C-reactive protein: a new predictor of adverse outcome in pulmonary arterial hypertension.

Abstract

Our aim was to investigate in a prospective study a potential role of C-reactive protein (CRP) in predicting the outcome in pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).
CRP is a well-known marker of inflammation and tissue damage, widely recognized as a risk predictor of cardiovascular and coronary heart diseases.
Plasma levels of CRP have been measured in consecutive patients diagnosed with PAH and CTEPH, at the time of right heart catheterization.
Circulating CRP levels were increased in CTEPH and PAH patients compared with those in control subjects (4.9 mg l(-1), 95% confidence interval [CI]: 3.9 to 6.2 mg l(-1); 4.4 mg l(-1), 95% CI: 3.5 to 5.4 mg l(-1); and 2.3 mg l(-1), 95% CI: 1.9 to 2.7 mg l(-1), respectively; p < 0.0001). In PAH patients, CRP levels correlated with New York Heart Association functional class (r = 0.23), right atrial pressure (r = 0.25), and 6-min walking distance (r = -0.19) and were significantly higher in nonsurvivors than in survivors (p = 0.003). All PAH, idiopathic PAH, and patients naive for disease-specific medication with CRP levels >5.0 mg l(-1) had a significantly lower survival rate (p = 0.02, p = 0.009, and p < 0.05, respectively). In CTEPH patients, circulating CRP levels significantly decreased 12 months after pulmonary endarterectomy (n = 23, 4.0 mg l(-1), 95% CI: 2.8 to 5.8 mg l(-1), to 1.6 mg l(-1), 95% CI: 2.2 to 3.0 mg l(-1); p = 0.004). PAH patients normalizing their CRP levels under treatment (n = 29), assigned as responders, had a significantly higher survival rate (p < 0.05). The proportion of patients treated with a parenteral prostacyclin-analogue was significantly higher among the responders than the nonresponders (55% vs. 17%, p = 0.002).
This is the first evidence of a role of an inflammatory marker, such as CRP, in predicting outcome and response to therapy in PAH.

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Pulmonary Hypertension
C-Reactive Protein
A New Predictor of Adverse
Outcome in Pulmonary Arterial Hypertension
Rozenn Quarck, PHD,* Tim Nawrot, PHD,†‡ Bart Meyns, MD, PHD,§ Marion Delcroix, MD, PHD*
Leuven and Diepenbeek, Belgium
Objectives
Our aim was to investigate in a prospective study a potential role of C-reactive protein (CRP) in predicting the
outcome in pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension
(CTEPH).
Background
CRP is a well-known marker of inflammation and tissue damage, widely recognized as a risk predictor of cardio-
vascular and coronary heart diseases.
Methods
Plasma levels of CRP have been measured in consecutive patients diagnosed with PAH and CTEPH, at the time
of right heart catheterization.
Results
Circulating CRP levels were increased in CTEPH and PAH patients compared with those in control subjects (4.9
mg·l?1, 95% confidence interval [CI]: 3.9 to 6.2 mg·l?1; 4.4 mg·l?1, 95% CI: 3.5 to 5.4 mg·l?1; and 2.3 mg·l?1,
95% CI: 1.9 to 2.7 mg·l?1, respectively; p ? 0.0001). In PAH patients, CRP levels correlated with New York
Heart Association functional class (r ? 0.23), right atrial pressure (r ? 0.25), and 6-min walking distance (r ?
?0.19) and were significantly higher in nonsurvivors than in survivors (p ? 0.003). All PAH, idiopathic PAH, and
patients naive for disease-specific medication with CRP levels ?5.0 mg·l?1had a significantly lower survival rate
(p ? 0.02, p ? 0.009, and p ? 0.05, respectively). In CTEPH patients, circulating CRP levels significantly de-
creased 12 months after pulmonary endarterectomy (n ? 23, 4.0 mg·l?1, 95% CI: 2.8 to 5.8 mg·l?1, to 1.6
mg·l?1, 95% CI: 2.2 to 3.0 mg·l?1; p ? 0.004). PAH patients normalizing their CRP levels under treatment (n ?
29), assigned as responders, had a significantly higher survival rate (p ? 0.05). The proportion of patients
treated with a parenteral prostacyclin-analogue was significantly higher among the responders than the nonre-
sponders (55% vs. 17%, p ? 0.002).
