Published ahead of print on April 15, 2004, doi:10.1164/rccm.200308-1142OC
© 2004 American Thoracic Society
Brain Natriuretic Peptide and Exercise Capacity in Lung Fibrosis and Pulmonary HypertensionDivision of Pulmonary Diseases, Department of Internal Medicine I, Ludwig Maximilians University, Klinikum Grosshadern, Munich, Germany Correspondence and requests for reprints should be addressed to Hanno H. Leuchte, M.D., Division of Pulmonary Diseases, Department of Internal Medicine I, Ludwig Maximilians University, Klinikum Grosshadern, Munich Marchioninistr. 15, 81377 Munich, Germany. E-mail: hleuchte{at}med.uni-muenchen.de
Pulmonary hypertension (PH) can develop in lung fibrosis, and contributes to increased morbidity and mortality. Noninvasive parameters in the evaluation of PH in lung disease could aid in the management of these subjects. In this study, we aimed to characterize the role of brain natriuretic peptide (BNP) and the six-minute walk distance (6-MWD) in the assessment of pulmonary hypertension (PH) in subjects with lung fibrosis. Subjects with lung fibrosis and elevated BNP levels (n = 20) had significantly more severe PH during right heart catheterization than those with lung fibrosis, and normal BNP levels (mean pulmonary arterial pressure (40.85 ± 3.2 mm Hg vs. 23.42±1.44 mm Hg, respectively) (n = 19) (p < 0.001). Significant correlations between lung volumes and BNP concentrations were not observed. A weak correlation existed between capillary pO2 and 6-MWD (r = 0.42; p < 0.001). The presence of moderate–severe PH was associated with significant reduction of the 6-MWD. BNP concentrations predicted moderate–severe PH with 100% sensitivity and high specificity (89%). We conclude that BNP is an excellent marker for the presence of PH in patients with lung fibrosis. In addition, our data suggest that PH contributes significantly to exercise limitation in patients with severe lung fibrosis, raising the possibility that treatment of PH may be beneficial in these patients.
Key Words: natriuretic peptide, brain • hypertension • pulmonary • fibrosis Pulmonary hypertension (PH) can develop in lung fibrosis of different etiologies, and may lead to increased morbidity and mortality (1–4). Once lung transplantation has been taken into consideration for severe lung fibrosis, the diagnosis and gradation of PH is of crucial importance as it influences decision making (5) in these patients. In addition, detection of PH may be important because pulmonary selective vasodilators have been suggested for the treatment of primary pulmonary hypertension (PPH) and patients with severe PH secondary to fibrotic lung disease (6–8). However, in advanced lung disease, PH may be difficult to diagnose noninvasively (9). Symptoms like dyspnea are nonspecific, and overt signs of cor pulmonale usually develop late in the course of the disease. Right heart catheterization allows a definitive diagnosis of PH and assessment of its severity (6). Nevertheless, right heart catheterization is still an invasive method, implicating risks for complication and increased costs. Because therapeutic and prognostic consequences may be drawn from the diagnosis and degree of severe PH in patients with lung fibrosis, additional examiner-independent and noninvasive parameters could aid in the management of these patients. Natriuretic peptides are potential candidates in the evaluation of the hemodynamic status of patients with PH. Atrial natriuretic and brain natriuretic peptide (BNP) represent the major hormones of the natriuretic peptide system. BNP is of special interest as it is predominately secreted by the cardiac ventricles (10). The role of BNP has been studied extensively in left ventricular heart failure. Elevated levels of this peptide have been associated with poor prognosis and diminished functional capacity (11–13). In addition, measurements of BNP plasma concentrations have been used in the differential diagnosis of dyspnea (14). In chronic right heart failure, however, only limited data are available. It has been reported, that in patients with primary PH or end stage lung disease with cor pulmonale, the natriuretic peptide system is highly activated (15–20). Moreover, patients with right ventricular overload after acute pulmonary embolism show increased levels of BNP, and this elevation is inversely correlated with prognosis of these patients (21, 22). However, the potential impact of chronic respiratory disease on BNP levels has not been investigated so far. The distance walked in six minutes during the 6-minute walk test (6-MWT) has been shown to be a useful indicator of the functional capacity of patients with chronic lung disease (23–26). In PH, the 6-MWT is also a valuable diagnostic tool to assess disease severity (27). Investigations on exercise impairment in lung fibrosis using the 6-MWT are limited (24, 26), and the impact of PH secondary to lung fibrosis has not been addressed so far. The aim of our study was to characterize the role of BNP and the 6-MWT in the noninvasive assessment of PH in patients with pulmonary fibrosis. Our hypothesis was that BNP would be a sensitive marker for the presence of PH and its severity in patients with lung fibrosis. Some of the results of this study have been previously reported in the form of an abstract (28).
