Open Journal of Respi ratory Diseases, 2011, 1, 1-13
doi:10.4236/ojrd.2011.11001 Published Online August 2011 (
Copyright © 2011 SciRes. OJRD
H-FABP in Pre Capillary Pulmonary Hypertension:
Comparison to Other Surrogate Parameters for
Prediction of Severity and Outcome
Hagen Schroetter1, Michael Halank2, Dirk Stolte1, Peggy Barthel1, Gert Hoeffken2,
Ruediger C. Braun-Dulleaus3, Ruth H. Strasser1, Alexander Schmeisser3
1University of Techno logy Dresden , Medical Clinic and Cardiology, Heart Center Dresden,
University Hospital, Germany
2University of Techno logy Dresden , Medical Clinic/Pneumology, University Hospital, Germany
3Otto-von-Guericke University Magdeburg, Medical Clinic/Cardiol ogy, Pneumology an d Angi ology, Germany
Received August 8, 2011; revised August 19, 2011; accepted August 23, 2011
Background: Heart-type fatty acid-binding protein (H-FABP) is a promising novel biomarker for risk strati-
fication of patients with chronic thromboembolic pulmonary hypertension (CTEPH). Whether disease seve-
rity in a group of patients with pre capillary pulmonary hypertension (PH) can be predicted by determination
of plasma H-FABP levels remains unknown. Methods: 41 consecutive patients with a mean (±SD) age of
60.6 ± 2.1 years and severe PH were studied with a mean follow up to 541 days (95% CI: 420; 661 days).
H-FABP, but also the biomarkers NT-Pro-BNP and big-endothelin (Big-ET1), were correlated to parameters
derived from right sided cardiac catheterization and cardio-pulmonary exercise test. Results: At baseline
H-FABP levels ranged from 620 to 15200 pg/ml (3648 502 pg/ml) and were weakly but significantly cor-
related to VO2AT (r = 0.37, p = 0.04) and VO2 peak (r = 0.38, p = 0.03). However, invasively measured
hemodynamic parameters of PH and right ventricular dysfunction did not correlate with H-FABP levels. In-
terestingly, moderate to high correlations between H-FABP and NT-Pro-BNP (r = 0.51, p = 0.01) and
Big-ET1 (r = 0.65, p = 0.01) and between Big-ET1 and NT-Pro-BNP (r = 0.5, p = 0.01) could be observed.
In contrast to H-FABP, NT-Pro-BNP, and even more Big-ET1, showed significant correlations to different
invasively measured hemodynamic parameters of the disease indicating severity and consequently prognosis
of severe pre-capillary pulmonary hypertension. However, in a multivariate Cox regression analysis, PVR,
mixed venous oxygen saturation and the VE/VCO2 slope (>60) as well as the heart rate recovery within one
minute (HRR) but none of the biomarkers were identified as independent factors of poor prognosis. In con-
trast, peak workload and mixed venous saturation were identified as risk markers in the idiopathic pulmonary
arterial hypertension subgroup. Conclusions: In contrast to the predictive value of H-FABP in CTEPH
H-FABP fails to be a reliable marker in PH or to be a novel predictor of mid and long term outcome. The
data suggest that an increased slope of VE/VCO2 and a decreased extent of HRR within one minute represent
more promising diagnostic non invasive parameters.
Keywords: Human Fatty Acid Binding Protein, Biomarker, Pulmonary Hypertension, Prognosis
1. Introduction
Pulmonary arterial hypertension (PAH) is a progressive
disease with poor prognosis due to fatal right heart fail-
ure. The accurate assessment of prognosis in these pa-
tients is difficult. Moreover, the optimal timing for com-
bining medical therapy or planning invasive procedures
such as atrial septostomy or lung transplantation remains
controversial [1]. Worsening of invasively determined
hemodynamic indices of right ventricular dysfunction, a
poor functional status, or a low distance in 6 minute walk
test (6MWT) [2-4] may be indicative of severity and
prognosis of pulmonary hypertension. The estimate of
right ventricular systolic pressure derived from Doppler
sonography is helpful to screen patients with PH but was
found not to be predictive for outcome [5,6]. A variety of
atrial, ventricular, and Doppler parameters were sugges-
ted to be associated with an increased risk of death or
need for transplantation in patients with PAH [7,8].
