Review Articles

Prognostic value of brain natriuretic peptides in

patients with pulmonary arterial hypertension:
A systematic review and meta-analysis
Paul M. Hendriks, MD a,b , Liza D. van de Groep, MD c , Kevin M. Veen, MD, PhD d , Mitch C.J. van Thor, MD, PhD c ,
Sabrina Meertens, MSc e , Eric Boersma, MSc, PhD, FESC a,f , Karin A. Boomars, MD, PhD b , Marco C. Post, MD,
PhD c,g , and Annemien E. van den Bosch, MD, PhD a The Netherlands

Abstract
Background Multiple biomarkers have been investigated in the risk stratification of patients with pulmonary arterial
hypertension (PAH). This systematic review and meta-analysis is the first to investigate the prognostic value of (NT-pro)BNP in
patients with PAH.
Methods A systematic literature search was performed using MEDLINE, Embase, Web of Science, the Cochrane Library
and Google scholar to identify studies on the prognostic value of baseline (NT-pro)BNP levels in PAH. Studies reporting hazard
ratios (HR) for the endpoints mortality or lung transplant were included. A random effects meta-analysis was performed to
calculate the pooled HR of (NT-pro)BNP levels at the time of diagnosis. To account for different transformations applied to
(NT-pro)BNP, the HR was calculated for a 2-fold difference of the weighted mean (NT-pro)BNP level of 247 pmol/L, for studies
reporting a HR based on a continuous (NT-pro)BNP measurement.
Results Sixteen studies were included, representing 6999 patients (mean age 45.2-65.0 years, 97.3% PAH). Overall,
1460 patients reached the endpoint during a mean follow-up period between 1 and 10 years. Nine studies reported HRs
based on cut-off values. The risk of mortality or lung transplant was increased for both elevated NT-proBNP and BNP with a
pooled HR based on unadjusted HRs of 2.75 (95%-CI: 1.86-4.07) and 3.87 (95% CI 2.69-5.57) respectively. Six studies
reported HRs for (NT-pro)BNP on a continues scale. A 2-fold difference of the weighted mean NT-proBNP resulted in an
increased risk of mortality or lung transplant with a pooled HR of 1.17 (95%-CI: 1.03-1.32).
Conclusions Increased levels of (NT-pro)BNP are associated with a significantly increased risk of mortality or lung
transplant in PAH patients. (Am Heart J 2022;250:34–44.)

Key words: Pulmonary arterial hypertension; Pulmonary hypertension; BNP; NT-proBNP; Prognosis

