Summary The recent development of treatment modalities for patients with idiopathic pulmonary arterial hypertension has been based on the evaluation of many different markers such as functional capacity, addressed by NYHA classification, six-minute walk test (6 MWT) and hemodynamic parameters. The aim of this study was to evaluate the correlation of N-terminal fragment (NT-proBNP) with other markers in IPAH and its potential for patient stratification. We studied 42 IPAH patients consecutively evaluated through right heart catheterization in the absence of any specific treatment for pulmonary hypertension. Blood samples, clinical evaluation and 6 MWF distance were collected at baseline. The levels of NT-proBNP showed a high correlation with hemodynamic parameters, such as pulmonary vascular resistance (r ¼ 0:80, Po0.001). A significant difference was found among patients with different functional classes, addressed by NYHA classification (Po 0.02 for all groups comparison). The discriminant analysis reinforced the ability of NT-proBNP to stratify patients according to NYHA functional class. Compared to the other variables studied (hemodynamics and 6 MWT), NTproBNP had the lowest level of overlap in the stratification of IPAH patients. We conclude that NT-proBNP differs among the different functional classes and correlates with other measures of disease severity, although its role in predicting survival still needs to be addressed.

1. Respiratory Medicine (2007) 101, 69–75
NT-proBNP as a tool to stratify disease severity in
pulmonary arterial hypertension
Rogerio Souzaa,b,c,, Carlos Jardima
, Caio Julio Cesar Fernandesa
,
Monica Silveira Lapaa
, Rogerio Rabelob
, Marc Humbertc
a
Pulmonary Division, Pulmonary Hypertension Unit, Heart Institute, University of São Paulo Medical
School, Sao Paulo, Brazil
b
Fleury Research Institute, Sao Paulo, Brazil
c
Centre des Maladies Vasculaires Pulmonaires, UPRES EA 2705, Hôpital Antoine Béclère,
Université Paris-Sud, Clamart, France
Received 23 November 2005; accepted 16 April 2006
KEYWORDS
Pulmonary hyperten-
sion;
Hemodynamics;
NT-proBNP;
Idiopathic pulmonary
arterial hyperten-
sion;
six-minute walk test;
Functional class
Summary The recent development of treatment modalities for patients with
idiopathic pulmonary arterial hypertension has been based on the evaluation of
many different markers such as functional capacity, addressed by NYHA classifica-
tion, six-minute walk test (6 MWT) and hemodynamic parameters. The aim of this
study was to evaluate the correlation of N-terminal fragment (NT-proBNP) with other
markers in IPAH and its potential for patient stratification.
We studied 42 IPAH patients consecutively evaluated through right heart
catheterization in the absence of any specific treatment for pulmonary hyperten-
sion. Blood samples, clinical evaluation and 6 MWF distance were collected at
baseline.
The levels of NT-proBNP showed a high correlation with hemodynamic
parameters, such as pulmonary vascular resistance (r ¼ 0:80, Po0.001). A significant
difference was found among patients with different functional classes, addressed by
NYHA classification (Po 0.02 for all groups comparison). The discriminant analysis
reinforced the ability of NT-proBNP to stratify patients according to NYHA functional
class. Compared to the other variables studied (hemodynamics and 6 MWT), NT-
proBNP had the lowest level of overlap in the stratification of IPAH patients.
We conclude that NT-proBNP differs among the different functional classes and
correlates with other measures of disease severity, although its role in predicting
survival still needs to be addressed.
2006 Elsevier Ltd. All rights reserved.
ARTICLE IN PRESS
0954-6111/$ - see front matter 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.rmed.2006.04.014
Corresponding author. R. Afonso de Freitas 451 ap 112, São Paulo-SP–Brazil. Tel/Fax: +55 11 3069 7202.
E-mail address: rgrsz@uol.com.br (R. Souza).

2. Introduction
Idiopathic pulmonary arterial hypertension (IPAH) is
a disorder of unknown etiology characterized by
the obstruction of small pulmonary arteries leading
to progressive right ventricular failure.1
Although
there was a significant development in therapies in
the last decade,2
the survival rate remains un-
satisfactory.3,4
Among all clinical trials of medical treatment for
IPAH, published in the recent years, the six minute
walk test (6 MWT) was the most-used end point.5
The 6 MWT is a submaximal test, highly reproduci-
ble, that has been shown to correlate with survival
and treatment response not only in IPAH3,6
but also
in other forms of pulmonary hypertension as those
related to scleroderma7
and Eisenmenger.8
The
6 MWT has been mostly studied in patients with
NYHA functional class III and IV; however, its role in
less-advanced disease (class I and II) has not been
addressed, resulting in the question of whether it
would be sensitive enough in this subset of
patients.