However, the drawback of Doppler sonography is its
operator-dependency. Therefore, simple, non invasive,
easily accessible and quantitative parameters which are
repeatedly available and possibly quantitative methods to
detect PH patients are still needed. Such parameters are
of utmost value for follow up during therapy. Cardiac
biomarkers in plasma such as plasma brain natriuretic
peptide (BNP) or the N-terminal part of its pro-hormone
(NT-pro-BNP) appear to have promising potential [9]
[10]. Thus, it has been demonstrated that plasma BNP
levels increase in correlation with the degree of right
ventricular (RV) dysfunction and are well predictive for
the functional status of patients with idiopathic pulmo-
nary hypertension (IPAH) [11,12]. Consequently, high
levels of BNP at baseline, and in particular, a further rise
in plasma BNP during follow up of 3 months are inde-
pendent prognostic factors in these patients [13]. NT-
pro-BNP could be related with cardiopulmonary hemo-
dynamics in patients with idiopathic PAH and with poor
long term prognosis in an unselected patient population
with pre-capillary PH [14]. Recently, other heart bio-
markers reflecting myocardial injury, such as troponin or
H-FABP gained increasing interest. Fatty acid-binding
proteins (FABPs) are relatively small (15 KDa) cytosolic
proteins that are widely distributed and highly expressed
in tissues undergoing active fatty-acid metabolism, such
as the heart and the liver [15]. The H-FABP (heart-type
fatty acid-binding protein) isoform is one of the most
abundant proteins in myocardial tissue, representing 5% -
15% of the whole aqueous cytosolic protein pool of the
heart. H-FABP is truly cytosolic and has not been found
outside the cell or in plasma under normal conditions
[16]. The fact that H-FABP is a small protein, allows
rapid diffusion and release from the injured myocardium
resulting in a rapid increase in the plasma which suggests
the H-FABP may be a valuable and easily accessible
biomarker. This has qualified H-FABP as a rapid marker
for example in myocardial infarction [17]. Therefore, it
is conceivable that H-FABP may also be a reliable bio-
marker in other cardiac diseases with myocardial damage
such as pulmonary hypertension or acute pulmonary
embolism (PE). In fact, Puls et al. [18] and Kaczynsky et
al. [19] identified H-FABP as an early, highly sensitive
and specific indicator of death or serious complications
in acute PE. Moreover, recently, Lankeit et al. [20] as-
sessed the prognostic value of this biomarker in a large,
single center population of 93 consecutive patients with
CTEPH. The results indicate that H-FABP is more sensi-
tive than cardiac troponins in predicting an adverse out-
come in these settings. But, the prognostic value of
H-FABP was not compared to that of BNP and NT-
Pro-BNP, which are commonly used as biomarkers in
pulmonary hypertension [21]. Moreover, it is unknown
whether H-FABP is a parameter that can be applied as a
prognostic marker not only in CTEPH patients but also
in patients with chronic pulmonary artery hypertension
(PH) due to various diseases.
Therefore, in the present study, we addressed the
question if H-FABP may be used as a prognostic indica-
tor and marker for the severity of the disease with vari-
ous forms of chronic pre-capillary PH. Therefore patients
with different disease stages and on different therapeutic
regimens were investigated. In addition, the predictive
value of H-FABP was compared with other well estab-
lished biomarkers such as NT-pro-BNP, invasive hemo-
dynamic measures and the exercise tests CPET and 6
MWT in this patient group.
2. Materials and Methods
2.1. Inclusion and Exclusion Criteria
41 consecutive patients (18 male, 23 female), referred for
invasive hemodynamic evaluation for chronic pre-capil-
lary PH from June 2004 to February 2007, were evalu-
ated. According to the revised classification of PH, 27
patients had pulmonary arterial hypertension (PAH), 23
IPAH and 4 were associated with systemic sclerosis. In
addition, 8 patients had angiographically verified chronic
thromboembolic PH (CTEPH), 5 patients interstitial lung
disease associated pulmonary hypertension sarcoidosis
associated fibrosis (n = 1), connective tissue disease (n =
2), idiopathic pulmonary fibrosis (n = 2) and 1 patient
was in the miscellaneous group diagnosed as having
sarcoidosis without fibrosis associated pulmonary hyper-
tension. At baseline examination, 13 patients were treated
with bosentan alone, 6 with sildenafil and 2 patients with
both (Table 1). At the follow up visit, all but 2 patients
were medicated with the endothelin receptor antagonists
or sildenafil. In 2 patients, a combination therapy was
initiated. In 2 patients a specific therapy could not be
initiated due to various contra-indications, lack of com-
pliance, or multimorbidity with a very short expected life
Exclusion criteria were: Patients with pulmonary hy-
pertension due to congestive left heart failure, hypertro-
phic or restrictive cardiomyopathy or caused by severe
left sided valvular heart diseases, patients with life limit-
ing severe concomitant disea es such as malignant neo- s
Copyright © 2011 SciRes. OJRD
Copyright © 2011 SciRes. OJRD
Table 1. Hemodynamic, biomarker and CPET baseline characteristics of 41 patients with pre-capillary pulmonary hyperten-
sion of different cause regarding of adverse and not adverse outcome (medications: numbers within parenthesis indicates
medication before baseline examination and outside the parenthesis after the examination); ETBR = endothelin receptor
Variable All patients n = 41Adverses outcome n = 9No adverse outcome n = 32p value
Female n 23 3 20
Age (years) years 60.6 ± 2.1 59.0 ± 3.8 61.0 ± 2.5 0.67
6MWT m 282 ± 26 277 ± 21 283 ± 31 0.88
VO2peak ml/kg*min 11.7 ± 0.6 11.5 ± 0.5 11.7 ± 0.7 0.81
Work load max Watt 57 ± 4 50 ± 4 59 ± 4 0.09
VE/VCO2Slope 55.2 ± 2.5 62.5 ± 4.9 53.1 ± 2.8 0.12
Heart rate recovery bpm 10.4 ± 0.8 5.7 ± 0.6 11.5 ± 0.9 0.004
Bosentan/Sitaxentan 11 5 6
Sildenafil 8 2 6
PAmean mmHg 50.2 ± 1.9 46.0 ± 1.9 51.4 ± 2.4 0.24
PCWP mmHg 7.7 ± 1.0 5.8 ± 2.0 8.3 ± 1.2 0.3
TPG mmHg 42.6 ± 2.0 40.2 ± 2.0 43.4 ± 2.4 0.51
RAP mmHg 8.8 ± 0.9 8.0 ± 2.8 9.1 ± 0.9 0.63
RVEDP mmHg 13 ± 2 13 ± 1 13 ± 3 0.93
SaO2 % 90 ± 2 91 ± 2 88 ± 2 0.55
SvO2 % 55 ± 2 55 ± 2 54 ± 3 0.87
CO l/min 3.7 ± 0.2 3.7 ± 0.5 3.7 ± 0.2 0.99
PVR dyn*s*cm5 1029 ± 91 1006 ± 78 1036 ± 117 0.83
NTpro-BNP fmol/ml 1711 ± 198 1258 ± 242 1870 ± 248 0.18
Big-ET fmol/ml 0.84 ± 0.13 1.04 ± 0.41 0.79 ± 0.12 0.58
H-FABP pg/ml 3648 ± 502 4004 ± 1202 3548 ± 557 0.71
plasms, pregnancy or juvenile patients (<18 years). All
patients were informed and signed the written informed
consent. The study was approved by the local ethic
2.2. Six Minute Walk Test (6-MWT),
Cardiopulmonary Exercise Test (CPET)
and Hemodynamic Evaluation
For evaluation of endurance, all patients performed a
6-MWT according to the American Thoracic Society
guidelines [22] at first. All patients underwent a cardio-
pulmonary exercise test (using the incremental cycling
test method, upright cycle ergometer, ramp rate 5 to 15
watts per min, Schiller co., Germany). Transnasal respi-
ration was avoided using a nose clip resulting in inspira-
tion of room air via a mouthpiece with a two way valve.
