Lung

, 189:377

Pulmonary Hypertension in a Stable Community-Based COPD Population

Authors

  • Vadim Fayngersh
    • Division of Pulmonary, Sleep and Critical Care MedicineThe Memorial Hospital of Rhode Island
    • Division of Pulmonary, Sleep and Critical Care MedicineThe Alpert Medical School of Brown University
  • Fotios Drakopanagiotakis
    • Division of Pulmonary, Sleep and Critical Care MedicineRhode Island Hospital
  • F. Dennis McCool
    • Division of Pulmonary, Sleep and Critical Care MedicineThe Memorial Hospital of Rhode Island
    • Division of Pulmonary, Sleep and Critical Care MedicineThe Alpert Medical School of Brown University
    • Division of Pulmonary, Sleep and Critical Care MedicineRhode Island Hospital
    • Division of Pulmonary, Sleep and Critical Care MedicineThe Alpert Medical School of Brown University
Article

DOI: 10.1007/s00408-011-9315-2

Cite this article as:
Fayngersh, V., Drakopanagiotakis, F., Dennis McCool, F. et al. Lung (2011) 189: 377. doi:10.1007/s00408-011-9315-2

Abstract

Study Objectives

The etiology and prevalence of pulmonary hypertension (PH) in patients with stable chronic obstructive pulmonary disease (COPD) is uncertain. This study was done to determine the prevalence of PH in stable COPD outpatients and to evaluate the relationship between PH and indices of pulmonary function.

Design

The study was a retrospective review of outpatients with COPD and PH defined as a history of cigarette smoking, pulmonary function tests (PFTs) that met GOLD criteria for airway obstruction, an echocardiogram within 6 months of PFTs, and a left ventricular ejection fraction (LVEF) >55%. Of the 159 individuals who met all inclusion criteria, 105 had a sufficient tricuspid regurgitant jet to measure systolic pulmonary artery pressure (sPAP). PH was defined as sPAP ≥36 mmHg.

Measurements and Results

The prevalence of PH was 60% (63/105) in the study group. The mean sPAP in patients with PH was 45 ± 6 mmHg. COPD patients with PH were older (71.1 ± 11.8 vs. 63.7 ± 10.2 years, P = 0.001), had lower FEV1% predicted (51.8 ± 18.8 vs. 62.7 ± 20.5%, P = 0.006), a higher RV/TLC (0.55 ± 0.10 vs. 0.48 ± 0.11, P = 0.001), and a lower % predicted DLCO (59.6 ± 19.5% vs. 71.9 ± 24.9%, P = 0.006). Only age (P < 0.002) and prebronchodilator FEV1% predicted (P < 0.006) predicted PH by logistic regression analysis. No differences were observed in gender, BMI, smoking status, pack years, total lung capacity (TLC), or residual volume (RV).

Conclusion

PH is common in COPD. Older individuals and those with more airway obstruction are at greater risk for developing PH.

Keywords

Pulmonary hypertensionChronic obstructive airway diseaseTransthoracic echocardiogramPulmonary function tests

Introduction

Chronic obstructive pulmonary disease (COPD) affects over 20 million Americans [1]. It is the fourth leading cause of death in the US and the only one of the top six causes of death that continues to increase in incidence [2]. Pulmonary hypertension (PH) is a common and well-established complication of COPD [3]. Its presence is associated with increased risks of exacerbation and decreased survival [47]. However, the prevalence of PH in a stable population of COPD patients in the primary-care setting is uncertain. Determination of prevalence of PH in COPD has been hampered by difficulties in obtaining valid data from an adequate population-based sample of COPD and by the need for pulmonary artery catheterization to provide accurate assessment of pulmonary hemodynamics.

Transthoracic echocardiography (TTE) is a readily available noninvasive technique that can be used to assess pulmonary arterial systolic pressures (sPAP) in COPD [8]. Although TTE is subject to limitations in individuals with COPD, right heart catheterization cannot be applied to “real-life” populations of stable COPD patients because of its inherent risks and expense [9]. The present study was designed to assess the prevalence of PH in clinically stable outpatients with COPD in a community hospital setting and to determine if indices of hyperinflation and expiratory flow limitation can identify those at risk for PH.

