Published ahead of print on January 13, 2006, doi:10.1164/rccm.200510-1545OC
© 2006 American Thoracic Society doi: 10.1164/rccm.200510-1545OC
Brain Natriuretic Peptide Is a Prognostic Parameter in Chronic Lung DiseaseDivision of Pulmonary Diseases, Department of Internal Medicine I, and Department of Clinical Chemistry, Ludwig Maximilians University, Klinikum Grosshadern, Munich, Germany Correspondence and requests for reprints should be addressed to Juergen Behr, M.D., Division of Pulmonary Diseases, Department of Internal Medicine I, Ludwig Maximilians University, Klinikum Grosshadern, Munich Marchioninistrasse 15, 81377 Munich, Germany. E-mail: juergen.behr{at}med.uni-muenchen.de
Rationale: The detection of pulmonary hypertension in patients with chronic lung disease has prognostic implications. The brain natriuretic peptide (BNP) has been suggested as a noninvasive marker for the presence and severity of pulmonary hypertension. Objectives: We evaluated circulating BNP levels as a parameter for the presence and severity of pulmonary hypertension in patients with chronic lung disease. Methods: BNP levels were measured in 176 consecutive patients with various pulmonary diseases. Right heart catheterization, lung functional testing, and a 6-min walk test were performed. The mean follow-up time was nearly 1 yr. Measurements and Main Results: Significant pulmonary hypertension (mean pulmonary artery pressure > 35 mm Hg) was diagnosed in more than one-fourth of patients and led to decreased exercise tolerance and life expectancy. Elevated BNP concentrations identified significant pulmonary hypertension with a sensitivity of 0.85 and specificity of 0.88 and predicted mortality. Moreover, BNP served as a risk factor of death independent of lung functional impairment or hypoxemia in uni- and multivariate analysis. Conclusion: We suggest BNP as a prognostic marker and as screening parameter for significant pulmonary hypertension in chronic lung disease.
Key Words: chronic obstructive pulmonary disease • fibrosis • hypertension, pulmonary • natriuretic peptide, brain Because patients with chronic diseases of the respiratory system represent a large and even growing population, there is a need for an early and reliable diagnosis of complicating pulmonary hypertension (PH) leading to additional dyspnea and increased mortality (1–5). Incessant exposure to hypoxemia is one of the mechanisms besides others leading to sustained pulmonary vasoconstriction and narrowing of the pulmonary vasculature. Consequently, PH develops leading to right heart enlargement with ventricular hypertrophy, and impaired cardiac function, known as cor pulmonale (6). However, although PH potentially develops in every hypoxemic or chronic lung disease (7), there is still uncertainty about the degree of a clinical relevant PH and about the time point when right heart catheterization should be initiated, as this is the method of choice to definitely diagnose PH (7). A safe, examiner-independent, and easy to perform method that allows a reliable identification of patients with an increased probability of clinical significant PH would be helpful. In particular, if this method could help to identify patients with an increased mortality risk. Brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) are the major hormones of the natriuretic peptide system, which is highly activated in different left and right heart diseases in the context of neurohumoral activation. BNP is of special interest in this field as it is predominately secreted by the cardiac ventricles (8). In left ventricular heart failure, elevated levels of BNP have been shown to be associated with diminished exercise tolerance and a poor prognosis (9, 10). In addition, in pulmonary arterial hypertension, BNP levels are elevated and seem to reflect clinical and hemodynamic status in this patient population (11–14). Moreover, elevated BNP concentrations resulting from PH secondary to end-stage lung disease have been reported (15) even in the absence of left ventricular failure (16). But still, BNP has neither been evaluated as a prognostic marker nor as a screening parameter of PH in pulmonary diseases in an adequate study size. The aim of our study was to evaluate if BNP could be helpful to identify patients with significant PH that leads to decreased functional status and an increased mortality in a cohort of patients with chronic lung disease (CLD).
Study Design We undertook a prospective study of 176 consecutive patients with CLD between March 2001 and June 2005.