Standard 12 channel ECG tracings were monitored at
rest, at one minute intervals and during the exercise and
the recovery period. After an adoption period of 3 minu-
tes of unloaded cycling, patients cycled under an increas-
ing load until a symptom-limited maximum was attained.
Various parameters were measured continuously. Heart
rate, systolic and diastolic blood pressure, respiratory
minute volume (VE in litre), ventilatory oxygen uptake
(VO2) at anaerobic threshold (AT) and at exertion maxi-
mum (peak), respiratory carbon dioxide delivery (VCO2)
and calculated data such as respiratory quotient (RQ);
respiratory efficacy (VCO2Slope), the oxygen pulse at
anaerobic threshold, and peak load (O2HRAT, O2HR
peak in ml) were monitored. Within 24 to 48 hours after
CPET/6MWT the diagnostic right heart catheterization
was performed while patients were in stable condition
during hospitalization. Baseline hemodynamic variables
including mean pulmonary arterial pressure (MPAP),
mean right atrial pressure (RAP), pulmonary capillary
wedge pressure (PCWP), and RV end-diastolic pressure
(RVEDP) were measured. Cardiac output (CO) was
measured by Fick’s method. Total pulmonary resistance
(PVR) was calculated by dividing mean pulmonary arte-
rial pressure by cardiac output, the resistance index (RI)
was calculated by the ratio of PVR and SVR.
2.3. Biomarker Testing
Central venous blood samples were collected at the time
of the initial right heart diagnostic catheter. Samples
were immediately stored at 80˚C until analysis ensuring
a single thaw for all consecutive samples from a single
Human-FABP was measured in serum using an
ELISA Test Kit based on the sandwich principle (HyCult
Biotechnology, Uden the Nederlands). The minimum
detection level for H-FABP was 250 pg/ml with mea-
surable concentrations up to 25.000 pg/ml. Serum NT-
Pro-BNP was determined, as well (Enzyme immunoas-
say, Biomedica, Austria). The minimum detection level
was 5 fmol/ml at 95% B/Bo. The absorbance was mea-
sured at 450nm. Big endothelin (BigET1) was measured
by an enzyme immunoassay for the quantitative deter-
mination of human big endothelin in EDTA plasma. The
detection limit was 0.025 - 0.05 fmol/ml and reached a
range between 0.025 - 25 fmol/ml. The cross reactivity
with ET1/2/3 and Big-ET2 is <1% (Enzyme immunoas-
say, Biomedica, Austria, The invest-
tigator who quantified the biomarker levels was blinded
for hemodynamic parameters of the patient or the clinical
course. Biomarker levels were not used to guide patient
management or to monitor the effects of treatment during
the initial hospital stay or at any time during the follow
up period.
2.4. Survival Estimates
Survival was estimated from the date of blood sampling
to March, 31, 2008, or cardiopulmonary death or lung
transplantation with a follow up rate of 100%.
2.5. Statistical Analysis
Based on the test result of equal distribution by the Kol-
mogorow-Smirnow test, the baseline characteristics of
survivors and non survivors were compared with the
execution of the two-sided t-test for all continuous, met-
ric scaled variables. All data were described by arithme-
tic mean SEM. Bivariate correlations between metric
scaled groups were recorded by Pearson’s coefficient r.
The Spearman rank correlation (rho) test was performed,
if at least one of the variables was non parametric. A
coefficient value between 0.2 and 0.5 [–0.2 and –0.5],
respectively, was regarded as a weak, a r or rho between
0.5 and 0.7 (–0.5 and –0.7 respectively) as a moderate
At march 31, 2008 data of vital status or date of death
from any cause or heart-lung transplantation (HLTx), the
combined end point, were assessed. Event (or censoring)
times for all patients were measured from the time of
study inclusion (time zero). All patients were evaluated
at the end of the follow up. To estimate the correlation of
biomarkers to survival, differences between groups with
normal or low marker levels vs. elevated marker levels
were determined by the log-rank statistic and the time to
the end point plotted according to Kaplan-Meier method.
First, all hazard ratios for death or HLTx were measured
unadjusted for covariates, followed by the use of Cox
proportional regression models for survival adjustment
for age, gender, specific pulmonary vasoreactive medica-
tion at baseline or specific therapy extension during the
follow up period. Hazard ratios were reported with their
associated 95% confidence interval. Hazard ratios were
illustrated by Forest plots graphs. For all test results we
considered a two tailed p 0.05 significant.