Pulmonary arterial hypertension (PAH) is an uncom- lar remodelling which leads to an increase in pulmonary
mon disease that is characterized by pulmonary vascu- vascular resistance (PVR) resulting in an increased pul-
monary arterial pressure. This will eventually cause right
ventricular failure. The prognosis of patients with PAH is
From the a Department of Cardiology, Erasmus University Medical Center, Rotterdam,
The Netherlands, b Department of Respiratory medicine, Erasmus University Medical primarily related to this progressive decline in right ven-
Center, Rotterdam, The Netherlands, c Department of Cardiology, St. Antonius Hospital, tricular function.1 , 2
Nieuwegein, The Netherlands, d Department of Cardio-thoracic surgery, Erasmus Uni-
versity Medical Center, Rotterdam, The Netherlands, e Medical Library, Erasmus Univer-
The survival rate of PAH is poor with a 5 years survival
sity Medical Center, Rotterdam, The Netherlands, f Department of Clinical epidemiology, after diagnosis varying around 60% despite PAH specific
Erasmus University Medical Center, Rotterdam, The Netherlands, g Department of Cardi-
ology, Utrecht University Medical Center, Utrecht, The Netherlands
medical treatment.3-6 Treatment options include support-
Abbreviations: BMI, Body mass index; BNP, Brain natriuretic peptide; PAH, Pulmonary ive therapy (e.g. oxygen therapy), PAH specific drugs and
arterial hypertension; PVR, Pulmonary vascular resistance; mPAP, Mean pulmonary arterial lung transplant.7 Multiple blood biomarkers have been
pressure; NT-proBNP, N-terminal pro hormone brain natriuretic peptide; NYHA, New York
Heart Association. investigated for the risk prediction of patients with PAH.
Submitted January 12, 2022; accepted May 4, 2022
Reprint requests: Annemien E. van den Bosch, MD, PhD, Erasmus University Medical
Centre, Department of Cardiology, Room RG-433, P.O. box 2040, 3000 CA, Rotterdam, © 2022 The Authors. Published by Elsevier Inc.
The Netherlands. This is an open access article under the CC BY license
E-mail address: a.e.vandenbosch@erasmusmc.nl. (http://creativecommons.org/licenses/by/4.0/)
0002-8703 https://doi.org/10.1016/j.ahj.2022.05.006
American Heart Journal
Volume 250
Brain natriuretic peptides remain the most promising
blood biomarkers. N-terminal-pro hormone brain natri-
uretic peptide (NT-proBNP) or brain natriuretic peptide
(BNP) are secreted by cardiomyocytes due to excessive
stretching of the ventricles. In PAH, as in other forms
of PH, increased myocardial stress and right ventricular
hypertrophy due to an increase in PVR and pulmonary
arterial pressure might cause a rise in (NT-pro)BNP.8
The overall treatment goal is achieving a clinically sta-
ble situation with a low risk of mortality.7 Multiple risk
stratification tools are developed to assess the risk of
mortality in patients with PAH. The ERS/ESC guidelines
provide a risk assessment tool, including 9 clinical pa-
rameters, that stratifies patients in different risk cate-
gories based on the 1-year mortality rate.7 These vari-
ables are also the basis of the risk assessment strategy
developed by the Prospective Registry of Newly Initiated
Therapies for Pulmonary Hypertension, the Swedish PAH
Register and the French Pulmonary Hypertension Reg-
istry.9-11 Other validated risk prediction tools have also
been developed, such as the Registry to Evaluate Early
and Long-term Pulmonary Arterial Hypertension Disease
Management (REVEAL) risk score and the REVEAL risk
score 2.0.12 , 13 More recently, the REVEAL Lite 2.0 risk
score has been developed. It uses 6 non-invasive charac-
teristics including (NT-pro)BNP. This risk score demon-
strated good discrimination between high risk and low
risk patients and showed that the discriminative power
improved when patients with missing (NT-pro)BNP were