Inclusion Criteria Participants had either predominant chronic obstructive ventilation impairment (n = 82) or a predominant restrictive ventilation impairment (n = 94) or reduced diffusion capacity.
Exclusion Criteria A written, informed consent was obtained from every patient and the institutional ethical requirements were met.
Right Heart Catheterization and Vasodilator Testing Right heart catheterization was performed as described before and cardiac index as well as pulmonary and systemic vascular resistance were calculated using standard formulas. Selected patients (n = 28) with PH underwent acute vasodilator test with inhaled nitric oxide or inhaled iloprost and the maximal changes were recorded. A positive vasoresponse was defined as a decrease in mean pulmonary artery pressure (PAP) and pulmonary vascular resistance of at least 20% (22). After a mean PAP greater than 35 mm Hg with normal capillary occlusion pressure (< 12 mm Hg) was identified as a risk factor for death, this level was defined as "advanced" or "significant" PH. In a next step, the impact of advanced PH on functional capacity and survival during the follow-up period was calculated.
Lung Function Testing
6-Min Walk Test
Blood Sampling and BNP Assay
Survival Estimates
Statistical Analysis The prognostic value of each variable was tested by univariate Cox proportional hazards regression analysis followed by a stepwise multivariate analysis. Survival was derived from Kaplan-Meier curves. A receiver operating characteristics (ROC) analysis was performed to compare the predictors of mortality. Another ROC analysis was done to assess the discriminatory ability of BNP to identify advanced PH and sensitivity and specificity were calculated. The Pearson correlation coefficient was calculated for BNP levels and age and was tested for two-sided significance. In general, p < 0.05 was considered statistically significant. Additional details of the methods used are provided in the online supplement.
Patient Characteristics: Lung Functional Parameters and the 6-Min Walk Test Patients' characteristics are included in Tables 1 and 2. Participants showed either predominant obstructive or restrictive ventilation deficit. Irrespective of the ventilation deficit, lung volumes and diffusion capacity were markedly reduced in all patients. Overall, while breathing room air, patients were hypoxemic and slightly hypercapnic and the functional capacity during the 6-min walk test was markedly reduced.
Patient Characteristics: Hemodynamic Parameters and Vasodilator Test Overall, patients had mild PH with an elevated mean PAP and pulmonary vascular resistance, and preserved cardiac function with mainly maintained cardiac output and cardiac index (Table 2, first row). Right atrial and capillary wedge pressures were in the normal range, but mixed venous oxygen saturation was diminished to 62.48 ± 0.74%. Twenty-eight patients with significant PH were tested for the presence of acute vasoreactivity. Seven patients (25%) showed a reduction of mean pulmonary artery pressure and pulmonary vascular resistance of at least 20% (difference mean PAP, 26.94 ± 1.8 mm Hg). Cardiac output rose accordingly, whereas systemic blood pressure and resistance did not change during vasodilator testing (data not shown in detail).
Characteristics of Survivors and Nonsurvivors In addition, the total lung capacity was higher in survivors, whereas nonsurvivors had more prominent hypoxemia and the distance during the 6-min walk test was less.
Predictors of Mortality
For the multivariate analysis, a stepwise introduction of covariates was performed for the parameters, which were predictors of mortality in the univariate analysis. The elevated BNP levels and the hemodynamic parameters were all significant predictors of mortality, independent of lung functional impairment. In addition, after multivariate analysis total lung capacity and capillary PO2  50 mm Hg predicted mortality independent of the remaining lung functional parameters.
Hemodynamics, BNP, Lung Function, and the 6-Min Walk Test in Lung Disease with Significant PH Regardless of the underlying ventilation deficit, patients with significant PH had elevated BNP levels and lower 6-min walk distances. Regarding their lung function parameters, patients with advanced PH had less impaired vital capacity and FEV1 values but capillary PO2 and PCO2 were lower (Table 5).