Subjects The study included 39 consecutive patients with pulmonary fibrosis (Table 1) . The patients enrolled were diagnosed as follows: (1) Twenty-eight patients had idiopathic pulmonary fibrosis (IPF), according to American Thoracic Society/European Respiratory Society–criteria (29). Of these, 10 were diagnosed as usual interstitial pneumonia, based on histopathologic and radiographic findings, and in 18 patients, the diagnosis of IPF was based on high-resolution CT scan; (2) three patients had fibrosis due to connective tissue disease (30), and showed a severe restrictive ventilation deficit (FVC < 55% predicted), and typical radiographic signs of parenchymal lung disease (31, 32); (3) four patients had fibrosis secondary to sarcoidosis, as defined in the American Thoracic Society/European Respiratory Society statement (33); (3) four patients had hypersensitivity pneumonitis (34).
Exclusion criteria were: age younger than 18 years or older than 65 years; left ventricular dysfunction; impaired renal function; restrictive ventilation pattern other than fibrosis; or significant obstructive lung disease. A written, informed consent was obtained from every patient and the study protocol was approved by the local ethics committee.
Lung Function Tests
6-MWT
Right Heart Catheterization Moderate–severe pulmonary hypertension was defined as mean Ppa > 35 mm Hg with normal PCWP (8). Subjects with Ppa < 35 mm Hg were defined as no or mild PH.
Blood Sampling and BNP Assay
Statistical Analysis Pearson's correlation coefficient was calculated for BNP, all hemodynamic and lung function parameters, and 6-MWD. Correlation was tested for two-sided significance. Receiver operating characteristic curves were used to assess the discriminatory ability of BNP. The optimal threshold value of BNP for the discrimination of moderate–severe PH was identified. In general, p values less than 0.05 were considered statistically significant. Additional details of the methods used are provided in the online data supplement.
Patient Characteristics Lung function tests showed restrictive lung disease with decreased TLC (3.03 ± 0.16 L; 51.29 ± 2.63% predicted.), FVC (1.66 ± 0.1 L; 45 ± 2.68% predicted) and FEV1 (1.45 ± 0.08 L; 48.81 ± 2.44% predicted.). The ratio of FEV1/FVC x100 showed no signs of obstructive lung disease (90.69 ± 2.48%). TLCO was severely reduced, to 27.8 ± 2.51% predicted. Blood gas analysis from the hyperemic earlobe (normal > 77 mm Hg) showed severe hypoxemia (capillary partial pressure of oxygen, 49.39 ± 1.7 mm Hg) and normocapnia (capillary partial pressure of carbon dioxide, 40.84 ± 0.94 mm Hg) without supplemental oxygen (Table 1). Hemodynamic parameters during right heart catheterization showed mild pulmonary hypertension with normal PCWP and RAP, and, mainly, maintained CO and CI. Mixed venous oxygen saturation was reduced. Exercise capacity was reduced, as indicated by an average 6-MWD of 270.5 ± 20.8 meters. Overall plasma BNP levels were moderately elevated, to 85.67 ± 24.96 pg/ml (Table 1).
Plasma BNP Levels in Subjects with IPF
Plasma BNP Levels in the Total Study Population
Correlation Analysis of Pulmonary Hemodynamics, Lung Function Parameters, 6-MWD, and BNP in IPF Subjects and the Total Study Population Among the IPF patients, plasma BNP levels were positively correlated with PVR (r = 0.8; p < 0.001) and Ppa (r = 0.74; p < 0.001). Moreover, BNP concentrations showed negative correlations with CO (r = –0.57; p = 0.001) and CI (r = –0.50; p < 0.01). Finally, BNP levels correlated inversely with the 6-MWD (r = –0.40; p < 0.05). Correlations between BNP levels and lung function parameters were not statistically significant. Among the total study population, plasma BNP levels were positively correlated with PVR (r = 0.72; p < 0.001) (Figure 2A) and Ppa (r = 0.63; p < 0.01) (Figure 2B). Inverse correlations were observed with CO (r = –0.54; p = 0.01) (Figure 2C), as well as with CI (r = –0.48; p < 0.01) and mixed venous oxygen saturation (r = –0.45; p < 0.01). The 6–MWD data showed a weak but statistically significant correlation with capillary partial pressure of oxygen (r = 0.42; p < 0.01). Furthermore, weak correlations were observed between 6–MWD and Ppa (r = –0.33; p < 0.05), RAP (r = –0.42; p < 0.05), and mixed venous oxygen saturation (r = 0.43; p < 0.05). Correlations between BNP levels and lung function parameters were not statistically significant (data not shown).
Comparison of IPF with No IPF Lung Fibrosis There were no significant differences with respect to the lung function and hemodynamic parameters or BNP levels between the IPF and no IPF groups (data not shown).