excluded from analysis.14 Clinicians can use these risk as-
sessment tools to monitor PAH patients in clinical prac-
tice. Plasma (NT-pro)BNP levels are part of all of these
risk stratification tools.
To our best knowledge, no systematic review of the evi-
dence for the prognostic value of (NT-pro)BNP on mortal-
ity has been performed yet, despite the widely accepted
position of (NT-pro)BNP in the risk stratification of pa-
tients with PAH. The aim of this systematic review and
meta-analysis is to determine the prognostic value of NT-
proBNP and BNP on mortality or lung transplant at the
time of diagnosis in patients with PAH.
Methods
This systematic review was performed according to the
PRISMA statement for reporting systematic reviews and
meta-analyses and the MOOSE guidelines.15 , 16 The pre-
defined study protocol was registered in PROSPERO in
2021 (registration number: CRD42021224963).
Search strategy
An exhaustive search strategy was developed by an ex-
perienced information specialist (SG). The search was
carried out in the databases Embase.com (date of in-
ception 1971), Medline ALL via Ovid (1946 to Daily
Update), Web of Science Core Collection (Science Ci-
Hendriks et al 35
tation Index Expanded (1975-present); Social Sciences
Citation Index (1975-present); Arts & Humanities Cita-
tion Index (1975-present); Conference Proceedings Cita-
tion Index- Science (1990-present); Conference Proceed-
ings Citation Index- Social Science & Humanities (1990-
present) and Emerging Sources Citation Index (2015-
present) and the Cochrane Central Register of Controlled
Trials via Wiley (date of inception 1992). Additionally, a
search was performed in Google Scholar from which the
200 most relevant references were downloaded using the
software Publish or Perish. After the original search was
performed in December 2020, the search was last up-
dated on May 11, 2021. The full search strategies of all
databases are available in supplementary file 1.
End points
The primary end point included in this systematic re-
view is mortality (all-cause mortality, cardiovascular mor-
tality or cardiopulmonary mortality), if reported as a sin-
gle endpoint. If mortality was not reported as a single
endpoint, the composite endpoint of mortality or lung
transplant was also included. Studies using a compos-
ite endpoint including endpoints other than mortality or
lung transplant were excluded to limit heterogeneity.
Study selection
Duplicates were removed from the database. Two au-
thors (PH and LG) independently screened the remain-
ing titles and abstracts for eligibility using predefined se-
lection criteria stated in Table I. Following the title and
abstract screening, the same 2 authors performed full-
text screening using the same selection criteria. Discor-
dances were resolved by consensus. All references of in-
cluded articles were manually searched for possible rele-
vant studies missed by the search syntax.
Quality assessment
All included full-text articles were critically assessed
for study quality by the first 2 authors using the QUIPS-
tool developed by Hayden et al.17 We assessed (1) study
participation, (2) study attrition, (3) prognostic factor
measurement, (4) outcome measurement, (5) study con-
founding, and (6) statistical analysis and reporting. Arti-
cles with a high risk of bias in one domain or moderate
risk of bias in 3 or more domains were excluded.
Data extraction
Data of the included articles were independently ex-
tracted by the first 2 authors using a predefined standard-
ized electronic extraction file based on the CHARMS-PF
checklist.18 The following characteristics were extracted
from each article: study design, number of participants,
age, sex, BMI, NYHA class, WHO classification, treat-
ment type, follow-up duration, type of biomarker, (NT-
pro-)BNP levels, renal function, analyzing assay, cut-off

