Abstract
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.
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).
We undertook a prospective study of 176 consecutive patients with CLD between March 2001 and June 2005.
We included clinically stable patients with a history of CLD who were scheduled for right heart catheter. An impaired lung function test and conclusive radiographic and immunologic or histopathologic findings were mandatory (17–21).
Participants had either predominant chronic obstructive ventilation impairment (n = 82) or a predominant restrictive ventilation impairment (n = 94) or reduced diffusion capacity.
Exclusion criteria comprised the following: thromboembolic disease, age younger than 18 yr, impaired renal function, and significant left heart disease. Patients with significant musculoskeletal disease were also excluded, if the disability would have led to an impaired performance during the 6-min walk test. Finally, patients were excluded if they had diagnoses that could per se influence prognosis (i.e., malignancies or severe neurologic disorders).
A written, informed consent was obtained from every patient and the institutional ethical requirements were met.
None of the patients received specific vasodilator therapy at initial evaluation.
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.
Pulmonary function test included spirometry, body plethysmography, and blood gas analysis in arterialized capillary blood from the ear lobe without supplemental oxygen in all patients (n = 176) (23). Parameters were calculated as percent of predicted (24).
The distance covered in 6 min was measured according to the American Thoracic Society statement (2002) in all patients (25). Supplemental oxygen was given in 90 patients.
The blood samples were drawn and analyzed as described before (14). Normalized BNP ratio was calculated as: measured BNP level/age- and sex-adjusted normal values (range, 18–75 pg/ml). This ratio was elevated when greater than 1.
Survival was estimated from the day of completion of the diagnostic tests to June 7, 2005, or cardiopulmonary death. All nonsurviving patients died of cardiopulmonary causes. The follow-up rate was 100%. Forty patients received lung transplantation during follow-up. These patients were included as “alive” until they received lung transplantation and were censored thereafter.
Data are shown as mean and standard error of mean (SEM) or 95% confidence interval (CI). Dependent of their distribution, comparison between groups was performed using the students t test for unpaired samples or Mann-Whitney U-test, respectively.
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.
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.
Diagnosis (n) | Age (yr) | TLC (L) | FEV1 (L) | FVC (L) | FEV1/FVC × 100 (%) | Cap. Po2 (mm Hg) | Cap. Pco2 (mm Hg) | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Chronic Obstructive Ventilation Impairment | ||||||||||||||
| COPD (n = 45) | 54.76 ± 7.26 | 8 ± 1.67 | 0.71 ± 0.27 | 1.9 ± 0.83 | 38.53 ± 7.58 | 51.9 ± 9.57 | 46. 85 ± 8.54 | |||||||