Hemodynamic measurements through right heart
catheterization have been shown to reflect prog-
nosis in pulmonary hypertension, allowing the
development of a formula based on the NIH
registry9,10
to predict survival. Nevertheless, it
requires an invasive procedure and it is not clear if
hemodynamics at rest clearly reflect the extent of
pulmonary vasculature involvement in IPAH,
although a baseline measurement is needed for an
accurate diagnosis of the disease.11
More recently, natriuretic peptides have been
used to address heart diseases, mainly left ven-
tricular dysfunction and myocardial infarction.12,13
Pro-BNP is a pro-hormone produced mainly by the
ventricles, which is cleaved into an inactive N-
terminal fragment (NT-proBNP) and into its active
form BNP (brain natriuretic peptide); eventually
both are secreted into circulation by the cardio-
myocytes.14
In pulmonary hypertension, BNP has
been shown to correlate to functional status15
and
treatment response,16
and to be an independent
predictor of survival.17,18
NT-proBNP has a longer
half-life in blood and has been shown to be a
marker of pulmonary hypertension in scleroderma
patients.19
In IPAH, NT-proBNP presented a good
correlation with hemodynamics20
and also reflected
treatment response.21
However, it has not been
demonstrated if natriuretic peptides would be able
to accurately stratify patients with IPAH from all
different functional statuses.
Stratification of patients is based mostly on NYHA
functional class.22
It is certainly easy to use but
relies on the patient and/or physician perception of
the functional limitations. This could impair its
ability to reflect changes mainly after specific
interventions. Thus, a non-invasive marker that
could reflect the functional capacity and could also
be correlated to the hemodynamic status would be
a useful tool for the correct stratification and
follow-up of IPAH patients.
The aim of this study was to evaluate the
correlation of NT-proBNP with different response
markers in IPAH and its potential for patient
stratification according to disease severity as an
adjuvant tool to NYHA functional class.
Methods
Patient group
From August 2003 to May 2005, 42 patients with the
final diagnosis of IPAH were consecutively enrolled
in this study. Patients were on conventional therapy
(anticoagulation, diuretics and cardiac glycosides)
but without any other specific therapy to pulmon-
ary hypertension. The diagnosis of IPAH was
confirmed based on the International Symposium
on pulmonary hypertension criteria.11
Thromboem-
bolic disease was ruled out by ventilation-perfusion
scan or spiral CT scan. Lung disease was excluded
by pulmonary function tests and CT scans. Con-
nective tissue diseases were excluded by physical
examination and serological markers. Patients that
presented a mean pulmonary artery pressure lower
than 25 mmHg or a pulmonary artery occlusion
pressure higher than 15 mmHg at the right heart
catheterization were excluded from the study. The
study was approved by our institutional ethics
committee.
Hemodynamics and exercise capacity
measurements
A clinical evaluation, including NYHA functional
class and 6 MWT, was performed at baseline. The
6 MWT was performed on the same day of the
clinical evaluation, according to the recommenda-
tions of the American Thoracic Society23
; the
distance walked was recorded, regardless of any
interruption.
Hemodynamic evaluation was performed in all
patients while breathing room air, at supine
position, within 1 week of the clinical evaluation
without any change in treatment or in clinical
status. All patients presented arterial oxygen
saturation greater than 90% at the beginning of
the measurements. A 7F flow-directed pulmonary
ARTICLE IN PRESS
R. Souza et al.
70

3. artery catheter (Baxter Healthcare Corporation,
Irvine, CA, USA) was used in all patients. Cardiac
output (CO) was measured by the standard thermo-
dilution technique. Cardiac index (CI) was calcu-
lated as CO divided by body surface area (m2
).
Indexed pulmonary vascular resistance was calcu-
lated by the following formula: 80 (mean pul-
monary artery pressurepulmonary artery
occlusion pressure)/CI.