36 Hendriks et al
Table I. Inclusion and exclusion criteria.
Inclusion
Population
Pulmonary arterial hypertension, (WHO class 1)
Biomarker
NT-proBNP,
BNP
Endpoint
All-cause mortality,
Cardiopulmonary mortality,
Composite endpoint of mortality or lung transplant
Outcome measurements
HR obtained by univariable cox-PH regression,
HR obtained by multivariable cox-PH regression
Publication type
English language,
Full text available
ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; HR, hazard ratio.
values and HR with accompanying 95% confidence inter-
vals. Corresponding authors were contacted when the
univariable or multivariable HR were not reported. Stud-
ies were excluded if additional information could not be
provided.
Statistical analysis
The interrater reliability for inclusion was evaluated
using the Cohen statistic K.19 Meta-analysis was per-
formed using random effects meta-analytic models with
weighted estimation by inverse-variance weights. Be-
tween study variance was estimated using restricted
maximum likelihood.20 , 21 A pooled crude unadjusted HR
was calculated based on reported univariable HRs. The
adjusted pooled HR was calculated based on multivari-
able HRs reported in the articles. Studies reporting mul-
tivariable cox-PH models containing more than one co-
variate per ten events were considered to be overfit and
were therefore excluded from our analyses of multivari-
able HRs.22 Separate meta-analyses were performed for
both BNP and NT-proBNP and for both dichotomously re-
ported HRs and HRs based on a continuous measurement
scale. Different types of statistical transformation are ap-
plied to (NT-pro)BNP across studies which influence the
HRs based on continuous measurements (e.g. HR per lo-
gunit, per 1000 pg/ml, per 2logunit increase). To be able
to compare and pool the results, we calculated for each
study with a HR based on a continuous measurement, the
HR for a 2-fold difference of the weighted (NT-pro)BNP
levels. The weighted mean (NT-pro)BNP was calculated
American Heart Journal
August 2022
Exclusion
Postcapillar y pulmonar y hypertension (WHO class 2),
Pediatric studies,
Animal studies
Atrial natriuretic peptides
All other composite endpoints
Multivariable HR obtained by overfitted cox-PH models
Non-English language,
Full text unavailable,
Conference abstracts
of all included studies based on the reported mean (NT-
pro)BNP levels and the number of study participants. In
the meta-analyses these calculated HRs based on a 2-fold
difference were pooled to ensure all HRs represent the
same difference on a continuous scale. Interstudy het-
erogeneity was assessed using Cochran’s Q and the I2 -
statistic. Publication bias was assessed by means of fun-
nel plots, the Egger’s test and Orwin’s fail safe N using
target log HRs of 0.1 and 0.05. Analyses were performed
using R version 4.0.5 (packages meta, metafor).
Funding
This research project was supported by an unrestrict-
ing research grant by Johnson & Johnson - Actelion phar-
maceuticals. The authors are solely responsible for the
design and conduct of this study, all study analyses, the
drafting and editing of the paper and its final contents.
Results
Our search strategy identified 2912 records after dupli-
cates were removed (Figure 1). We excluded 2860 arti-
cles based on title and abstract screening. Fifty-two arti-
cles were carefully read in full text after which 16 stud-
ies were included in our systematic review and meta-
analysis.11 , 23-35 The Cohen statistic K for agreement on
study inclusion was 0.84. The excluded studies with de-
tailed reason of exclusion are presented in Supplemen-
tary Table I. Twelve corresponding authors were con-
tacted for essential missing data, one provided the nec-
essary information.
American Heart Journal
Volume 250
Figure 1
Flowchart showing the process of inclusion of publications.
Study characteristics
The studies included in this systematic review were
published between 2006 and 2020. Six of the fourteen ar-
ticles had a prospective study design. A total of 6999 pa-
tients with (NT-pro)BNP measurements were included.
The mean age ranged from 41-65 years and 53% to
80% was female. Of all patients 97.2% was diagnosed
with PAH (WHO class 1). The mean follow-up differed
between 1 and 10 years after diagnosis. During this
follow-up period, 1421 patients died and 39 underwent
lung transplant. The weighted mean NT-proBNP was 248
pmol/L. Other patient and study characteristics are sum-
marized in Table II. Methodological assessment of each
included article is presented in Supplementary Table II.
Hendriks et al 37
Twelve studies reported a univariable HR (Supplemen-
tary Table III). Four studies reported a HR for BNP and
ten studies reported a HR for NT-proBNP. Ten studies
used a dichotomous cut-off point, 5 studies used a contin-
uous difference. Fifteen studies reported a multivariable
cox model. Three of these studies were excluded from
the analysis because they reported overfitted multivari-
able cox proportional hazards models.36-38 Three studies
reported a HR for BNP and eleven for NT-proBNP. Eight
studies reported a dichotomous cut-off value and 6 were
based on a continuous difference. All reported HRs are
based on measurements performed at the time of diagno-
sis. Details of assays used for (NT-pro)BNP measurements
and cut-off values are shown in Supplementary Table IV.
 38 Hendriks et al
Table II. Characteristics of included studies.