| CF (n = 13) | 28.92 ± 6.11 | 5.62 ± 1.32 | 0.87 ± 0.3 | 1.5 ± 0.43 | 60.78 ± 22.33 | 53.37 ± 6.2 | 45.33 ± 6.1 | |||||||
| Sarcoid. (n = 10) | 48.4 ± 6.3 | 4.77 ± 1.12 | 1.45 ± 0.49 | 2.22 ± 0.74 | 66.85 ± 14.05 | 53.07 ± 10.01 | 35.56 ± 4.19 | |||||||
| LAM (n = 5) | 47 ± 9.82 | 5.8 ± 0.82 | 0.92 ± 0.4 | 1.87 ± 0.66 | 46.51 ± 10.12 | 58 ± 4.24 | 35 ± 5.35 | |||||||
| BOS (n = 3) | 38 ± 7.81 | 5.72 ± 1.75 | 0.65 ± 0.45 | 1.21 ± 0.76 | 53.53 ± 6.78 | 52.97 ± 6.9 | 47.77 ± 12.34 | |||||||
| Bronchiectasis (n = 3) | 57 ± 7 | 3.63 ± 1.38 | 0.72 ± 0.32 | 0.98 ± 0.3 | 66.76 ± 19.11 | 48.5 ± 11.85 | 49.93 ± 11.64 | |||||||
| Chronic Restrictive Ventilation Impairment | ||||||||||||||
| IPF (n = 55) | 53.33 ± 8.6 | 2.86 ± 0.77 | 1.47 ± 0.51 | 1.68 ± 0.65 | 90.18 ± 12.73 | 50.54 ± 12.17 | 40.66 ± 5.73 | |||||||
| CTD (n = 17) | 56.82 ± 10.32 | 3.27 ± 1.11 | 1.49 ± 0.5 | 1.81 ± 0.66 | 83.44 ± 7.86 | 52.12 ± 13.18 | 38.51 ± 5.91 | |||||||
| Hypers. Pn. (n = 8) | 49 ± 8.42 | 2.94 ± 1 | 1.15 ± 0.32 | 1.31 ± 0.37 | 88.86 ± 8.43 | 54.04 ± 8.95 | 46.45 ± 6.65 | |||||||
| HistioX (n = 6) | 38.83 ± 10.61 | 5.7 ± 1.07 | 2.82 ± 0.98 | 3.58 ± 0.84 | 76.79 ± 19.11 | 54.33 ± 9.11 | 33.42 ± 9.13 | |||||||
| Seq. TB/ARDS (n = 5) | 64.2 ± 3.7 | 3.29 ± 1.26 | 1.18 ± 0.47 | 1.53 ± 0.81 | 79.77 ± 10.65 | 51.8 ± 10.94 | 44.8 ± 4.09 | |||||||
| Fibrosis (n = 3) | 44.33 ± 13.61 | 2.83 ± 185 | 1.32 ± 0.79 | 1.7 ± 1.36 | 85.68 ± 15.31 | 47 ± 7.92 | 39.6 ± 5.74 | |||||||
Variable | Study Population (n = 176) | Survivors (n = 145) | Nonsurvivors (n = 31) |
|---|---|---|---|
| Age | 50.98 ± 0.84 | 50.7 ± 092 | 52.26 ± 2.11 |
| Sex, F/M | 101/75 | 81/64 | 20/11* |
| BNP (elevated/nonelevated) | 75/101 | 37/108 | 17/14* |
| Hemodynamic variables | |||
| Mean PAP, mm Hg | 30.35 ± 0.95 | 28.53 ± 0.99 | 38.52 ± 2.34† |
| PCWP, mm Hg | 9.71 ± 0.31 | 10.05 ± 0.38 | 8.87 ± 0.76 |
| RAP, mm Hg | 6.02 ± 0.26 | 6.05 ± 0.3 | 5.87 ± 0.55 |
| PVR, dyne · s · cm−5 | 375.22 ± 24.07 | 317.85 ± 20.44 | 643.56 ± 83.06† |
| CO, L/min | 5.05 ± 0.11 | 5.2 ± 0.11 | 4.34 ± 0.24* |
| CI, L · min−1 · m−2 | 2.94 ± 0.62 | 3.03 ± 0.07 | 2.53 ± 0.14* |
| Lung function parameters | |||
| TLC, L | 4.77 ± 0.19 | 4.99 ± 0.21 | 3.72 ± 0.32† |
| TLC, % pred | 84.44 ± 3.17 | 88.16 ± 3.61 | 67.17 ± 5.41‡ |
| FVC, % pred | 49.85 ± 1.52 | 50.71 ± 1.72 | 45.83 ± 3.07 |
| FEV1, % pred | 40.77 ± 1.5 | 40.39 ± 1.7 | 42.6 ± 3.19 |
| DlCO, % pred | 29.81 ± 1.2 | 30.02 ± 1.31 | 28.84 ± 3.03 |
| Cap. Po2, mm Hg | 51.87 ± 0.78 | 53.17 ± 0.86 | 45.72 ± 1.55† |
| Cap. Pco2, mm Hg | 42.38 ± 0.6 | 42.46 ± 0.66 | 42.02 ± 0.66 |
| 6MWD, m | 278.67 ± 9.64 | 289.42 ± 10.35 | 228.71 ± 23.95‡ |
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).
During a mean follow-up period of 10.6 ± 0.68 mo, 31 patients (18%) died of cardiopulmonary causes (Table 2). Patients who died during the follow-up time (nonsurvivors) more frequently had an elevated BNP level (i.e., normalized ratio > 1) and prominent PH with significantly impaired right heart function compared with the survivors.
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.