Conclusions
This is the first evidence of a role of an inflammatory marker, such as CRP, in predicting outcome and response
to therapy in PAH.(J Am Coll Cardiol 2009;53:1211–8) © 2009 by the American College of Cardiology
Foundation
Pulmonary hypertension is a rare and severe disorder,
characterized by an elevated pulmonary arterial pressure
(PAP). On the basis of common clinical features, 5 catego-
ries of pulmonary hypertension have been identified (1).
Among them, pulmonary arterial hypertension (PAH) is
characterized by an intrinsic distal vessel arteriopathy and
chronic thromboembolic pulmonary hypertension (CTEPH)
by proximal vessel occlusions occasionally followed by distal
vessel remodeling. The pathophysiological processes com-
monly involved in PAH include vasoconstriction, vascular
remodeling, and thrombosis (2). Although inflammatory cell
infiltrates had been observed around the distal pulmonary
arteries (3), the potential role of inflammation in the
pathogenesis of PAH has only recently been investigated.
Increased plasma levels of interleukin-1, interleukin-6, and
CX3C chemokine fractalkine (4,5) and increased expression
of CCL3 chemokine macrophage inflammatory protein-1
alpha in lung biopsies (6) have been reported. In CTEPH,
dysregulated thrombosis and/or thrombolysis, as causes of
intraluminal thrombus organization and fibrous vessel oblit-
eration, have been inconsistently evidenced (7). Recent
works also suggest the importance of systemic inflammation
in the genesis of the disease. The CCL2 chemokine
monocyte chemoattractant protein-1 is up-regulated in
plasma and in large pulmonary arteries of CTEPH patients
(8). An increased prevalence of inflammatory disease in
From the *Center for Pulmonary Vascular Diseases, Pneumology Department, and
†Occupational, Environmental and Insurance Medicine, Public Health Department,
Katholieke Universiteit Leuven, Belgium; ‡School of Life Sciences, Hasselt Univer-
sity, Diepenbeek, Belgium; and the §Cardiac Surgery Department, Universitaire
Ziekenhuizen, Leuven, Belgium. Dr. Delcroix received research grants and speaker
fees from Actelion, Encysive, Pfizer, and LungRx. Dr. Delcroix is holder of the
Actelion chair for pulmonary hypertension at the Katholieke Universiteit Leuven. Dr.
Nawrot is the recipient of a fellowship from the Fonds voor Wetenschappelijk
Onderzoek-Vlaanderen.
Manuscript received September 5, 2008; revised manuscript received December 2,
2008, accepted December 8, 2008.
Journal of the American College of Cardiology
© 2009 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 53, No. 14, 2009
ISSN 0735-1097/09/$36.00
doi:10.1016/j.jacc.2008.12.038

Page 2

patients with CTEPH versus
acute pulmonary embolism has
been reported (9).
C-reactive protein (CRP) is a
marker of inflammation and tis-
sue damage. It has been identi-
fied as a predictor of risk for
cardiovascular events (10). Be-
sides its commonly accepted role
of bystander and marker of clin-
ical risk in various inflammatory
diseases, CRP may also be an
active player in the physiopathol-
ogy of the vascular wall, as dem-
onstrated in atherosclerosis (11).
The role of CRP in pulmonary
hypertension is completely un-
known. The aim of the present
study was to investigate a poten-
tial role of CRP as a predictor of
pulmonary hypertension severity
and outcome.
Methods
Study population. This prospec-
tive study included all consecutive
patients diagnosed with PAH and
CTEPH, as defined by the
Venice classification (1), who un-
derwent right heart catheteriza-
tion at the University Hospital of
Leuven between April 1, 2004, and April 30, 2008. Healthy
subjects were recruited out of screening programs from the
departments of urology and gynecology. The study protocol
has been approved by the Institutional Ethics Committee of
the University Hospitals Leuven, and participants gave
informed consent.
Clinical parameters. Medical records of the patients were
reviewed, and the following data were extracted: sex, age,
weight and size, modified New York Heart Association
(NYHA) functional class (1), 6-min walking distance
(6MWD), current disease-specific drug use (prostacyclin
analogues, endothelin receptor antagonists, and phosphodi-
esterase inhibitors) at the time of catheterization, date of
symptom onset, and date of diagnosis. At study entry,
patients and healthy control subjects completed a question-
naire that provided information about smoking habits, and
history of diabetes mellitus and hypertension. The right
heart catheterization included measurements of mean right
atrial pressure (RAP), PAP, pulmonary vascular resistance
(PVR), and cardiac index. PAH and CTEPH patients were
stratified into subgroups of low versus high disease severity
according to NYHA functional class (I to II or III to IV).