First author, Year Study Study WHO NYHA class III NT-proBNP BNP level BMI Renal function PAH specific Mean or End point
design population classification or IV (%) level medication median
follow-up in
years

Andreassen, P N: 61 1: 40 (66%) 95 266 ± 274 - NR NR NR 2.0 ± 1.5 Cardiopulmonary

200624 Age: 47.2 4: 19 (31%) pmol/L mortality (n = 15)
±15.5 5: 2 (3%)
Female: 69%
Benza, 201025 P N: 2716 1: 2716 49 1455 ± 3296 286 ± 530 NR Renal ERA: 1231 1.4 All-cause mortality
Age: 50.4 ± (100%) pg/ml pg/mL insufficiency: (46,9%) (n = 340)
16.8 104 (4%) PDE5-i: 1301
Female: 79% (49,6%)
Prostacyclines:
1095 (41,6%)
Boucly, 201712 R N: 603 1: 603 74 NR - 27.8 ±7 NR ERA: 307 (30%) 2.8 All-cause mortality
Age: 57 ±17 (100%) PDE5-i: 151 (1.3-4.7∗ ) or lung transplant
Female: 59% (15%) (n = 269)
Prostacyclines: 9
(1%)
Duijnhouwer, P N: 217 1: 175 (81%) 71 1587 - BSA: 1.80 NR NR 4.1 All-cause mortality
202026 Age: 65 4: 42 (19%) (341-4048∗ ) (1.64-1.94) (n = 85)
(51-73∗ ) pg/ml
Female: 69%
Fijalkowska, P N: 55 1: 50 (91%) NR 1674 - NR NR ERA: 7 (13%) 2.1 ± 0.9 All-cause mortality
200637 Age: 41 ± 4: 5 (9%) (51-1951∗ ) PDE5-i: 10 (18%) (n = 16)
15.1 pg/mL Prostacyclines: 36
Female: 76% (65%)
Geenen, 201928 P N: 106 1: 54 (51%) 54 205.0 - 28.2 ± 6.5 eGFR <30 NR 3.3 All-cause mortality
Age: 59 3: 15 (14%) (87.9-407.0∗ ) ml/min/1.73 (2.3-4.6∗ ) or lung transplant
(47-69∗ ) 4: 21 (20%) pmol/L m2 : 3 (2.8%) (n = 29)
Female: 64% 5: 16 (15%)
Helgeson, 2018 R N: 138 1: 138 71 - 406 ± 443 27.9 ± 8.4 eGFR <50 Oral PAH med: 10 All-cause mortality
29
Age: 59.2 ± (100%) pg/mL ml/min/1.73 46 (33%) (n = 63)
13.6 m2 : 0 (-) Prostacyclines
Female: 75% inh./i.v.: 23
(17%)
Lim, 201938 P N: 148 1: 148 NR 2318.5 ± - NR NR ERA: 3 (3%) 10 All-cause mortality
Age: 50.8 ± (100%) 4381.3 PDE5-i: 60 (54%) (n = 67)
15.9 Prostacyclines: 1
Female: 77% (1%)

American Heart Journal

sGC stimulators: 1
(1%)
Combination: 36

August 2022
(32.4%)
(continued on next page)
 Volume 250
American Heart Journal
Table II. (continued)

First author, Year Study Study WHO NYHA class III NT-proBNP BNP level BMI Renal function PAH specific Mean or End point
design population classification or IV (%) level medication median
follow-up in
years

Maurer, 202030 R N: 65 1: 65 (100%) 41 1838 ± 2088 - NR Creatinine: NR 4.2 All-cause mortality

Age: 45.2 ± ng/L 80.0 ± 22.9 (1.2-7.5∗ ) (n = 16)
6.8 µmol/L
Female 68%
Mauritz, 201131 R N: 198 1: 198 59 6818 - NR NR NR 3.2 ± 1.9 All-cause mortality
Age: 54 ±17 (100%) (287-3039∗ ) (n = 54)
Female: 53% pg/L
Nickel, 201232 R N: 109 1: 109 NR 1292 - NR Creatinine: ERA: 33 (30%) 3.2 All-cause mortality
Age: 55 (100%) (300-3510∗ ) 80.0 (68-96) PDE5-i: 51 (47%), (2.1-5.8∗ ) or lung transplant
(42-68∗ ) ng/L µmol/L Prostacyclines: 25 (n = 57)
Female: 72% (23%)
Radchenko, R N: 281 1: 229 (81%) 75 1360.3 ± - 25.4 ± 7.4 Creatinine: PDE5-i: 143 1.9 ± 1.2 All-cause mortality
201933 Age: 45.5 ± 4: 52 (19%) 240.6 pg/mL 85.2 ± 24.9 (51%), (n = 31)
14.3 µmol/L Prostacyclines: 70
Female: 74% (25%)
Combination: 66
(23%)
Rhodes, 201134 R N: 139 1: 139 73 909 ± 849 - NR Creatinine: 96 ERA: 64 (46%) 4.0 ± 2.4 All-cause mortality
Age: 47.6 ± (100%) fmol/mL ± 30 µmol/L PDE5-i: 22 (16%) (n = 49)
15.8 Prostocyclines: 12
Female: 70% (9%)
Roy, 201435 P N: 90 1: 71 (79%) 35 - 63.6 NR Creatinine: ERA: 52 (48,1%) 2.4 ± 1.0 All-cause mortality
Age: 55.2 4: 19 (21%) (22.1-250.3∗ ) 92.0 ± 27.9 PDE5-i: 33 (n = 33)
±15.7 pg/mL µmol/L (30.6%)
Female: 71% Prostacyclines: 15
(13,9%)
Simpson, 202036 R N: 2017 1: 2017 63 672 - NR NR ERA: 1205 (60%) 1 All-cause mortality
Age: 55 ±15 (100%) (217-2164∗ ) PDE5-i: 1546 (n = 324)
Female: 80% pg/mL (77%),
Prostacyclines:
699 (35%)
Torbicki, 200339 P N: 56 1: 51 (91%) NR 2923 ± 4794 - NR NR Calcium 1.4 ± 0.7 All-cause mortality
Age: 41 ± 15 4: 5 (9%) antagonist: 15 (n = 12)
Female: 77% (27%)
ERA: 7 (13%)