Univariate analysis revealed an elevated plasma BNP level as a significant predictor of mortality (Tables 3 and 4). The hemodynamic parameters, that were identified as predictors of mortality included: a mean PAP ⩾ 35 mm Hg, a pulmonary vascular resistance ⩾ 320 dyne · s · cm−5, a cardiac output ⩽ 4.4 L/min, and a cardiac index ⩽ 2.55 L · min−1 · m−2. These results were reproduced irrespective of the underlying diagnosis or ventilation deficit (data not shown in detail). Overall, a forced vital capacity < 1.52 L, a total lung capacity ⩽ 3.72 L, and a capillary Po2 ⩽ 50 mm Hg at room air were also predictive of mortality. Sex and age were not predictors of mortality.
Variable | Risk Ratio Estimates | 95% Confidence Interval | p Value |
|---|---|---|---|
| Mean PAP, ⩽ 35 mm Hg | 3.67 | 1.79–7.51 | < 0.001 |
| PVR, ⩾ 320 dyne · s · cm−5 | 4.24 | 1.89–9.5 | < 0.01 |
| CO, ⩽ 4.4 L/min | 2.4 | 1.16–4.95 | < 0.05 |
| CI, ⩽ 2.55 L · min−1 · m−2 | 2.45 | 1.2–5 | < 0.05 |
| Cap. Po2, ⩽ 50 mm Hg | 3.04 | 1.36–6.81 | < 0.01 |
| TLC, ⩽ 3.72 L | 3.05 | 1.38–6.75 | < 0.01 |
| FVC, < 1.52 L | 2.1 | 1.02–4.33 | < 0.05 |
| BNP, normalized ratio > 1 | 2.94 | 1.45–5.99 | < 0.01 |
Covariate | Mean PAP | PVR | CO | CI | Po2 | TLC | FVC | BNP |
|---|---|---|---|---|---|---|---|---|
| Variable Mean PAP | NS | 3.07‡ | 3.04‡ | 3.09‡ | 3.32‡ | 3.5‡ | 2.99* | |
| (1.39–6.77) | (1.38–6.71) | (1.49–6.39) | (1.62–6.81) | (1.71–7.18) | (1.04–8.04) | |||
| PVR | NS | 4.03 | 3.67† | 3.74‡ | 4† | 3.95‡ | 3.56* | |
| (1.55–10.49) | (1.5–9) | (1.66–8.43) | (1.79–8.99) | (1.75–8.89) | (1.32–9.65) | |||
| CO | NS | NS | NS | 2.6 | 2.38* | 2.3* | NS | |
| (1.25–5.42) | (1.15–4.92) | (1.11–4.77) | ||||||
| CI | NS | NS | NS | 2.87† | 2.38* | 2.67* | NS | |
| (1.39–5.93) | (1.16–4.87) | (1.3–5.5) | ||||||
| Po2 | 2.43* | 2.53* | 3.23† | 3.47† | 2.86* | 2.74* | 2.69* | |
| (1.07–5.52) | (1.12–5.69) | (1.44–7.25) | (1.54–7.8) | (1.27–6.42) | (1.21–6.21) | (1.19–6.05) | ||
| TLC | 2.74* | 3.88† | 2.38* | 3.02† | 2.9† | 2.68* | 2.95† | |
| (1.27–5.91) | (1.33–6.24) | (1.15–4.92) | (1.4–6.48) | (1.35–6.25) | (1.2–5.97) | (1.37–6.35) | ||
| FVC | NS | NS | NS | 2.32* | NS | NS | 2.12* | |
| (1.12–4.76) | (1.03–4.36) | |||||||
| BNP | NS | NS | 2.37* | 2.33* | 2.6† | 2.8† | 2.97† | |
| (1.09–5.15) | (1.07–5.1) | (1.27–5.32) | (1.37–5.69) | (1.46–6.04) |
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.
As mentioned previously, advanced (or clinically significant) PH was defined as a mean PAP ⩾ 35 mm Hg. This was observed in 47 patients (26.7%). In this group, mean PAP was 47.44 ± 1.53 mm Hg, right atrial pressure was 7.4 ± 0.6 mm Hg, pulmonary vascular resistance was 741.53 ± 55.27 dyne · s ·cm–5, cardiac output measured 4.27 ± 0.18 L/min, cardiac index was 2.47 ± 0.1 L · min−1 · m−2, and mixed venous oxygen saturation was 56 ± 1.58%.