Ability of BNP Levels to Predict Significant Pulmonary Hypertension Based on the hypothesis that clinical significant PH leads to increased BNP levels we sought for the ability of plasma BNP to predict advanced PH (Figure 1). When a normalized BNP ratio > 1 (i.e., measured value > age- and sex-specific value) was applied as cutoff, patients with advanced PH were identified, with a sensitivity of 0.85 and a specificity of 0.88 (area under the curve [AUC], 90.9; p < 0.001). The positive and negative predictive values were 0.73 and 0.92, respectively.
With respect to the absolute values, a threshold value of plasma BNP of 33 pg/ml provided a sensitivity of 0.87 and a specificity of 0.81 (AUC, 89.3%; p < 0.001). BNP levels were not correlated to age and did not significantly differ between male and female participants (data not shown in detail).
Survival Estimates Based on Elevated BNP Levels
The subgroup analysis of the two major groups supported these findings. Thirty-one of 88 patients (35.2%) with interstitial lung disease had elevated BNP levels. Eleven (35.5%) of these died, whereas 10 (17.5%) of the patients with normal BNP died during follow-up (p < 0.05). Six of 45 patients with chronic obstructive pulmonary disease (13.3%) had elevated BNP levels. Two of these patients (33.3%) died, whereas none of the patients with normal BNP died during the observation period (p < 0.05).
Survival Estimates Based on the Hemodynamic Status These findings were confirmed by the subgroup analysis. Twenty-eight of 88 patients (31.8%) with interstitial lung disease had a mean PAP > 35 mm Hg. Twelve patients (42.9%) of this group died, whereas nine patients (15%) in the group without significant PH died during follow-up (p < 0.05). Four of 45 patients (8.9%) with chronic obstructive pulmonary disease had significant PH. Two of these patients died during follow-up, whereas none of the patients without advanced PH died (p < 0.01). Further hemodynamic parameters that reflect the severity of PH (i.e., pulmonary vascular resistance, cardiac output, and cardiac index) showed comparable results (data not shown in detail).
Survival Estimates Based on the Lung Functional Status and Hypoxemia
Patients with a more restrictive lung function impairment (i.e., total lung capacity
Comparison of Different Predictors of Mortality
The number of patients with CLD who seek medical attention is increasing and accurate noninvasive tests to detect significant PH leading to decreased functional status and an increased mortality could aid in the clinical management of these patients. In our study, we observed that elevated BNP levels predicted survival in patients with CLD, irrespective of its etiology or clinical severity. Because we excluded significant left heart disease in every patient, BNP elevation was a result of PH. Accordingly, normalized plasma BNP levels were able to predict clinical significant PH, which was diagnosed in more than one-fourth of our study population with good sensitivity and specificity as compared with a right heart catheter as the diagnostic reference tool. Moreover, in comparison with other parameters as severe hypoxemia or lung volumes, plasma BNP levels were superior to predict mortality in our study population. In addition we identified a mean PAP  35 mm Hg as a degree of significant PH, leading to a decreased functional capacity during the 6-min walk and an increased mortality. The natriuretic peptide system with ANP and BNP as its major peptides is highly activated in patients with impaired cardiac function in the context of neurohumoral activation. Recently, it has been shown that patients with BNP elevation are at an increased overall risk for cardiovascular events and death (26). Earlier studies showed that increased BNP levels correlate with the severity of congestive heart failure (9). In the absence of a significant left heart disease, BNP serves as a marker of an increased workload of the right heart originating from idiopathic pulmonary arterial hypertension (12–14). In pilot studies, we and others were able to demonstrate that even in distinct lung diseases PH leads to increased BNP levels (15, 16). Although elevated BNP concentrations have been observed repeatedly, the pathophysiologic mechanisms are not completely understood. However, the demand of an increased natriuresis in these patients is not explanatory enough. Additional properties have been discussed, including a direct vasodilative and an antiproliferative action of BNP. However, an excessive increase of endogenous BNP beyond a certain degree does not seem to be beneficial (27). Nevertheless, up to a distinct level BNP secretion in PH seems to counteract impending right heart failure, reflecting a serious hemodynamic status with high mortality. In our present study, the participants had an overall bad prognosis from the severity of