For survival and event-free survival, the observation period
was from study entry until death or June 25, 2008. Death,
lung transplantation, and start of parenteral prostacyclin
analogues were assigned as clinical worsening events.
Blood samples. Blood samples were collected on
ethylenediaminetetra-acetic acid at the time of right heart
catheterization, and plasma was prepared. CRP levels
(Tina-quant C-Reactive Protein, Roche Diagnostics, Vil-
voorde, Belgium) were determined in the University Hos-
pital routine laboratory. The upper limit of normal (ULN)
was 5 mg·l?1.
Statistical analysis. Database management and statistical
analyses were performed using SAS software version 9.1
(SAS Inc., Cary, North Carolina) and GraphPad Prism
version 4.01 (GraphPad Software Inc., La Jolla, California).
Continuous and normally distributed values were expressed
as mean ? SD. Values not normally distributed were
log-transformed to normalize their distribution and ex-
pressed as a geometric mean with a 95% confidence interval
(CI). Differences between the 3 groups were analyzed using
analysis of variance followed by post-hoc tests (Bonferroni)
for continuous variables and a chi-square test for categorical
variables. Differences between 2 groups were compared
using a Student t test. Differences within groups before and
after treatment were analyzed using a paired t test. Associ-
ations between variables were investigated using Pearson
correlation. Survival curves for patients were contrasted with
baseline levels of CRP above and below the ULN by
Kaplan-Meier survival function estimate and log-rank test.
The sensitivity and specificity of CRP to predict survival
was assessed by a receiver-operator characteristic (ROC)
analysis. Cox regression was applied to model the relation
between failure time (time to death for PAH, and time to
death or persistent pulmonary hypertension for CTEPH,
defined by a PAP ?35 mm Hg at 3 days post-surgery) and
the plasma CRP concentration at baseline, adjusting for
other explanatory variables including sex, age, body mass
index, smoking status (current and past), PAP, RAP, PVR,
cardiac index, NYHA functional class, etiology, and
6MWD. We identified covariates by a stepwise regression
procedure with the p values for variables to stay in the model
set at 0.10. Covariates considered for entry in the model
were age, sex, body mass index, smoking status, PAP, RAP,
PVR, cardiac index, NYHA functional class, 6MWD,
etiology, and logCRP. All p values were for 2-sided tests. A
value of p ? 0.05 was considered statistically significant.
Results
Characteristics of the study population. One hundred
and four patients with PAH, 79 patients with CTEPH, and
a control group of 95 healthy subjects were included in the
study. Patient demographics and clinical characteristics at
study entry are reported in Table 1. Among the PAH
patients, 50 (49%) had idiopathic pulmonary arterial hyper-
tension (IPAH) and 54 (51%) had PAH associated to other
diseases including connective tissue disease (24%), congen-
ital heart disease (7%), portal hypertension (10%), myelo-
Abbreviations
and Acronyms
CI ? confidence interval
CRP ? C-reactive protein
CTEPH ? chronic
thromboembolic pulmonary
hypertension
IPAH ? idiopathic
pulmonary arterial
hypertension
NT-proBNP ? N-terminal
fragment of brain
natriuretic peptide
NYHA ? New York Heart
Association
PAH ? pulmonary arterial
hypertension
PAP ? mean pulmonary
arterial pressure
PEA ? pulmonary
endarterectomy
PVR ? pulmonary vascular
resistance
RAP ? mean right atrial
pressure
ROC ? receiver-operator
characteristic
ULN ? upper limit of
normal
6MWD ? 6-min walking
distance
1212Quarck et al.
CRP and Pulmonary Arterial Hypertension
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proliferative disorders (5%), pulmonary veno-occlusive dis-
ease (3%), drug abuse (1%), and human immunodeficiency
virus (1%). Sixty-seven (68%) PAH patients were naive for
disease-specific medication. Among the CTEPH patients,
58 (75%) had a history of acute venous thromboembolism
and 53 (66%) had at least 1 thrombophilic disorder. During
the observation period (mean 786 days, range 4 to 1,554
days), 27 PAH and 8 CTEPH patients died. Forty-four
(56%) CTEPH patients underwent a pulmonary endar-
terectomy (PEA). Nine PAH patients underwent a lung
transplantation, and 11 started intravenous or subcutane-
ous prostacyclin analogues.