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).
Study population (n = 176) | Mean PAP < 35 mm Hg (n = 129) | Mean PAP > 35 mm Hg (n = 47) | |
|---|---|---|---|
| Age, yr | 50.98 ± 0.84 | 52.23 ± 1.68 | 50.52 ± 0.97 |
| Sex, F/M | 101/75 | 75/54 | 26/21 |
| Mean follow-up time, mo | 10.58 ± 0.66 | 10.67 ± 0.79 | 10.34 ± 1.33 |
| 6MWD, m | 278.67 ± 9.64 | 290.83 ± 11.29 | 244.56 ± 17.8* |
| BNP, pg/ml | 98.42 ± 17.12 | 25.94 ± 3.71 | 297.35 ± 53.82† |
| BNP, normalized ratio | 2.31 ± 0.49 | 0.59 ± 0.1 | 7 ± 1.62† |
| Lung function parameters | |||
| TLC, L | 4.77 ± 0.19 | 4.99 ± 023 | 4.16 ± 0.26 |
| FVC, % pred | 49.85 ± 1.52 | 47.42 ± 1.69 | 56.52 ± 3.13* |
| FEV1, % pred | 40.77 ± 1.5 | 36.92 ± 1.57 | 51.56 ± 3.15† |
| DlCO, % pred | 29.81 ± 2 | 30.81 ± 1.48 | 27.65 ± 2.02 |
| Cap. Po2, mm Hg | 51.87 ± 0.79 | 53.8 ± 0.93 | 46.58 ± 1.23† |
| Cap. Pco2, mm Hg | 42.38 ± 0.6 | 43.3 ± 0.66 | 39.87 ± 1.25* |
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.
Figure 1. Ability of plasma brain natriuretic peptide (BNP) to predict significant pulmonary hypertension.
[More] [Minimize]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).
Fifty-four of 176 patients (30.68%) had elevated plasma BNP levels (Figure 2A). Of these, 17 patients (31.48%) died during the follow-up period. The mean survival time of these patients was 24.29 ± 3.07 mo. In contrast, the mean survival time of the remaining 122 patients without BNP elevation was 33.44 ± 1.93 mo (p < 0.01).
Figure 2. (A) Parameters predictive of survival after univariate analysis. Calculation of BNP ratio: measured BNP value/individual normal BNP value. (B) Survival estimates based on the presence of significant pulmonary hypertension. Mean PAP = mean pulmonary artery pressure.
[More] [Minimize]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).
Forty-seven of 176 patients (26.7%) were diagnosed as having advanced PH. Eighteen (38.3%) of this group died after a mean survival time of 22.36 ± 3.1 mo (Figure 2B). In contrast, 13 of the remaining 129 patients (16.77%) died during the follow-up period. The mean survival time of these patients was 34.23 ± 1.84 mo (p < 0.001).
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).
Severe hypoxemia with a capillary Po2 ⩽ 50 mm Hg was seen in 82 patients (46.6%). Twenty-three (28.04%) of these patients died after a mean survival time of 26.06 ± 2.5 mo, whereas the patients with less hypoxemia lived significantly longer (mean survival time, 35.29 ± 2.25 mo; p < 0.01).
Patients with a more restrictive lung function impairment (i.e., total lung capacity ⩽ 3.72 L) died earlier than patients with higher total lung capacity (24.13 ± 2.15 vs. 33.22 ± 2.14 mo; p < 0.01). Also, a forced vital capacity < 1.52 L led to decreased survival time (22.01 ± 1.71 vs. 31.99 ± 2.19 mo).
ROC analysis demonstrated that the prognostic value of plasma BNP levels to predict mortality (AUC, 67.3%) was comparable to that of mean PAP (AUC, 72.9%) but superior to total lung capacity (AUC, 38.5%) and Po2 (AUC, 29.2%) and all other hemodynamic or lung functional parameters (Figure 3).
Figure 3. Ability of different parameters to predict survival in chronic lung disease. BNP ratio = brain natriuretic peptide ratio (> 1); cap. Po2 = capillary oxygen partial pressure (< 50 mm Hg); mean PAP = mean pulmonary arterial pressure (> 35 mm Hg); TLC = total lung capacity (< 3.72 L).
[More] [Minimize]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.
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