Hendriks et al 39
Prostacyclines: 37
(66%)
ERA, endothelin receptor antagonist; NR, not reported; NYHA, New York heart association; P, prospective; PAH, pulmonary arterial hypertension; PDE5-I, phospodiesterase-5 inhibitor; R, retrospective; WHO, world health
organization.
∗
Interquartile range.

40 Hendriks et al
Figure 2
Meta-analysis calculating the pooled hazard ratio of hazard ratios based on dichotomous cut-off values. Abbreviations: BNP, brain natriuretic
peptide; CI: confidence interval; NT-proBNP: N-terminal prohormone of brain natriuretic peptide; RE: random effects.
Outcome data
All included studies systematically showed an associa-
tion between (NT-pro)BNP and mortality or lung trans-
plant. Nine studies reported a HR based on a dichoto-
mous cut-off of NT-proBNP (Figure 2). Meta-analysis
shows a significantly increased risk of mortality or lung
transplant with an unadjusted pooled HR of 2.75 (95% CI:
1.86-4.07) and adjusted pooled HR of 2.51 (95% CI: 1.52-
4.14). Four studies reported a HR based on a dichoto-
mous cut-off of BNP (Figure 3). Pooling of these effects
resulted in an unadjusted pooled HR of 3.87 (95% CI:
2.69-5.57) and adjusted pooled HR of 2.39 (95% CI: 1.49-
3.82).
Of the 7 studies investigating the prognostic effect of
(NT-pro)BNP using a continuous scale, 6 used NT-proBNP
and one used BNP. A 2-fold difference in NT-proBNP re-
sulted in a significantly increased risk of mortality or lung
transplant with an unadjusted pooled HR of 1.17 (95% CI:
1.03-1.32) and adjusted pooled HR of 1.19 (1.08-1.32).
The HR observed in the single study investigating BNP
was 1.15 (95% CI: 1.06-1.23).
Publication bias was assessed using Funnel plots, Eg-
ger’s test and Orwin’s fail safe N. The results of these
analyses are presented in Supplementary Table V. Both
the Egger’s test and funnel plots imply the presence
of publication bias in some analyses. However, Orwin’s
fail safe N is >20 at a target log HR of 0.05 in all
analyses.
American Heart Journal
August 2022
Discussion
This systematic review and meta-analysis demonstrated
a significantly higher risk of mortality or lung transplant
with elevated levels of (NT-pro)BNP at the time of diag-
nosis. This highlights the importance of the use of (NT-
pro)BNP as a prognostic marker and endorses the impor-
tance of brain natriuretic peptides in the risk stratifica-
tion of patients with PAH. Patients with a higher (NT-
pro)BNP at the time of diagnosis, have a significantly de-
creased survival.
In PAH, increased myocardial stress, volume overload,
hypoxia and pro-inflammatory cytokines may result in
transcription of the NPPB gene, eventually leading to the
production of BNP.39 Circulating BNP binds to the na-
triuretic peptide receptor A that induces vasodilatation,
natriuresis and decreased aldosterone activity.39 Multi-
ple studies demonstrated correlations between circulat-
ing BNP and NT-proBNP levels and pulmonary hemody-
namics in PAH: NT-proBNP levels correlate with mPAP,
PVR, right atrial pressure and cardiac index.39-42 Changes
in NT-proBNP levels have also shown to correlate with
changes in pulmonary hemodynamics.41 , 42 An increase
of (NT-pro)BNP levels may reflect right ventricular re-
modeling leading to impaired right ventricular systolic
function.40 , 41
Besides pulmonary hypertension, there are multiple
other factors that can lead to elevated (NT-pro)BNP lev-
els. Myocardial stress can also be caused by left heart dis-
American Heart Journal
Volume 250
Figure 3