Methods

Pulmonary function tests (PFT) and echocardiography databases from the pulmonary outpatient practices of the Memorial Hospital of Rhode Island and the Rhode Island Hospital from May 2002 to February 2008 were reviewed. Both hospitals are major teaching affiliates of the Alpert Medical School of Brown University. The study was approved by the Rhode Island Hospital Committee on the Protection of Human Subjects (Committee # 011208) and by the Memorial Hospital of Rhode Island Committee for the Use of Human Subjects in Research (Committee # 08-38). Subjects were identified as having COPD by ICD billing codes and had airways obstruction by GOLD criteria for COPD (FEV1/FVC <0.70 post bronchodilator administration). Other inclusion criteria were (1) echocardiography completed as an outpatient within 6 months of PFTs, (2) history of previous or current cigarette smoking, (3) total lung capacity (TLC) ≥80% predicted, (4) left ventricular ejection fraction (LVEF) ≥55% on echocardiography, and (5) a measurable tricuspid regurgitant jet identified on echocardiography. PFTs were completed according to American Thoracic Society standards [10]. Lung volumes were measured by body plethysmography, maximal expiratory flow rates were reported after administration of a bronchodilator, and hemoglobin-corrected diffusing capacity for carbon monoxide (DLCO) was measured using the single-breath technique. Smoking history was obtained via questionnaire and verbally confirmed by the technician completing the PFT. Patients with an ICD billing code for sleep apnea were excluded. The echocardiograms were read by cardiologists who were unaware of the patient’s enrollment into the study. Pulmonary hypertension was defined as sPAP ≥36 mmHg. We used this threshold to define PH in accordance with the most recent recommendations made by the Working Group on Diagnosis and Assessment of Pulmonary Arterial Hypertension during the 4th World Symposium on Pulmonary Hypertension (Dana Point, CA, January 2008) [11].

Statistical Analysis

Normally distributed continuous data were expressed as mean ± one standard deviation. Nonparametric data were expressed as mean and interquartile range. The Kolmogorov–Smirnov test was used to assess normality. A two-tailed Student’s t-test or Mann–Whitney test was used for comparing continuous variables as appropriate. Correlations were conducted between sPAP and PFT values for lung volumes and spirometry employing Pearson’s correlation or Spearman’s ρ. Statistically significant values (P < 0.05) were then considered for inclusion into multivariate modeling. Logarithmic transformations were performed on specific airways conductance (sGaw). Square root transformation was completed on FEV1/FVC. Backward elimination logistic regression was then performed with the dependent variable of the presence versus the absence of PH. Previously identified significant independent variables were placed into the model. Criterion for model entry was F > 0.05 and for removal F < 0.10.

Results

During the screening period, 2,643 patients were identified as having COPD on outpatient PFTs. Of these, 177 had TTE and a LVEF ≥55%. Of the 177 individuals with PFTs and normal LV function, 154 had a TTE and PFTs within 6 months of each other and 105 had a tricuspid regurgitant jet that could be identified by Doppler ultrasound. The average interval between pulmonary function testing and TTE was 55 days. The sPAP was ≥36 mmHg in 63 of the 105 individuals (60%). When increasing the threshold for the definition of PH to a sPAP ≥40 mmHg, 49 individuals (47%) still met the criteria for PH. Ten individuals had a sPAP ≥50 mmHg (Fig. 1). The mean sPAP in patients with PH was 44 ± 6 mmHg. Assuming the 49 subjects without a tricuspid jet seen on TTE did not have an elevated sPAP, the prevalence of PH would be 41%. However, it is likely that some of the individuals in whom a jet could not be visualized also had PH.
https://static-content.springer.com/image/art%3A10.1007%2Fs00408-011-9315-2/MediaObjects/408_2011_9315_Fig1_HTML.gif
Fig. 1

