Diagnostics/ CPX; Medical Graphics Corporation, St. Paul, MI, USA) was used to collect data. The maximum work rate for half a minute was saved. Continuous monitorization of 12-lead electrocardiography, blood pressure, and pulse oxygen saturation was performed during CPET. The peak oxygen uptake (PVO 2 mL/kg/min), peak CO 2 output, carbon dioxide production/oxygen uptake (VCO 2 /VO 2 ), heart rate reserve (HRR), VO 2 /HR, and minute ventilation/carbon dioxide production (VE/VCO 2 ) values were assessed. To determine the anaerobic threshold (AT L/ min), the two-slope method was used. To determine age-predicted values, the equation of Wasserman et al. [20] was used. Symptoms occurred at the end of the test, including fatigue, dyspnea, and dizziness.

Statistical Analysis
For statistical analysis, the Statistical Package for the Social Sciences for Windows version 20.0 (IBM SPSS Corp.; Armonk, NY, USA) was used. We used the Mann-Whitney U test for comparisons of continuous variables between the COPD-PH and COPD-nonPH groups and the chi-square test for comparisons of nominal variables. We performed Pearson's correlation analysis for continuous variables. A linear regression analysis was performed to investigate the association between CPET parameters and symptoms assessment tests. A p-value <0.05 was considered to be statistically significant.

Results
A total of 64 patients (34 patients with COPD without PH, 30 patients with COPD with PH) were included in the study. Baseline characteristics of the cases are summarized in Table 1. The mean age was similar between groups (60 [55-65] vs. 61 [55-72] years in COPD-nonPH and COPD-PH, respectively). The hospitalization rate was higher in patients with COPD-PH than patients without COPD-nonPH. The difference was statistically significant (p=0.006). However, the CAT score and mMRC were similar between the groups (p=0.387 and p=0.275, respectively).
The functional evaluation of the patients is shown in • An elevated PAP in patients with COPD limits the exercise capacity.
• Using CPET in the functional evaluation of patients with COPD may be beneficial in the early detection of pulmonary hypertension.
Although the maximum load and VE were lower in the COPD-PH group, end-tidal pressure of CO 2 (PETCO 2 ) was higher (p=0.034, p=0.046, and p=0.045, respectively). The correlations between VO 2max , PETCO 2 , and mPAP are shown in Figure 1. The leg fatigue was the main cause for stopping the test in both groups (86% in the COPD-PH group, 58% in the COPD-nonPH group).
Correlations between CPET parameters and CAT, mMRC, and mPAP are shown in Table  3. While there were negative correlations between mPAP and VO 2 max, VE, and maximum voluntary ventilation (MVV), a positive correlation was detected between mPAP and PETCO 2 . These correlations were statistically significant (p=0.028, p=0.008, p=0.008, and p=0.004, respectively). Statistically significant negative correlations were detected between MVV, VO 2max , AT, maximum load, VE, and We also generated a linear regression model for the prediction of the association with symptoms assessment tests and CPET parameters. We found that AT is an independent predictor of COPD assessment (CAT score), p=0.005.

Discussion
Our results show that pulmonary hypertension in patients with COPD negatively impacts their functional capacity, but there is no effect on symptoms assessment. To the best of our knowledge, ours is the first study to evaluate both the functional capacity and symptoms assessment in patients with COPD-PH.
Patients with COPD-PH exhibited a lower 6MWT distance, VO 2 max, maximum load, and MVV, and a higher PETCO 2 . An elevated PAP value led to both the reduced exercise capacity and abnormal gas exchange. There were no differences between patients with COPD with and without PH in terms of mMRC and CAT score.
The reduction of exercise capacity in COPD is multifactorial. An increased airway resistance and lung compliance lead to a dynamic hyperinflation, which together with respiratory muscle fatigue, reduces the ventilatory reserve [21][22][23]. The 6MWT and CPET are important in evaluating patients' exercise capacity. The gas exchange dysfunction can also be detected with CPET. Studies evaluating the exercise capacity in patients with COPD showed that patients with COPD-PH had a lower VO 2 max, maximum load values, and 6MWT distance [24][25][26][27]. The COPD-PH group in the present study also had lower results with regard to these parameters when compared to patients with COPD without PH. These findings support the negative effect of PH development on exercise capacity in patients with COPD.
Evaluating gas exchange during CPET revealed that patients with COPD-PH have a higher PETCO 2 . Although patients with isolated PH show lower PETCO 2 values secondary to increased ventilatory response, reduced maxi-  The evaluation of patients' symptoms assessment using CAT and mMRC revealed no difference between the groups. Mirdamadi et al. reported a weak relationship between subjective symptoms and objective parameters in patients with COPD [28]. The negative correlations we observed between CPET parameters and CAT and mMRC scores support their findings, despite the fact that there was no difference based on PH.
In patients with COPD, the PH progression correlates better with the degree of airflow obstruction and pulmonary gas exchange impairment [6,7]. Nevertheless, in our study, there was no difference in PFT parameters between groups. It may be due to fact that the majority of patients had moderate obstruction.
One of the limitations of our study is the small sample size. Another limitation is that PH was not confirmed with right heart catheterization. Instead, we calculated mPAP, which yields results comparable to catheterization. Patients were not evaluated according to systolic PAP.
An elevated PAP in patients with COPD limits the exercise capacity. There is a negative correlation between functional capacity and symptoms assessment. Using CPET in the functional evaluation of patients with COPD may be beneficial in the early detection of PH, further studies to confirm the diagnosis, and planning an appropriate treatment.