Comparison of Patients with Moderate–Severe and No or Mild PH
Receiver Operating Characteristic Analysis of BNP Levels
In this study, we aimed to characterize plasma BNP concentrations as a suitable, noninvasive parameter for the assessment of PH in patients with pulmonary fibrosis of different etiologies. In addition, we evaluated the potential influence of impaired lung function as a contributory factor to BNP elevation, and investigated the impact of PH on exercise capacity during the 6-MWT in these subjects. Since the presence of PH in pulmonary fibrosis is associated with poor prognosis (1–4), its detection is of special interest. Moreover, selected pulmonary vasodilators have been suggested as a treatment option for primary and nonprimary PH (6–8). In addition, once lung transplantation is considered in selected patients, the decision process is strongly influenced by the presence of PH (5). We were able to establish BNP as a predictor of moderate–severe PH. With high sensitivity and specificity, BNP can be regarded as a potentially helpful diagnostic tool to detect clinically important PH in patients with pulmonary fibrosis. We determined that subjects with lung fibrosis and elevated BNP levels had significantly higher Ppa and PVR values than subjects with fibrosis and normal BNP. Accordingly, CO, CI, and mixed venous oxygen saturation were significantly lower in subjects with elevated BNP. In addition, robust correlations existed between BNP levels and hemodynamic parameters, indicating the severity of PH. These results were consistently observed in a homogeneous group of IPF subjects and in the total study population, including subjects with lung fibrosis of different etiologies. Since we did not observe significant correlations between BNP levels and lung function parameters, a direct effect of pulmonary impairment on BNP levels could not be established in our study population comprising patients with progressed disease. Interestingly, subjects with moderate–severe and no or mild PH did not differ significantly in lung function parameters, including diffusing capacity for carbon monoxide and capillary blood gases. This observation suggests that factors in addition to destruction of lung tissue may be responsible for the development of PH in pulmonary fibrosis patients. Although it has been reported that BNP is expressed in lung tissue, (38) no significant correlation between lung function impairment and BNP levels was demonstrated. This does not exclude that some BNP is secreted by lung tissue, however, our data do not particularly support this thesis (14). The natriuretic peptide system has repeatedly been shown do be associated with the disease severity, prognosis, and exercise performance in left (11–13) and right (15, 19, 20) heart failure.The pathophysiologic mechanisms that lead to an activation of the natriuretic peptide system are not completely understood. Direct vasodilatory properties of natriuretic peptides have been discussed (39), and this property might be beneficial as it potentially could ameliorate PH. Increased natriuresis is the main feature of these peptides, and this could be a mechanism to counteract increasing volume overload and right heart failure. However, it has not been shown that elevated levels of these peptides are beneficial in PH patients (16, 21, 22). Investigations on the natriuretic peptide system in PH have been mainly performed in patients without parenchymal lung diseases. There are a few studies focusing on PH and BNP levels in patients with chronic respiratory disease (17, 40), but the role of impaired lung volumes has not been assessed. In our study, comprised mainly of subjects with progressed disease, we clearly demonstrated that in subjects with pulmonary fibrosis, BNP levels were closely related to the presence or absence of significant pH, but independent from impaired lung function. PH in patients without underlying lung disease leads to decreased functional status due to right heart failure (27, 41, 42). Patients with severe lung disease are limited in their exercise performance during the 6-MWT because of their ventilatory limitations and hypoxemia (23–25). In our study, the exercise tolerability, measured as 6-MWD, was correlated with resting capillary PO2, but without significant correlations to any of the lung function parameters. Since only patients with severe lung function impairment were included in our study, we investigated only a narrow pattern of lung volumes. This may be responsible for the absence of correlations between ventilatory impairment and exercise capacity. In contrast, the 6-MWD was significantly lower in subjects who showed moderate–severe PH, secondary to lung fibrosis. Moreover, reduction of 6-MWD was related to the severity of associated PH. However, aggravated hypoxemia during the 6-MWT may have contributed to exercise limitation during the 6-MWT, offering additional explanation. We conclude that plasma BNP concentrations are not significantly influenced by impairment of lung function per se, and represent an excellent marker for the assessment of pulmonary hemodynamics and exercise capacity in patients with lung fibrosis. Naturally, we are aware of the numerous limitations of our small study. Namely, we included subjects with different etiologies of pulmonary fibrosis. However, an independent analysis of the IPF subjects representing a homogeneous subgroup, provided results comparable with the total study population. The inclusion of patients with scleroderma may have influenced results because PH can develop, especially in the limited form of scleroderma, as a consequence of direct involvement of pulmonary vasculature, without significant fibrosis (30). By choosing an FVC of less than 55% predicted in this small cohort, we tried to assure that a significant parenchymal involvement was present (31). Despite these limitations, we suggest the use of plasma BNP as a screening parameter for PH in pulmonary fibrosis. Since PH seemed to independently contribute to exercise limitation in lung fibrosis subjects, our data may indicate that specific treatment of PH may be beneficial. Further studies are needed to confirm our observations, and to demonstrate if treatment of PH in pulmonary fibrosis could improve exercise capacity and survival in these patients.
This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org Conflict of Interest Statement: H.H.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; C.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; R.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; M.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; W.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; M.V. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; J.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this article. Received in original form August 16, 2003; accepted in final form April 13, 2004
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