NT-proBNP measurements
Blood samples were collected at the beginning of
right heart catheterization. In 12 patients, the
blood tests were taken more than 7 days after
hemodynamic measurements; therefore, their va-
lues were not used in the correlation analysis. The
samples were centrifuged within 60 min of collec-
tion. The resulting serum samples were stored at
70 1C. The NT-proBNP measurements were per-
formed on an Elecsys 2010 instrument by a
sandwich immunoassay (Roche Diagnostics, Basel,
Switzerland).
Statistical analysis
All the results are expressed as mean (SEM). We used
a Pearson correlation coefficient to evaluate the
correlation between NT-proBNP and the other
continuous variables. We have also used analysis
of variance (ANOVA) for the evaluation of all
continuous variables and NYHA functional class; a
Bonferroni post hoc test was applied for multiple
comparisons when statistical significance was ob-
tained. A multiple regression model was used to
estimate the impact of hemodynamic data and NT-
proBNP in the NYHA functional class determination.
A discriminant function analysis was performed to
determine the ability of NT-proBNP to classify
patients according to NYHA functional class.
Results
Baseline hemodynamics and clinical characteristics
of the 42 patients enrolled in the study are listed in
Table 1. These data are in accordance with
previously published data from IPAH patients.
Linear regression analysis disclosed a significant
association between NT-proBNP and right atrial
pressure (r ¼ 0:68, P ¼ 0:004), mean pulmonary
artery pressure (r ¼ 0:58, Po0.001), cardiac index
(r ¼ 0:70, Po0.001) and indexed pulmonary
vascular resistance (r ¼ 0:80, Po0.001) (Fig. 1).
There was a trend in the association between NT-
proBNP and the 6 MWT distance (r ¼ 0:31,
P ¼ 0:052). Functional class presented significant
correlation with 6 MWT (r ¼ 0:49; P ¼ 0:001),with
NT-proBNP (r ¼ 0:81; Po0.001) and with hemody-
namic data, considering cardiac index (r ¼ 0:70;
Po0.001), indexed pulmonary vascular resistance
(r ¼ 0:72; Po0.001) and mean pulmonary artery
pressure (r ¼ 0:52; P ¼ 0:002).
We used analysis of variance to assess the
differences between each one of the measured
parameters at the different functional classes. The
NT-proBNP levels were significantly different at
each one of the functional classes (Po0.02 for all
group comparison) (Fig. 2). The discriminant ana-
lysis evidenced a high significant model (Table 2)
that allowed patient stratification into the differ-
ent NYHA functional classes according to NT-
proBNP. Cardiac index, although significantly dif-
ferent at global analysis (Po0.001), showed no
significant difference among functional classes II, III
and IV (P40.26); the same pattern was noted with
6 MWT distance and indexed pulmonary vascular
resistance, and the global comparison resulted in a
significant difference among groups (P ¼ 0:005 and
0.001, respectively), but the post hoc analysis
showed only differences between more preserved
(functional classes I and II) and more advanced
disease (functional classes III and IV) (Po0.04).
The analyses of NT-proBNP, 6 MWT distance and
cardiac index in a multiple regression model with
NYHA as the dependent variable resulted in a very
significant model (r ¼ 0:89; Po0.001) where NT-
proBNP was the only significant factor (Po0.001).
ARTICLE IN PRESS
Table 1 Baseline clinical and hemodynamic data.
Age (yr) 37 (2)
Gender (male/female) 10/32
Functional Class I 4
II 15
III 16
IV 7
Six-min walk test distance(m) 427 (21)
NT-proBNP (pg/mL) 1074 (201)
Right atrial pressure (mmHg) 12 (2)
Mean pulmonary artery pressure
(mmHg)
67 (5)
Pulmonary artery occlusion
pressure (mmHg)
9 (2)
Cardiac index (L/min/m2
) 2.3 (0.2)
Indexed pulmonary vascular
resistance (dyn cm5
s m2
)
2029 (202)
Results are presented as mean (SEM).
NT-proBNP for severity stratification in PH 71

4. Discussion
Our results showed that NT-proBNP not only has a
strong correlation with hemodynamic parameters but
also differs among the NYHA functional class allowing
patients’ stratification according to disease severity.