their underlying lung disease. But still, even in this group with a severely reduced life expectancy, we were able to identify patients with additionally increased mortality risk, irrespective of the degree of lung function impairment or hypoxemia. Our study was not designed to conclude on the impact of distinctive lung volumes as predictors of mortality and we included patients with a variety of lung diseases and consecutively different patterns of lung functional impairment. However, despite the relatively narrow range of lung functional variables in the study population, we identified a reduced vital capacity and severe hypoxemia at room air as predictors of mortality. Both are features of advanced lung diseases irrespective of their etiology. Moreover, as expected, a restrictive pattern of lung functional impairment was another independent predictor of mortality. This observation is in line with the knowledge of the prognostic impact of specific diseases (e.g., advanced interstitial lung diseases), which represented a large number of patients in our study. However, even in the subgroup analysis, BNP and advanced PH had a significant impact on survival of patients with chronic obstructive pulmonary disease. In addition, our data are in line with the generally accepted notion that disease severity and mortality correlate with the degree of lung functional impairment and underline the significant role of hypoxemia in this context. PH and elevated BNP levels were stronger risk factors of mortality as compared with lung volumes and hypoxemia in this study population. Interestingly, we found that participants with significant PH had less impaired lung volumes, but significantly more pronounced hypoxemia. From these results, we cannot conclude if hypoxemia caused PH or was an indicator of PH in our population and the mixture of patients with obstructive and restrictive lung diseases may also have biased this observation. Because patients with hypoxemia-associated forms of PH from underlying lung disease are numerous (6, 7) and represent a large therapeutic target, new medical options in addition to long-term oxygen therapy are under investigation (21, 28, 29). Interestingly, we observed the preserved ability of pulmonary vasodilation in response to the tested substances in 7 of 28 patients (25%) who underwent a vasodilator trial. Our finding of a maintained vasoreactivity does not allow any therapeutic consequence or conclusion of the mechanisms leading to PH (30), but this information may be important for future treatments in this population. Our study clearly had limitations. We did not compare our data with cardiac imaging procedures, especially echocardiography. Echocardiography allows an estimation of the pulmonary artery pressure and gives an overall impression of the right and left heart deformities and function. Nevertheless, this technique is (time) demanding and may be of limited accuracy in advanced lung disease (31). Moreover, the role of echocardiography is well established in patients with pulmonary arterial hypertension or with thromboembolic disease, but the role in chronic lung disease is less clear (32). In addition, we included patients who were scheduled for right heart catheter to rule out PH. This could have biased the estimated prevalence of significant PH and consequently the predictive values in our cohort. Moreover, we included a broad spectrum of lung diseases and cannot conclude on the prevalence of PH in a distinct lung disease. However, the incidence of PH in specific lung disease has been reported before, indicating a higher incidence of PH in interstitial lung diseases (1–5, 30, 33). Despite the mixture of the study population, our data allow an estimation of the prevalence of PH in a "real life" setting of patients with advanced lung diseases, because all participants underwent right heart catheterization as the reference diagnostic tool. Despite these limitations and because PH seems to be a common problem in advanced CLD, integration of BNP measurement into clinical routine could have advantages. In conclusion, plasma BNP facilitates noninvasive detection of significant PH with high accuracy and can be suggested as a screening test for the presence of PH. In addition, BNP allows an assessment of the relevance of PH and could serve as a useful prognostic parameter in chronic lung disease.
The authors thank Mrs. Elisabeth Becker and her team for excellent technical assistance. The excellent assistance of Mr. Tobias Meis is gratefully acknowledged.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Originally Published in Press as DOI: 10.1164/rccm.200510-1545OC on January 13, 2006 Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form October 1, 2005; accepted in final form January 12, 2006
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TOP
ABSTRACT
METHODS