Statistical analysis was performed with SPSS for
Windows, release 11.5.
3. Results
During a mean follow up period of 541 days (95% CI
420; 661) 9 of 41 consecutive patients (22%) died of
cardiopulmonary cause or underwent lung transplanta-
tion (n = 4). Most of the patients who died (n = 6, 15%)
died in the first year after the baseline visit. (Figure 1).
Thereafter, the Kaplan-Meier survival curve levelled off
for the rest of the observation period.
3.1. Comparison of Characteristics of All
Patients with Pre-Capillary Pulmonary
At baseline, the characteristics of the patients with ad-
verse outcome compared to those without adverse out-
Copyright © 2011 SciRes. OJRD
Figure 1. Kaplan-Meier survival curve in PH patients. The
graph represents the survival with a maximum observation
time of 1159 days.
come did not differ significantly. Also there was no sig-
nificant difference in the use of medications. At baseline,
neither the distance of the 6 minute walk test, VO2peak,
VE/VECO2 Slope nor RA mean, the PVR or cardiac
output were able to discriminate between the two groups
(Table 1). Moreover, no difference was found in the se-
rum levels of the biomarkers NT-pro BNP, Big-ET and
H-FABP. Only the heart rate recovery within the first
minute after stress test was significantly delayed in pa-
tients with adverse outcome compared to patients with-
out adverse outcome (5.7 ± 0.6 bpm vs. 11.5 ± 0.9 bpm,
p = 0.004; Table 1). The maximal work load showed
only a trend toward lower values in patients with adverse
outcome (p = 0.09).
Comparison of characteristics of the selected IPAH
group of patients with adverse and without adverse out-
come In the group of 23 IPAH patients 6 patients died
(26%) of cardiopulmonary causes, and four patients un-
derwent a lung transplantation during the follow up pe-
riod. Patients with no adverse outcome had faster heart
rate recovery within the first minute after stress test (11 ±
1 vs. 5.6 ± 0.7 bpm, p = 0.01) and reached a higher
maximal work load (63 ± 0.5 vs. 45 ± 3 Watt, p = 0.01).
In right heart catheter survivors had a PCWP within the
normal range but significantly higher than patients with
an adverse outcome (8 ± 1 vs. 3 ± 1 mmHg, p = 0.04).
The arterial oxygen saturation was significantly higher in
the survivor group, too (92 ± 1 vs. 87 ± 1 %, p = 0.03)
(Table 2). Also in IPAH patients, V02peak, VE/VECO2
slope, RAP, PVR or cardiac output failed to discriminate
between those with or without adverse outcome. Simi-
larly, the serum levels of the biomarkers NT-pro BNP,
Big-ET and H-FABP could not indicate the risk of pa-
tients for worsening right heart failure or death (Table
3.3. Correlation of the H-FABP with Exercise
(CPET), Hemodynamic Parameters and
with Other Biomarkers (NT-Pro BNP,
Big-ET) in All Patients with
Pre-Capillary PH
3.3.1. CPET
At baseline evaluation, H-FABP levels in plasma ranged
from 620 to 15200 pg/ml (3648 502 pg/ml) and were
weakly correlated with VO2 AT (r = 0.37, p = 0.04) and
VO2 peak (r = 0.38, p = 0.03) (Table 3(a)).
3.3.2. Hemodynamic Parameters
Plasma H-FABP levels did not correlate with invasively
measured hemodynamic parameters of pulmonary hy-
pertension and right ventricular dysfunction. (Table 3(b)).
3.4. Bivariate Correlation of H-FABP with the
Biomarkers NT-Pro-BNP and Big-ET1
At the time of baseline evaluation, mean NT-Pro-BNP
levels were 1711 ± 198 fmol/ml and Big-ET 0.84 ± 0.13
fmol/ml (Table 1). Interestingly, we observed a moder-
ate correlation between H-FABP and NT-Pro-BNP (r =
0.51, p = 0.01). The correlation between H-FABP and
Big-ET was even closer (r = 0.65, p = 0.01). Big-ET and
NT-Pro-BNP were moderately associated with each an-
other (r = 0.5, p = 0.01; Table 3(a)). Like H-FABP, Big-
ET and NT-Pro-BNP correlated weakly with VO2 peak (r
= 0.39, p = 0.02 and r = 0.45, p = 0.03, respectively).
But in contrast to H-FABP, NT-Pro-BNP, and even more
Big-ET, showed significant correlations to invasively
measured hemodynamic parameters with known prog-
nostic significance (NT-Pro-BNP: RAP: r = 48, p = 0.02,
mixed venous saturation (SVO2) r = 0.64, p =< 0.001;
(Big-ET: MPAP: r = 0.41, p = 0.04; RI r = 0.53, p =
0.004; SVO2: r = 0.53, p = 0.002; RVEDP: r = 0.53, p =
0.001 and RAP: r = 0.73, p = 0.001).
3.5. Risk Estimates for Adverse Outcome
3.5.1. H-FABP in Comparison to NT-Pro-BNP and
The impact of these biomarkers on observed outcome
was assessed by Kaplan-Meier Analysis according to
median values of baseline. No relevant cut off values for
a significant prediction of death or transplantation were
dentified by ROC analysis of the analysed biomarkers. i
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Table 2. Hemodynamic, biomarker and CPET baseline characteristics of 23 patients with IPAH regarding of adverse and not
adverse outcome (medications: numbers within parenthesis indicates medication before baseline examination and outside the
parenthesis after the examination).