The small number of patients enrolled should be
seen as a limitation of our study, even considering
ARTICLE IN PRESS
Figure 1 Linear regression between NT-proBNP and indexed pulmonary vascular resistance (r ¼ 0:80, Po0.001).
Figure 2 Association of different markers and NYHA functional class. (A) CI—cardiac index; (B) PVRi—indexed
pulmonary vascular resistance; (C) 6 MWT—6-min walk test; (D) Ln NT-proBNP.
R. Souza et al.
72

5. that the clinical and hemodynamic data from our
population resembled previously described data
from IPAH patients.9
Seven of our patients were
included in our previous study about NT-proBNP20
;
nevertheless, the broader spectrum of functional
capacity in this study strengthens our previous
findings on the correlations of NT-proBNP and
hemodynamic variables in PAH.
Hemodynamic measurements are well recog-
nized as prognostic markers since they somehow
reflect the progressive obstruction to blood flow
that is characteristic of pulmonary arterial hyper-
tension.5
However, it is not clear if baseline
hemodynamics reflect all the heterogeneity of the
pulmonary circulation in the presence of the
disease.24,25
Right heart catheterization is still
mandatory for diagnostic confirmation, for the
acute vasodilator challenge and treatment follow-
up,26
in spite of its limitation due to invasiveness.
Natriuretic peptides have been used as markers
of heart disease based on the observation that they
are involved in the activation of the cyclic
guanylate cyclase system as a counterregulatory
mechanism in heart failure, probably with in-
creased cardiac wall stress as the trigger mechan-
ism.27,28
Natriuretic peptides have also been correlated
with hemodynamic parameters and prognosis in
patients with heart failure.29,30
In pulmonary
hypertension, NT-proBNP has been correlated to
the hemodynamics and to the acute response to
nitric oxide.20
Similar results have been described
in systemic sclerosis-related pulmonary hyperten-
sion.31
The same behavior can be found in this
study, in a larger population of patients. Further-
more, NT-proBNP demonstrated an ability to
stratify patients according to the functional class
superior to any other marker studied, even con-
sidering patients with functional class I or IV.
Previous studies with BNP have addressed disease
stratification in patients with pulmonary hyperten-
sion, but the limited spectrum of functional classes
of these studies did not allow a proper analysis of
the ability of BNP to reflect disease severity in such
patients,32
despite its role as a prognostic marker.18
One of the limitations of the use of the NYHA
functional classification is the subjectivity that may
be involved in the patients’ report of their
symptoms and physicians’ interpretation. Even
though, the NYHA functional classification has been
shown to correlate with prognosis in pulmonary
hypertension.3
In our study, patients’ functional
class was addressed by the same trained physician,
blinded to all other variables of study, including the
results of NT-proBNP throughout the inclusion
period; hence the variability might be lower than
that usually reported. This approach was chosen
once the main objective was to show that NT-
proBNP could be used as an adjuvant and not
necessarily a substitute tool to functional class. The
NT-proBNP was independently associated with
functional class in our study; furthermore, the
discriminant analysis evidenced a high significant
model where levels of NT-proBNP allowed the
stratification of patients at least as the NYHA
functional class, although this model should be
confirmed in another study population in order to
be used. This result, together with the high
stability of NT-proBNP in the serum and the fact
that this test can be performed under routine
laboratory conditions,14,31
indicates that NT-
proBNP may be a useful test in the clinical setting
for patient stratification, potentially better than
the 6 MWT, considering patients with less severe
disease.
The 6 MWT is a highly reproducible test and has
been used as the primary end point in most of the
clinical trials in pulmonary hypertension.33–36
Nevertheless, the majority of the patients included
in those trials were of functional classes III and IV;
there are no data validating the use of 6 MWT in
patients with less-advanced disease. In our study,
although 6 MWT would perfectly differentiate pa-
tients with classes III and IV from patients with
functional classes I and II, we found no significant
difference within these two subsets, even with a
ARTICLE IN PRESS
Table 2 Discriminant model for stratification in NYHA functional class according to NT-proBNP.
NYHA functional class
I II III IV
Ln NT proBNP (a) 2.624 4.438 5.774 7.084
(Constant)(b) 5.272 12.502 20.202 29.714
To classify a patient into the NYHA functional class based on the NT-proBNP level, the obtained level should be log transformed
and then multiplied by (a) and added to (b) for each column. The column that determines the highest value will then evidence
to which NYHA functional class that level of NT-proBNP is related.