Distribution of subjects according to pulmonary artery pressure

There were no differences in gender, body mass index (BMI), number of current smokers, pack-years, or use of supplemental oxygen between patients with and without PH. However, patients with PH were significantly older than patients without PH (Table 1). To adjust for the difference in age between COPD patients with and without PH, percent predicted values were used to compare lung volumes and values of maximal expiratory flow rates obtained during spirometry. Individuals with COPD and PH had lower values of prebronchodilator FEV1% predicted, lower FEV1/FVC ratios, lower specific airways conductance, and lower DLCO (Table 1). The TLC and residual volume (RV) % predicted did not differ between the two groups, but the inspiratory capacity/TLC (IC/TLC) ratio was lower, and functional residual capacity (FRC) % predicted as well as the RV/TLC ratio was higher in patients with PH (Table 1).
Table 1

Differences in age, gender, weight, tobacco use, pulmonary function tests, and left ventricular ejection fraction between patients with and without pulmonary hypertension

 

+PH

−PH

P

n = 63 (60.0%)

n = 42 (40.0%)

Age (years)

71.1 (11.8)

63.7 (10.2)

0.0012

Male (%)

52

57

0.6313

BMI

27.7 (7.8)

28.7 (6.8)

0.4721

Current smokers (%)

46

52

0.5237

FEV1% predicted

51.8 (18.8)

62.7 (20.5)

0.0057

Post FEV1% predicted

56.1 (17.7)

63.3 (19.3)

0.0704

FEV1/FVC

52.0 (22.9)

60.6 (17.1)

0.0112

RV% predicted

150.0 (64.7)

127.4 (61.1)

0.0670

FRC% predicted

136.9 (35.2)

124.2 (25.9)

0.0436

TLC% predicted

112.0 (21.0)

108.2 (16.2)

0.3258

IC% predicted

82.5 (24.0)

91.6 (22.9)

0.0553

RV/TLC

0.55 (0.10)

0.48 (0.11)

0.0012

IC/TLC

0.32 (0.10)

0.39 (0.09)

0.0023

DLCO% predicted

59.6 (19.5)

71.9 (24.9)

0.0062

sGaw

0.057 (0.060)

0.092 (0.045)

0.0082

Pack-years

46.0 (31.5)

40.0 (27.0)

0.1258

LVEF (%)

65.0 (2.0)

69.0 (2.0)

<0.0001

Continuous variables are reported as mean and standard deviation; nonparametric continuous variables are reported as median and interquartile range, designated with . Student’s t test or Mann–Whitney test was used for comparison of continuous variables as appropriate. Discrete variables are given in percentage; χ2 test was used in comparing discrete or ordinal variables

PH pulmonary hypertension defined as RVSP ≥36 mmHg, BMI body mass index, FEV1 forced expiratory volume in 1 s, RV residual volume, FRC functional residual capacity, TLC total lung capacity, IC inspiratory capacity, DLCO diffusion capacity, sGaw specific airways conductance, LVEF left ventricular ejection fraction

To determine if the degree of PH was associated with the severity of COPD, indices of forced expiratory flow, hyperinflation, and gas exchange impairment were correlated with echocardiographic measures of sPAP in the 63 subjects with COPD and PH. The FEV1% predicted, FEV1/FVC, IC% predicted, sGaw, IC/TLC, RV/TLC, and DLCO% predicted were all found to correlate with sPAP (Table 2). These variables were then entered into a backwards elimination logistic regression model, with the presence or absence of PH as the dependent variable. Only the prebronchodilator FEV1% predicted (odds ratio [OR] = 0.969, 95% confidence interval [CI] = 0.948–0.991, P < 0.006) (Fig. 2) and age (OR = 1.064, 95% CI = 1.024–1.106, P < 0.002) were predictors for PH (C statistic = 0.747).
Table 2

Correlations between right ventricular systolic pressure and age and pulmonary function tests

 

Correlation

P value

Age

0.306

0.0015

DLCO% predicted

−0.298

0.0025

sGaw

−0.343

0.0005

IC/TLC

−0.386

<0.0001

FEV1/FVC

−0.306

0.0015

FEV1% predicted

−0.345

0.0003

Post FEV1% predicted

−0.279

0.0077

RV/TLC

0.407

<0.0001

IC% predicted

−0.331

0.0006

Pearson correlation or Spearman’s ρ (designated by ) were employed as applicable. RVSP and sGaw were log transformed while the square root was taken of FEV1/FVC

https://static-content.springer.com/image/art%3A10.1007%2Fs00408-011-9315-2/MediaObjects/408_2011_9315_Fig2_HTML.gif
Fig. 2