Subgroup of IPAH patients (n = 23)
Variable IPAH patients n = 23Adverses outcome n = 6No adverse outcome n = 17 p value
Gender female 13 2 11
Age (years) years 61.3 ± 2.5 55.8 ± 5.0 63.1 ± 2.9 0.22
6MWT m 319 ± 27 298 ± 8 323 ± 30 0.73
VO2peak ml/kg*min 12.0 ± 0.8 11.0 ± 0.5 12.3 ± 1.0 0.24
Work load max. Watt 59 ± 5 45 ± 3 63 ± 5 0.01
VE/VCO2Slope 56.7 ± 3.3 66.7 ± 2.6 53.9 ± 5.0 0.12
Heart rate recovery bpm 9.8 ± 1.0 5.6 ± 0.7 11 ± 1.0 0.01
Bosentan/Sitaxentan 7 3 4
Sildenafil 4 2 2
PAmean mmHg 48 ± 2 46 ± 2 49 ± 3 0.5
PCWP mmHg 7 ± 1 3 ± 1 8 ± 1 0.04
TPG mmHg 42 ± 2 43 ± 2 41 ± 3 0.69
RAP mmHg 7 ± 1 5 ± 2 8 ± 1 0.18
RVEDP mmHg 12 ± 2 10 ± 3 13 ± 2 0.34
SaO2 % 91 ± 1 87 ± 1 92 ± 1 0.03
SvO2 % 57 ± 2 54 ± 3 58 ± 2 0.38
CO l/min 3.7 ± 0.2 3.3 ± 0.2 3.8 ± 0.3 0.16
PVR dyn*s*cm5 998 ± 91 1058 ± 73 977 ± 122 0.7
NTpro-BNP fmol/ml 1667 ± 245 1272 ± 339 1799 ± 304 0.21
Big-ET fmol/ml 0.67 ± 0.14 0.84 ± 0.49 0.61 ± 0.12 0.84
H-FABP pg/ml 3010 ± 536 3259 ± 975 2928 ± 492 0.34
(Figure 2, Kaplan Meyer curve for NTproBNP not
shown). The multivariate, logistic forward stepwise Cox
regression analysis with death or HLTx as dependent
factors was adjusted for age, gender, specific pulmonary
vasoreactive medication at baseline or specific therapy
extension during the follow up period. Neither in unse-
lected patients with pre-capillary PH nor in the IPAH
group, plasma H-FABP demonstrated a significant pre-
dictive value for an adverse outcome (HR of 1,0 for an
increase by 1 pg/ml; 95%CI 0,99; 1,01). Surprisingly,
nearly the same results were obtained after analysis of
NT-Pro-BNP in the unselected group but also in the
IPAH group (Table 4). Only Big-ET showed a trend for
a positive prediction of an adverse outcome for each in-
crease of BigET1 by 1 fmol/ml (all patients: HR 1.88
(0.89 - 3.97), p = 0.09; IPAH: HR 5.01 (0.65 - 38.71), p
= 0.12).
3.5.2. Outcome Estimates Based on Hemodynamic
and Exercise Tested Variables: Multivariate
Predictive Analysis
In the multivariate Hazard ratio proportional test for
hemodynamic factors of pulmonary hypertension and/or
right ventricular dysfunction, only a PVR over 900 dyn*s*
Table 3. Bivariate correlation of HFABP, Big-ET and BT-Pro-BNP with exercise parameters (CPET) (a) and invasive mea-
sured parameters of pulmonary hypertension and right ventricular dysfunction (b) in 41 patients with pre-capillary pulmo-
nary hypertension. VO2 = Oxygen consumption; AT = aerob/anaerob threshold; peak= maximum of exertion; 6MWD = 6
minute walk distance. MAP = mean arterial pressure; MPAP mean pulmonary artery pressure; PCWP = pulmonary capil-
lary wedge pressure; TPG = trans pulmonary pressure gradient; mRAP=mean right atrial pressure; RVEDP = right
end-diastolic filling pressure; PVR = pulmonary vascular resistance, SVR: systemic vascular resistance).
Bivariate correlation of CPET and biomarkers at baseline
Parameter Unit H-FABPp BNP p BigET1 p
VO2AT ml/min*kg 0.37 0.04 0.21 0.34 0.35 0.06
VO2peak ml/min*kg 0.38 0.03 0.45 0.03 0.39 0.02
VO2peak predicted % 0.32 0.06 0.26 0.23 0.33 0.05
VE/VCO2Slope 0.05 0.76 0.12 0.58 0.16 0.42
Workload peak Watt 0.22 0.20 0.30 0.15 0.20 0.27
Workload peak predicted % 0.11 0.54 0.39 0.06 0.30 0.08
Oxygenpulse AT ml/beat 0.04 0.90 0.11 0.76 0.19 0.59
Oxygenpulse peak ml/beat 0.32 0.06 0.35 0.10 0.13 0.48
Oxygenpulse peak predicted % 0.19 0.27 0.23 0.28 0.24 0.17
6 MWD m 0.13 0.79 0.58 0.42 0.31 0.54
Heart rate recovery beats 1st min 0.03 0.85 0.18 0.43 0.18 0.42
NTproBNP fmol/ml 0.51 0.01 0.50 0.01
H-FABP pg/ml 0.51 0.01 0.65 0.01
BigET1 fmol/ml 0.65 0.01 0.50 0.01
Bivariate correlation of hemodynamics and biomarkers at baseline
Parameter Unit HFABP p BNP p BigET1 p
MAP mmHg 0.12 0.49 0.10 0.61 0.09 0.66
MPAP mmHg 0.14 0.39 0.10 0.62 0.41 0.04
PCWP mmHg 0.01 0.96 0.01 0.97 0.27 0.15
TPG mmHg 0.13 0.45 0.10 0.64 0.25 0.12
RAP mmHg 0.13 0.44 0.48 0.02 0.73 0.001
RVEDP mmHg 0.14 0.47 0.20 0.44 0.53 0.001
SaO2 % 0.04 0.83 0.15 0.47 0.11 0.51
SvO2 % 0.29 0.07 0.64 0.00 0.53 0.002
Cardiac Index l/min*m2 0.14 0.40 0.33 0.10 0.25 0.13
PVR dyn*s*cm5 0.07 0.70 0.13 0.54 0.14 0.40
SVR dyn*s*cm5 0.11 0.55 0.10 0.64 0.07 0.69
Resistance Index 0.26 0.12 0.17 0.42 0.53 0.004
Copyright © 2011 SciRes. OJRD
Figure 2. Kaplan Meier survival curves of patients with pre-capillary pulmonary hypertension in dependence of elevated
levels of the three biomarkers H-FABP (upper graph) and Big-ET1 (lower graph). No differences in outcome could be seen in
patients with elevated or normally ranged biomarker levels.