NT-proBNP for severity stratification in PH 73

6. significant correlation with hemodynamics and
functional classes when considering the whole
population.
The lack of survival data could be considered a
limitation of the study once the proposition of cut-
off values that could determine not only disease
severity but also long-term prognosis would be of
major impact in the utilization of NT-proBNP in
daily practice; however, this would demand for a
larger and homogeneous cohort, considering the
many therapeutical options available nowadays. In
spite of this limitation, our results showed that
disease severity can be addressed by NT-proBNP,
justifying the long-term studies needed to define
true values for risk stratification.
Our study showed that NT-proBNP, among the
different variables studied, including hemodynamic
parameters and 6 MWT, was the marker with lower
degree of overlap considering the different func-
tional classes. This brings up the possibility of a
more specific and certainly less subjective stratifi-
cation of patients, which could be of significant
importance for the follow-up of patients under
different treatment strategies.
With the growing interest in pulmonary hyper-
tension pathophysiology and treatment, a better
patient stratification is necessary to appropriately
address the therapeutic options available and those
still to be tested. Our results strengthen the
previous findings on the use of NT-proBNP as an
independent marker in IPAH. Although its role in
predicting survival still needs to be addressed, NT-
proBNP differs among the different functional
classes and correlates with other measures of
disease severity.
Acknowledgment
This study is greatly indebted to an educational
grant received from CAPES—Ministry of Educa-
tion—Brazil.
References
1. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary
arterial hypertension. N Engl J Med 2004;351:1425–36.
2. Rubin LJ. Diagnosis and management of pulmonary arterial
hypertension: ACCP evidence-based clinical practice guide-
lines. Chest 2004;126:7S–10S.
3. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous
epoprostenol infusion in primary pulmonary hypertension:
prognostic factors and survival. J Am Coll Cardiol 2002;40:
780–8.
4. McLaughlin VV, Sitbon O, Badesch DB, et al. Survival with
first-line bosentan in patients with primary pulmonary
hypertension. Eur Respir J 2005;25:244–9.
5. Hoeper MM, Oudiz RJ, Peacock A, et al. End points and
clinical trial designs in pulmonary arterial hypertension:
clinical and regulatory perspectives. J Am Coll Cardiol
2004;43:48S–55S.
6. Paciocco G, Martinez FJ, Bossone E, Pielsticker E, Gillespie
B, Rubenfire M. Oxygen desaturation on the six-minute walk
test and mortality in untreated primary pulmonary hyper-
tension. Eur Respir J 2001;17:647–52.
7. Badesch DB, Tapson VF, McGoon MD, et al. Continuous
intravenous epoprostenol for pulmonary hypertension due to
the scleroderma spectrum of disease. A randomized,
controlled trial. Ann Intern Med 2000;132:425–34.
8. Sandoval J, Aguirre JS, Pulido T, et al. Nocturnal oxygen
therapy in patients with the Eisenmenger syndrome. Am J
Respir Crit Care Med 2001;164:1682–7.
9. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary
hypertension. A national prospective study. Ann Intern Med
1987;107:216–23.
10. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients
with primary pulmonary hypertension. Results from a
national prospective registry. Ann Intern Med 1991;115:
343–9.
11. Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and
differential assessment of pulmonary arterial hypertension.
J Am Coll Cardiol 2004;43:40S–7S.
12. Stein BC, Levin RI. Natriuretic peptides: physiology, ther-
apeutic potential, and risk stratification in ischemic heart
disease. Am Heart J 1998;135:914–23.
13. Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid
measurement of B-type natriuretic peptide in the emer-
gency diagnosis of heart failure. N Engl J Med 2002;347:
161–7.
14. Yap LB, Mukerjee D, Timms PM, Ashrafian H, Coghlan JG.
Natriuretic peptides, respiratory disease, and the right
heart. Chest 2004;126:1330–6.
15. Leuchte HH, Holzapfel M, Baumgartner RA, et al. Clinical
significance of brain natriuretic peptide in primary pulmon-
ary hypertension. J Am Coll Cardiol 2004;43:764–70.
16. Leuchte HH, Holzapfel M, Baumgartner RA, Neurohr C,
Vogeser M, Behr J. Characterization of brain natriuretic
peptide in long-term follow-up of pulmonary arterial
hypertension. Chest 2005;128:2368–74.