Meta-analysis calculating the pooled hazard ratio for mortality of hazard ratios based on continuous measurements. Hazard ratios represent
a 2-fold difference of the weighted mean (NT-pro)BNP at baseline. Abbreviations: BNP, brain natriuretic peptide; CI: confidence interval;
NT-proBNP: N-terminal prohormone of brain natriuretic peptide; RE: random effects.
ease including left ventricular dysfunction, left ventric-
ular hypertrophy and left heart failure.39 , 43 Extra-cardiac
disease like impaired renal function will also increase the
levels of (NT-pro)BNP. Furthermore, (NT-pro)BNP levels
are inversely correlated with obesity, diabetes mellitus
and metabolic syndrome.39 , 44 Demographic factors such
as female gender and increased age are also associated
with higher levels of (NT-pro)BNP.39 , 44 This might be an
argument to opt for age and sex standardized normal
values of (NT-pro)BNP. In this systematic review we ex-
tracted data on renal function and BMI. Unfortunately,
not all included studies provided these data. The studies
that did report on renal function and BMI showed normal
renal function and BMI in the vast majority of patients.
Even though it was not possible to perform a subanalysis
on patients with normal renal function and normal BMI,
we expect the possible introduced bias by these patients
to be very limited.
In this meta-analysis we focused on the prognostic
value of (NT-pro)BNP at the time of diagnosis. Some
studies also demonstrated that an increase of NT-proBNP
over time is associated with an increased risk of mortal-
ity.30 , 31 Mauritz et al. investigated serial NT-proBNP mea-
surements after diagnosis and initiation of PAH-specific
medical treatment. They showed that a decrease of 15%
of NT-proBNP per year was associated with improved sur-
vival. They also found that extrapolating the baseline NT-
proBNP level based on follow-up NT-proBNP measure-
ments was a better discriminative factor between sur-
vivors and non-survivors than the measured value of NT-
Hendriks et al 41
proBNP at baseline itself.30 This highlights that not only
the baseline levels of (NT-pro)BNP might be important
in the risk stratification of PAH-patients, but that (NT-
pro)BNP measurement during follow-up is also impor-
tant in the continuous risk assessment of patients with
PAH.
Geenen et al. investigated multiple biomarkers in pa-
tients with pulmonary hypertension.27 They demon-
strated that the use of a panel of 6 blood biomarkers was
able to discriminate well between high and low risk pa-
tients. This multi-biomarker approach improved the pre-
dictive value of NT-proBNP on transplant free survival. A
multi-biomarker approach in the risk stratification of PAH
poses an interesting prospect for the future and requires
more research.
Measurements of (NT-pro)BNP are implemented in
multiple risk stratification tools for patients with PAH like
the ESC/ERS-guidelines, the REVEAL-risk score and the
French registry.7 , 12 , 45 These meta-analyses showed that
indeed, (NT-pro)BNP should be a cornerstone of identi-
fying high-risk patients. The ERS/ESC guideline does not
distinguish between the use of NT-proBNP or BNP. Both
peptides are cleared by the kidney, but NT-proBNP is
more stable with a half-life of 70 minutes as compared
to BNP with 22 minutes. It has been demonstrated that
NT-proBNP performed slightly better in comparison to
BNP in prognostic models for chronic heart failure.46
There are several limitations regarding this study. First
of all, there is noticeable heterogeneity across studies