Table 4. Multivariate Hazard ratio for biomarkers in all PH patients. H-FABP and NT pro BNP revealed a HR beneath 1,
whereas BigET1 possessed an increase HR of 1.88 for each increase of BigET1 by 1 fmol/ml, but all HR’s are not significant.
All PH patients (n = 41) IPAH patients (n = 23)
Biomarker Unit HR 95% CI p HR 95% CI p
H-FABP pg/ml 1 0.99 1.01 0.44 1 0.99 1.01 0.14
Nt pro BNP fmol/ml 1.01 0.98 1.01 0.54 1 0.99 1.01 0.7
Big-ET1 fmol/ml 1.88 0.89 3.97 0.09 5.01 0.65 38.71 0.12
cm5 was a strong hemodynamic parameter indicating a
worse outcome (HR 25.66; p = 0.01) (Figure 3). In addi-
tion, an arterial oxygen saturation of haemoglobin above
90% revealed a HR of 0.07 (p = 0.02) and a mixed ve-
nous Hb oxygen saturation more than 58% indicated a
HR of 0.1 (p = 0.01) for deteriorated outcome by each
declining percent of saturation. Neither, elevated MPAP,
increased right or left ventricular and atrial filling pres-
sures, nor the cardiac index were reliable values for the
prognosis of PH patients. With regard to variables in the
exercise test, respiratory efficacy, derived from the VE/
VCO2 slope with a cut off point of 60 (HR 8.24; p = 0.02)
as well as the heart rate recovery (HRR), a marker of
heart frequency decline in the early recovery period after
the maximum of cycling exertion with a cut off point of
8 bpm within the 1st minute (HR 21.63; p < 0.01) were
strongly associated with a poor prognosis. This result is
independent of heart rate at rest (Figure 4). Surprisingly,
neither VO2 peak (>12.5m/kg/min, HR 0.4, p = 0.27) nor
6MWD (>320 m) were significantly associated with a
better outcome in our mixed population (HR 0.93, p =
0.86). There was also no significant difference in 6MWD
between the group treated with specific medication and
those with newly diagnosed, yet untreated PH (p = 0.66).
However this result is limited by the fact that only 28
patients underwent a 6 MWD. According to the results of
the whole PH population, we detected that SvO2 >58%
was independently associated with a better prognosis in
patients with IPAH (HR 0.02, p = 0.03). In contrast, in
patients with IPAH, the maximum of reached workload
(>50 watt) (HR 0.02, p = 0.04) and peak oxygen con-
sumption (>12.5 ml/kg/min) (HR 0.02, p = 0.06) reached
statistical significance or tended to be associated with a
better outcome. VE/VCO2 slope of more than 60 (HR
2,64; p = 0,4) as well as a HRR below 8 bpm/1st min (HR
101,3; p = 0,21) failed to predict a worse outcome in this
IPAH subgroup (Table 5). Due to the only few events in
this group and the consecutvely wide spreading confi- i
Copyright © 2011 SciRes. OJRD
Figure 3. Multivariate Hazard ratio proportional test for hemodynamic factors predicting survival in PH patients. PVR > 900
dyn*s*cm5 is associated with an increased, low arterial and mixed venous Hb oxygen saturation with a decreased risk of
death/HLtx. The levels of significant association are indicated.
Figure 4. Multivariate Cox regression proportional analysis with Hazard ratios for exercise parameters predicting worse
outcome in PH. A VE/VCO2 Slope more than 60 contributes to an 8 fold, a HRR below than 8 beats within the first minute
following peak exertion leads to a 22 fold increase in death/HLTx.
dence interval no statistical significance was reached.
4. Discussion and Conclusions
The prognostic assessment of pulmonary hypertension is
difficult but important, particularly in the context of op-
timal timing for invasive procedures such as atrial sep-
tostomy or lung transplantation. Therefore, a simple,
non-invasive, and repeatedly available method is desir-
able. Promising and indicative are studies measuring
cardiac biomarkers in plasma such as plasma brain nat-
Table 5. Hazard ratio proportional test in the group of 23
IPAH patients. Displayed are only the 3 variables with the
strongest interrelation to an adverse outcome. SvO2 and the
maximum of workload in CPET show the strongest inter-
relation in IPAH patients.