Association between prebronchodilator FEV1% predicted and systolic pulmonary artery pressure (sPAP)

To determine if left ventricular dysfunction, a common comorbidity in COPD, affected PAP in our cohort of COPD individuals, we compared sPAP with left ventricular ejection fraction. No correlation with sPAP was seen over the range of LVEF, indicating that PH was not due to left ventricular systolic dysfunction in this cohort.

Discussion

In the present study, we found that PH occurs frequently in a stable outpatient population of COPD patients. Measures of TLC and RV did not predict the presence of PH. Only age and prebronchodilator FEV1% predicted were independent predictors of PH in our population of patients, suggesting that PH in COPD is associated more with increasing age and airflow obstruction than with lung hyperinflation. These findings are similar to those of previous studies with smaller cohorts that examined PH in COPD, many of whom had severe obstruction and were studied in tertiary-care facilities [5, 9, 12, 13].

It is unlikely that the high prevalence of PH in our study was due to advanced age. The mean age of 68.2 ± 11.6 years in our study participants was higher than the 54.6 years reported in a study by Thabut et al. [14], but nearly identical to that of participants in a study by Scharf et al. [15]. Both of these earlier studies used right heart catheterization to measure pulmonary arterial pressure (PAP) and reported a prevalence of PH that was higher than the present study. Our finding that COPD patients with PH were older than those without PH may indicate that lung disease was present for a longer period in these individuals. A gradual increase in PAP over time has been noted in patients with COPD [16] as well as in the general population [17]. However, we were not able to determine how long patients in our study had COPD at the time of TTE and, thus, are unable to determine if COPD was present for a longer period of time in those with PH than those without. Whether the increased morbidity and mortality associated with advanced age in COPD [18, 19] can be attributed to the higher prevalence of PH will require further study.

Our finding that DLCO correlated inversely with sPAP in patients with COPD is similar to earlier studies that assessed PAP by right heart catheterization [15, 20] or by echocardiography [9, 21]. Chaouat et al. [22] also noted that individuals with COPD and PH “disproportionate” to the degree of airways obstruction had a marked decrease in DLCO. However, a recently published prospective study demonstrated no relationship between DLCO and PH in COPD patients [23]. Reduced DLCO occurs in patients with idiopathic PAH in the absence of parenchymal or small airways disease [24]. Thus, it is possible that the reduced DLCO seen in our COPD patients with PH is the result of more severe pulmonary vascular disease rather than an indicator of the severity of emphysema.

Our findings of significant correlations between RV/TLC and sPAP as well as between sGaw and sPAP suggest that the degree of airflow limitation may be a risk factor for PH in COPD. This is supported by our finding that % predicted FEV1 was the only pulmonary function parameter that independently predicted PH in COPD in the logistic regression analysis. Previous studies examining the relationship between spirometry and PH have been conflicting. Some investigators have shown an inverse correlation between FEV1 and PAP [15, 20]. Studies by Higham et al. [8] and Bishop et al. [25] found weak associations between FEV1 and sPAP (correlation coefficients of −0.26 and −0.28 respectively), similar to our study (−0.35). Others studies failed to show a relationship [14, 23, 25, 26]. This discrepancy may be due to the differences in the severity of COPD between cohorts. For example, in the studies of Thabut et al. [14] and Scharf et al. [15], the mean FEV1 was 24 and 39% predicted, respectively. Our study examined patients with a less severe degree of airflow obstruction (mean FEV1 = 56 ± 20% predicted), and our findings suggest that in this population, reduced FEV1 is a risk factor for PH.