CRP and severity in PAH. Circulating CRP levels were
significantly higher in CTEPH and PAH patients (4.9
mg·l?1, 95% CI: 3.9 to 6.2 mg·l?1and 4.4 mg·l?1, 95% CI:
3.5 to 5.4 mg·l?1) compared with those seen in control
subjects (2.3 mg·l?1, 95% CI: 1.9 to 2.7 mg·l?1, analysis of
variance p ? 0.0001) (Fig. 1). CRP levels were not
statistically different between the different subcategories of
PAH.
In PAH patients, CRP levels correlated with NYHA
functional class (r ? 0.23, p ? 0.02) and RAP (r ? 0.25,
p ? 0.01) and inversely correlated with 6MWD (r ?
?0.19, p ? 0.04). CRP levels were significantly higher in
NYHA functional class III to IV compared with those seen
in NYHA functional class I to II (5.9 mg·l?1, 95% CI: 4.4
to 7.9 mg·l?1vs. 3.2 mg·l?1, 95% CI: 2.3 to 4.3 mg·l?1,
p ? 0.004) and in nonsurvivors compared with those seen in
survivors (8.3 mg·l?1, 95% CI: 5.0 to 13.6 mg·l?1vs. 3.6
mg·l?1, 95% CI: 2.9 to 4.5 mg·l?1, p ? 0.0008). This last
observation was also found in IPAH patients (8.0 mg·l?1,
95% CI: 3.3 to 19.2 mg·l?1vs. 3.6 mg·l?1, 95% CI: 2.7 to 4.8
mg·l?1, p ? 0.02) and in treatment-naive PAH patients (8.5
mg·l?1, 95% CI: 4.3 to 16.7 mg·l?1vs. 3.6 mg·l?1, 95% CI:
2.7to4.9mg·l?1,p?0.03).Thenonsurvivorsalsohadalower
6MWD (233 ? 150 m vs. 371 ? 152 m, p ? 0.0001) and a
higher RAP (12 ? 6 mm Hg vs. 8 ? 5 mm Hg, p ? 0.0002)
and NYHA functional class (2.8 ? 0.7 vs. 2.4 ? 0.8, p ?
0.01). Severity did not affect CRP levels in CTEPH patients.
CRP as a predictor of outcome in PAH. Survival Kaplan-
Meier analyses showed that all PAH, IPAH, and
treatment-naive PAH patients with CRP levels higher than
ULN had a significantly lower survival rate (2-year survival
of 65% vs. 82%, p ? 0.02 [Fig. 2A]; 61% vs. 96%, p ? 0.009
[Fig. 2B]; and 63% vs. 87%, p ? 0.05 [Fig. 2C], respec-
tively). In accordance, all PAH, IPAH, and treatment-naive
PAH patients with CRP ? ULN had a higher NYHA
functional class (p ? 0.02, p ? 0.02, and p ? 0.003,
respectively) and a lower 6MWD (p ? 0.0001, p ? 0.01,
and p ? 0.0009, respectively), without any significant
differences in the hemodynamic profile.
Similarly, event-free survival Kaplan-Meier analyses
showed that all PAH, IPAH, and treatment-naive PAH
patients with CRP ? ULN had a significantly lower
event-free survival rate (2-year event-free survival of 57% vs.
76%, p ? 0.01 [Fig. 2D]; 54% vs. 95%, p ? 0.009 [Fig. 2E];
and 63% vs. 78%, p ? 0.04 [Fig. 2F], respectively).
Accordingly, the significantly lower CRP levels observed in
event-free PAH patients (3.6 mg·l?1, 95% CI: 2.8 to 4.6
mg·l?1vs. 6.3 mg·l?1, 95% CI: 4.3 to 9.4 mg·l?1, p ? 0.01)
and in event-free treatment-naive PAH patients (3.5
mg·l?1, 95% CI: 2.5 to 4.9 mg·l?1vs. 6.5 mg·l?1, 95% CI:
3.9 to 10.7 mg·l?1, p ? 0.04) were accompanied by a
significantly lower NYHA functional class (p ? 0.01 and
ControlPAHCTEPH
1
10
100
****
-1)
Figure 1CRP Levels in Patients With Pulmonary Hypertension
C-reactive protein (CRP) levels were measured in plasma of patients with pul-
monary arterial hypertension (PAH) (n ? 104), chronic thromboembolic pulmo-
nary hypertension (CTEPH) (n ? 79), and control subjects (n ? 95). Black
lines represent geometric mean. Analysis of variance, p ? 0.0001;