Variable HR 95% CI p
SvO2 > 58% 0.02 0.001 0.710.03
Workload peak > 50 watts 0.02 0.001 0.730.04
VO2 peak > 12,5 ml/kg*min0.03 0.001 1.230.06
Copyright © 2011 SciRes. OJRD
riuretic peptide (BNP) or the N-terminal part of its pro-
hormone [23,24]. The stimuli for increased secretion of
BNP are ventricular wall stretch and volume overload
[25]. Recently, newer myocardial biomarkers reflecting
myocardial injury, but not stretch per se, such as troponin
or H-FABP, have gained interest. In this study, we inve-
stigated the H-FABP to determine whether H-FABP is
an indicator of disease severity and survival in patients
with various forms of chronic pre-capillary PH within
different stages of the disease and under different medi-
cal therapies. The salient finding of our study is that
baseline serum levels of H-FABP are not able to predict
an adverse outcome. In a midterm follow up period of
about two years, baseline H-FABP concentrations were
not different between patients with an adverse outcome
compared to those with a favourable course. These data
indicate the low predictive value of the biomarker. In
addition, the probability of event free survival (HR 1.0,
CI 0.99 - 1.01, p = 0.44) was not predicted by increased
levels of H-FABP. Similar results were obtained in the
subgroup of 23 patients with IPAH. Only a weak correla-
tion of H-FABP with the established prognostic parame-
ter for CPET VO2 peak (r = 0.38, p = 0.03) could be
established. The H-FABP plasma levels failed to show
any correlations with the other known prognostic hemo-
dynamic markers of PH and right ventricular dysfunction
(such as RAP, PVR, SVO2, CO) [26] and exercise
(6MWT, VE/VCO2) parameters. Our findings are in con-
trast to the results of Lankeit et al. [28] who examined
the prognostic value of H-FABP in 93 consecutive pa-
tients with the diagnosis of PH, namely CTEPH. They
found significantly higher H-FABP levels in patients
with an adverse outcome, while a multivariate analysis
revealed that H-FABP (HR 1.11, CI 1.02 - 1.22, p =
0.015) was an independent predictor of adverse outcome,
along with RAP and pulmonary endarterectomy (PEA).
Inter- estingly, in this selected study group baseline
H-FABP levels were only weakly correlated with other
prognostic relevant hemodynamic parameters (CO,
PCWP, RAP and 6MWD). The exact reasons for these
apparent discrepancies to our results are unclear, espe-
cially in case of comparable median H-FABP levels be-
tween the different study groups. The main difference
between the study groups consisted in the different aeti-
ologies of PH and consecutive treatment options during
the follow up. Particularly, the very selected entity
(CTEPH) and the longer observation time in the study of
Lankeit et al. [29] could be one explanation. In fact, 56%
of the CTEPH patients underwent surgical PEA and
showed a drastic relieve of hemodynamic impact on their
right atriums and ventricles. In addition, PEA was asso-
ciated with a highly significant lower risk of an adverse
outcome. In our unselected patient group with pulmonary
hypertension of various aetiologies only 8 patients were
diagnosed as CTEPH but without surgical accessibility
of the thromboembolic lesions. During the observation
period almost all patients received different medications
for PH. In summary, these data indicated, that H-FABP
even though representing an easily accessible biomarker,
is not a reliable predictor for the outcome of these pa-
tients and thus cannot be used reliably to develop thera-
peutic strategies for individual patients with PH. In addi-
tion we did compare the hemodynamic and prognostic
value of H-FABP with Big-ET and with the natriuretic
peptide NT-Pro-BNP, which has already been shown to
have prognostic relevance in patients with PH. Surpris-
ingly, we observed moderate correlations between
H-FABP and NT-Pro-BNP (r = 0.51, p = 0.01) but
higher correlations to Big-ET (r = 0.65, p = 0.01).
Big-ET and NT-Pro- BNP were moderately correlated to
each another (r = 0.5, p = 0.01), too. Like H-FABP,
Big-ET and NT-Pro-BNP correlated weakly with VO2
peak (r = 0.39, p = 0.02 and r = 0.45, p = 0.03, respec-
tively). But in contrast to H-FABP, NT-pro-BNP, and
even more Big-ET showed weak to strong correlations to
invasively measured he- modynamic parameters with
known prognostic signifi- cance (NT-Pro-BNP: mRAP: r
= 48, p = 0.02, mixed venous saturation (SVO2) r =
0.64, p < 0.001; (Big-ET: PAP: r = 0.41, p = 0.04; re-
sistance index r = 0.53, p = 0.004; SVO2: r = 0.53, p =
0.002; RVEDP: r = 0.53, p = 0.001 and mRAP: r = 0.73,
p = 0.001). Using the multi- variable Cox`s proportional
hazard model NT-pro-BNP, comparable to H-FABP, had
not emerged as an inde- pendent predictor of outcome in
our study group of very unselected patients but also in
the subgroup of IPAH patients. Only, increasing Big-ET
levels, tended to be predictive for an adverse outcome in
the whole group (HR 1.88, CI 0.89 - 3.97, p = 0.09) and
in IPAH (HR 5.01, CI 0.65 - 38.7, p = 0.12). Accordingly,
Big-ET, compared with H-FABP and NT-pro-BNP,
showed the highest correlations with different prognostic
relevant hemodynamic parameters of pulmonary hyper-
tension and right ventricular dysfunction. In contrast to
the biomarker H-FABP, hemodynamic and exercise test
parameters were proved to have at least a good correla-
tion with survival. In the multivariate Hazard ratio pro-
portional test, the hemodynamic parameters PVR, SVO2
und SAO2 and the exercise parameters VE/VECO2 slope
at AT and, sur- prisingly, the heart rate recovery (HRR)
were independ- ently associated with an adverse vs. a
favourable out- come. Most interestingly in this context
is the non-inva- sive derived CPET parameter HRR (<8
beats within the first minute) with its very powerful pre-
dictive value (HR 21.63, CI 2.85 - 321.21, p = 0.01) for
adverse outcome in our patient group. The rise in heart
rate during exercise is considered to be due to the com-