42 Hendriks et al
regarding the study population, assays used for (NT-
pro)BNP measurement and used cut-off values. Despite
this heterogeneity, all studies show a systematic asso-
ciation between (NT-pro)BNP at the time of diagnosis
and mortality or lung transplant. Several studies were
excluded from the meta-analysis using adjusted HRs be-
cause they used an overfitted cox-PH model. This might
lead to a loss of evidence, however calculations based
on an overfitted cox-PH model may be biased and the
95%-confidence intervals may not be reliable. Exclud-
ing these studies does ensure pooling of only appro-
priately calculated multivariable HRs.22 The funnel plots
and Egger’s test are suggestive of publication bias in the
analysis of the adjusted HR based on dichotomous NT-
proBNP values and the unadjusted HR based on contin-
uous NT-proBNP levels. However, when interpreting the
Orwin’s fail safe N, there has to be a substantial amount
of publications missed by our search syntax to nullify
the significant effect of (NT-pro)BNP on the prognosis of
PAH. Since the used search strategy represented a broad
search of the literature, it is very unlikely that possible
unpublished articles will change the main outcome of
this systematic review. It is possible that the extent of
the relationship between (NT-pro)BNP and mortality or
lung transplant could not be determined exactly for these
analyses. However, it is very unlikely that the main asso-
ciation between mortality or lung transplant changes due
to possible publication bias.
Future perspective
The measurement of (NT-pro)BNP is widely available
and well known to physicians. We demonstrated that the
level of (NT-pro)BNP at the time of diagnosis provides
major prognostic insight in patients with PAH. Since the
population of PAH patients is becoming more and more
heterogeneous, (NT-pro)BNP may be of value to help dis-
criminate between high and low risk patients at baseline.
In the future, more research is needed to evaluate the
value of (NT-pro)BNP during follow-up, for example af-
ter treatment initiation. Several risk scores already exist,
but it would be interesting to evaluate whether the pre-
dictive value of (NT-pro)BNP can be improved by using a
multi-biomarker panel.
Conclusion
Based on our systematic review and meta-analysis NT-
proBNP and BNP are powerful predictors of mortality or
lung transplant in patients with PAH at the time of di-
agnosis. The measurement of (NT-pro)BNP should be a
cornerstone of clinical care and risk stratification in PAH.
Availability of data and material
The datasets generated and/or analyzed during the cur-
rent study are available from the corresponding author
on reasonable request.
American Heart Journal
August 2022
Conflict of interest
The authors declare that they have no conflict of inter-
est.
Funding
This research project was supported by an unrestrict-
ing research grant by Johnson & Johnson - Actelion phar-
maceuticals.
Supplementary materials
Supplementary material associated with this article can
be found, in the online version, at doi:10.1016/j.ahj.
2022.05.006.
CRediT authorship contribution
statement
Paul M. Hendriks: Conceptualization, Data curation,
Formal analysis, Writing – original draft, Writing – re-
view & editing. Liza D. van de Groep: Conceptualiza-
tion, Data curation, Formal analysis, Writing – original
draft, Writing – review & editing. Kevin M. Veen: For-
mal analysis, Writing – review & editing. Mitch C.J. van
Thor: Writing – original draft, Writing – review & edit-
ing. Sabrina Meertens: Data curation, Writing – origi-
nal draft. Eric Boersma: Formal analysis, Writing – re-
view & editing. Karin A. Boomars: Conceptualization,
Supervision, Writing – review & editing. Marco C. Post:
Conceptualization, Supervision, Writing – review & edit-
ing. Annemien E. van den Bosch: Conceptualization,
Supervision, Writing – review & editing.
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