17. Nagaya N, Nishikimi T, Okano Y, et al. Plasma brain
natriuretic peptide levels increase in proportion to the
extent of right ventricular dysfunction in pulmonary
hypertension. J Am Coll Cardiol 1998;31:202–8.
18. Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain
natriuretic peptide as a prognostic indicator in patients with
primary pulmonary hypertension. Circulation 2000;102:
865–70.
19. Allanore Y, Borderie D, Meune C, et al. N-terminal pro-brain
natriuretic peptide as a diagnostic marker of early pulmon-
ary artery hypertension in patients with systemic sclerosis
and effects of calcium-channel blockers. Arthritis Rheum
2003;48:3503–8.
20. Souza R, Bogossian HB, Humbert M, et al. N-terminal-pro-
brain natriuretic peptide as a haemodynamic marker in
idiopathic pulmonary arterial hypertension. Eur Respir J
2005;25:509–13.
21. Souza R, Jardim C, Martins B, et al. Effect of bosentan
treatment on surrogate markers in pulmonary arterial
hypertension. Curr Med Res Opin 2005;21:907–11.
22. McLaughlin VV, Presberg KW, Doyle RL, et al. Prognosis of
pulmonary arterial hypertension: ACCP evidence-based
clinical practice guidelines. Chest 2004;126:78S–92S.
ARTICLE IN PRESS
R. Souza et al.
74

7. 23. ATS statement: guidelines for the six-minute walk test. Am J
Respir Crit Care Med 2002;166:111–7.
24. McGregor M, Sniderman A. On pulmonary vascular resis-
tance: the need for more precise definition. Am J Cardiol
1985;55:217–21.
25. Castelain V, Chemla D, Humbert M, et al. Pulmonary artery
pressure–flow relations after prostacyclin in primary pul-
monary hypertension. Am J Respir Crit Care Med 2002;165:
338–40.
26. Badesch DB, Abman SH, Ahearn GS, et al. Medical therapy
for pulmonary arterial hypertension: ACCP evidence-based
clinical practice guidelines. Chest 2004;126:35S–62S.
27. Venugopal J. Cardiac natriuretic peptides—hope or hype?
J Clin Pharm Ther 2001;26:15–31.
28. Yap LB, Ashrafian H, Mukerjee D, Coghlan JG, Timms PM. The
natriuretic peptides and their role in disorders of right heart
dysfunction and pulmonary hypertension. Clin Biochem
2004;37:847–56.
29. Arad M, Elazar E, Shotan A, Klein R, Rabinowitz B. Brain and
atrial natriuretic peptides in patients with ischemic heart
disease with and without heart failure. Cardiology 1996;87:
12–7.
30. Nagaya N, Nishikimi T, Uematsu M, et al. Secretion patterns
of brain natriuretic peptide and atrial natriuretic peptide in
patients with or without pulmonary hypertension complicat-
ing atrial septal defect. Am Heart J 1998;136:297–301.
31. Mukerjee D, Yap LB, Holmes AM, et al. Significance of plasma
N-terminal pro-brain natriuretic peptide in patients with
systemic sclerosis-related pulmonary arterial hypertension.
Respir Med 2003;97:1230–6.
32. Leuchte HH, Neurohr C, Baumgartner R, et al. Brain
natriuretic peptide and exercise capacity in lung fibrosis
and pulmonary hypertension. Am J Respir Crit Care Med
2004;170:360–5.
33. Barst RJ, Rubin LJ, Long WA, et al. A comparison of
continuous intravenous epoprostenol (prostacyclin) with
conventional therapy for primary pulmonary hypertension.
The primary pulmonary hypertension study group. N Engl J
Med 1996;334:296–302.
34. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for
pulmonary arterial hypertension. N Engl J Med 2002;346:
896–903.
35. Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost
for severe pulmonary hypertension. N Engl J Med 2002;347:
322–9.
36. Hoeper MM, Faulenbach C, Golpon H, Winkler J, Welte T,
Niedermeyer J. Combination therapy with bosentan and
sildenafil in idiopathic pulmonary arterial hypertension. Eur
Respir J 2004;24:1007–10.
ARTICLE IN PRESS
NT-proBNP for severity stratification in PH 75