The alveolar hyperinflation and loss of elastic recoil that occur in emphysema may increase PVR by compressing intra-alveolar vessels or by decreased tethering of extra-alveolar vessels. Both factors can contribute to the development of PH in patients with COPD, especially during exercise [27]. However, the lack of any correlation between TLC, RV, or FRC and sPAP in the present study and the lack of correlation between lung elastic recoil at TLC or FRC and sPAP or PVR in patients referred to the National Emphysema Treatment Trial suggest that hyperinflation is an unlikely cause of PH in COPD [28]. Furthermore, no difference in pulmonary hemodynamics was observed after 6 months between COPD patients treated medically and those treated with lung volume reduction surgery despite substantial differences in TLC [29].

Hypoxic pulmonary vasoconstriction has long been implicated in the pathogenesis of PH associated with chronic lung diseases. However, hypoxic pulmonary hypertension is characterized by increased muscularization of distal pulmonary arteries, whereas histopathological studies of pulmonary vessels obtained from patients with COPD and PH have shown prominent remodeling and injury of the intimal layer. Furthermore, smooth muscle thickness has not correlated with PAP [3033] and pathological findings have not correlated with arterial blood gas tensions or hematocrit [32]. Finally, supplemental oxygen has little effect on reversing pulmonary hypertension in patients with COPD [34]. For example, 53% of patients with COPD had PH in the Nocturnal Oxygen Therapy Trial and the mean PaO2 in those patients was 51.2 ± 5.4 mmHg [35]. Twenty years later, the prevalence of PH in COPD has not decreased despite the widespread use of supplemental oxygen [15, 20]. In our study, there was no difference in the use of supplemental O2 between patients with and without PH. Although data regarding resting oxygen saturation was limited in our study (data available for 40 of 63 subjects with PH and 22 of 42 subjects without PH), there was no difference in resting oxygen saturation between those with and without PH (92.2 ± 3.8 vs. 93.0 ± 3.6% sat, respectively). Taken together, these findings suggest that the pulmonary vasculopathy induced by COPD is not due to hypoxia-induced vascular remodeling alone.

Left ventricular systolic or diastolic dysfunction can also elevate PAP and is not uncommon in COPD as these individuals often suffer from coronary artery disease, diabetes mellitus, and hypertension [36]. In order to avoid COPD patients with pulmonary venous hypertension caused by impaired left ventricular function, we excluded patients with left ventricular ejection fraction <55% from data analysis. We also found no correlation between LVEF and sPAP, suggesting that left ventricular systolic function was not a major determinant of PH in our cohort, although we cannot exclude the possible contribution of left ventricular diastolic dysfunction.

TTE has been shown to be a reliable, noninvasive alternative to cardiac catheterization for measurement of right ventricle pressures [28, 37, 38]. Although the ability of TTE to accurately identify or exclude PH in COPD has recently been called into question [39], other studies have found TTE to be a useful tool for assessing PAP in COPD [4042], and our findings are consistent with those of similar sized studies that assessed PH by right heart catheterization [15, 25]. Furthermore, the use of TTE to assess PAP allows screening of large numbers of clinically stable patients with COPD. Thus, TTE may prove useful in determining factors that influence PAP in COPD. Other limitations related to the retrospective nature of our study include unknown indications for PFTs and echocardiograms, lack of dyspnea scores, and the possibility that diastolic dysfunction was present. However, by design, all study patients were stable outpatients thereby minimizing the likelihood that acute cardiac dysfunction was contributing to PH.

In summary, our study suggests that PH occurs frequently in stable outpatients with COPD and that advanced age and low prebronchodilator FEV1 are independent risk factors for PH. Identifying PH in patients with COPD is important because of its association with increased morbidity and mortality. Although few studies have examined the long-term benefits of modern antipulmonary hypertensive drugs in COPD patients with PH [4345], these therapies have been shown to improve exercise capacity and survival in patients with idiopathic PAH and PH associated with scleroderma. Patients with severe PH and mild to moderate COPD (PH “out-of-proportion” to the degree of airflow limitation) may be candidates for these therapies. In our study, 10 of 63 PH individuals had a sPAP >50. These individuals may represent the “clinically” significant group who may be at increased risk for mortality and morbidity. Further studies are needed to determine if the early detection of PH by TTE can affect outcome in patients with COPD.

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© Springer Science+Business Media, LLC 2011