Copyright © 2011 SciRes. OJRD
bination of parasympathetic withdrawal and sympathetic
activation [27]. The fall in heart rate immediately after
exercise is considered to be a function of reactivation of
the parasympathetic nervous system [28]. Increased va-
gal activity has been associated with a reduction in the
risk of death [29]. In contrast, a slow rate of heart rate
recovery after exercise testing is a powerful and inde-
pendent predictor of overall mortality. This easily avail-
able marker is independent from workload, the presence
or absence of myocardial perfusions defects, and changes
in heart rate during exercise [30]. In patients with left
heart failure, delayed heart rate recovery is a significant
predictor of both sudden cardiac death and mortality due
to pump failure [31]. With regard to pulmonary diseases,
different observations are consistent with the existence of
an important imbalance of autonomic dysfunction in pa-
tients with various grades of lung disease. For example,
Seshadri et al. [32] demonstrated that in COPD patients
either obstructive or restrictive abnormalities found on
spirometry are associated with abnormal heart rate re-
covery. With re- gard to pulmonary hypertension,
Velez-Roa et al. [33] reported that the activity of the
sympathetic nervous sys- tem, as assessed by peroneal
nerve microneuropathy, is markedly increased in patients
with pulmonary arterial hypertension. This sympathetic
overactivity appears to be related to right atrial distention
and decreased cardiac output. Both may be improved by
atrial septostomy, a live saving intervention for patients
with severe PAH, to bridge for lung transplantation. In
fact, Ciarka et al. [34] showed that atrial septostomy in
PAH patients decreases sympathetic nerve hyperactivity,
mostly related to de- creased right atrial distension. The
specific role of an additionally modulated parasympa-
thetic reactivation, reflected by a diminished HRR, was
not examined in these studies. Recently, Swigris et al.
[35] could show that in patients with idiopathic pulmo-
nary fibrosis and pulmonary hypertension an abnormal
heart rate recovery after 6MWT appeared to be the most
potent predictor of mortality (HR 5,2). The findings of
the present study, however, demonstrated that a dimin-
ished HRR (<8 beat within the first minute) was able to
indicate an adverse outcome in patients with pre-capil-
lary pulmonary hyper-tension of different causes. Thus,
the present study strongly supports the notion that in pa-
tients with pre-capillary pulmonary hypertension the
imbalance of the autonomic nerve system is of utmost
importance for prognosis. Future studies with larger
numbers of patients and potentially longer follow up
have to define the exact role of such an autonomic dys-
function in the pathophysiology and prognosis of pul-
monary arterial hypertension.
The main limitations of the present study are the
population size of only 41 patients. This is due to the low
prevalence of this disease. In an attempt to evaluate the
different prognostic parameters in patient groups with
distinct aetiologies of pre-capillary pulmonary hyperten-
sion, we calculated the results at first for all patients,
followed by a calculation for the IPAH patients only. But,
the even smaller number of patients of the latter group
(IPAH, n = 23) with only 6 major events in the follow up
period does not allow any final conclusions and may
only be considered as pilot data. One of the best evalu-
ated prognostic predictors in patients with IPAH and
other causes of pre-capillary hypertension is the 6MWD
[36]. In our study only 28 patients underwent the 6MWD
test. However, in the present study an independent prog-
nostic value of this exercise parameter could not be
achieved, neither in IPAH patients nor in the total, unse-
lected PH hypertension group. Again, this may be due to
the different severities and stages of the disease. Further
studies have to address this valid point.
In conclusions, the present study indicates that H-
FABP is neither a reliable parameter of disease severity
nor a novel predictor of mid and long term outcome in
patients with various forms of pre-capillary pulmonary
hypertension. Also, other biomarkers such as NT-Pro-
BNP and Big-ET did not appear to be useful tools for
outcome stratification in this patient group. They reflect
the disease severity better, because of their moderate to
high correlation to different hemodynamic and exercise
parameters. Still, they did not prove to be independent
predictors of event free survival. More promising diag-
nostic tools with prognostic relevance for such typically
unselected patients could be the well known and estab-
lished exercise parameters of an increased slope of
VE/VCO2, but also a delayed HRR, the latter indicative
for a diminished vagal activity. Both are noninvasive and
easily measurable parameters. Especially, the quite pow-
erful and easily accessible predictive value of heart rate
recovery (HRR) may provide the rationale for new stud-
ies defining the temporal relation of autonomic nervous
system distortion to right heart failure with bad prognosis
in pulmonary arterial hypertension.
5. Acknowledgements
H.S. thanks MH who participated in the design of the
study and helped to perform right heart catheterization
and CPET, DS who participated in study coordination,
data acquisition and performing statistical analysis. Sin-
cere thanks are given to PB carried out the immunoas-
says, to GH, RCBD and RHS helped to draft the manu-
script and revised it critically and to AS who conceived
of the study, and participated in creating design, partici-
pated in the sequence alignment, drafted the manuscript,
performed right heart catheterization and gave final ap-
Copyright © 2011 SciRes. OJRD
proval of the version to be published. All authors read
and approved the final manuscript.
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