**p ? 0.01 versus control.
Characteristics of the Study Population
Table 1Characteristics of the Study Population
PAH
(n ? 104)
CTEPH
(n ? 79)
Control
Subjects
(n ? 95)
p Value
(ANOVA,
Chi-Square)
Age, yrs
BMI, kg/m2
58 ? 1562 ? 14*56 ? 160.02
26 ? 628 ? 626 ? 50.10
Sex, female, %6662540.18
Ever smoking, %4657510.35
Current3318170.09
Past678283—
Diabetes type II, %13.910.16.30.18
AHT, %26.938.018.90.01
PAP, mm Hg50 ? 1345 ? 11ND0.004
RAP, mm Hg
PVR, dyne·s·cm?5
Cardiac index, l·min?1·m2
9 ? 67 ? 5ND0.11
850 ? 397804 ? 381ND0.43
2.42 ? 0.812.19 ? 0.53ND0.02
6MWD, m335 ? 162322 ? 148ND0.59
NYHA functional class, n2.5 ? 0.82.8 ? 0.5ND0.02
I100ND—
II4022ND—
III4352ND—
IV115ND—
*p ? 0.05 versus control.
AHT ? arterial systemic hypertension; ANOVA ? analysis of variance; BMI ? body mass index;
CTEPH ? chronic thromboembolic pulmonary hypertension; ND ? not done; NYHA ? New York
Heart Association; PAH ? pulmonary arterial hypertension; PAP ? mean pulmonary arterial
pressure; PVR ? pulmonary vascular resistance; RAP ? mean right atrial pressure; 6MWD ? 6-min
walking distance.
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p ? 0.007, respectively) and RAP (p ? 0.005 and p ? 0.01,
respectively) and a higher 6MWD (p ? 0.0003 and p ?
0.006, respectively).
All PAH and IPAH patients with a CRP ? ULN had a
significantly lower time to death (1.7 ? 1.2 years vs. 2.3 ?
1.3 years, p ? 0.04; 1.8 ? 1.2 years vs. 2.7 ? 1.3 years, p ?
0.02, respectively), without any significant change in time to
clinical worsening.
According to ROC analyses, CRP plasma levels of 4.75,
4.9, and 5.0 mg·l?1, respectively, were the best cutoff values
for all PAH, IPAH, and treatment-naive PAH patients.
Sensitivity was 63% (95% CI: 42% to 81%) and specificity
64% (95% CI: 52% to 74%) for all PAH patients, 70% (95%
CI: 35% to 93%) and 69% (95% CI: 51% to 81%) for IPAH
patients, and 62% (95% CI: 35% to 85%) and 63% (95% CI:
48% to 76%) for treatment-naive PAH patients.
PAH
012345
0
20
40
60
80
100
120
p=0.02
Time (years)
Percent event-free
IPAH
012345
0
20
40
60
80
100
120
p=0.009
Time (years)
Percent event-free
treatment-naive PAH
012345
0
20
40
60
80
100
120
p<0.05
Time (years)
Percent event-free
F
E
D
PAH
012345
0
20
40
60
80
100
120
CRP>5mg
p=0.02
Time (years)
Percent survival
IPAH
012345
0
20
40
60
80
100
120
p=0.009
Time (years)
Percent survival
treatment-naive PAH
012345
0
20
40
60
80
100
120
p<0.05
Time (years)
Percent survival
C
B
A
CRP>5mg
CRP>5mg
CRP>5mg
CRP>5mg
CRP>5mg
Figure 2Survival and Event-Free Survival in PAH Patients According to Plasma CRP Levels
Kaplan-Meier curves comparing survival (A to C) and event-free survival rates (D to F) during the follow-up of PAH patients with CRP ?5 or ?5 mg·l?1. (A and D) All PAH
patients (n ? 104); (B and E) idiopathic pulmonary arterial hypertension (IPAH) patients (n ? 50); (C and F) treatment-naive PAH patients (n ? 67). Abbreviations as in
Figure 1.
1214Quarck et al.
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The univariate analysis showed that age, etiology,
NYHA functional class, 6MWD, RAP, and CRP signif-
icantly predicted mortality of all PAH and treatment-naive
PAH patients (Table 2). Only 6MWD and CRP signifi-
cantly predicted mortality of IPAH patients (Table 2). Both
before (Fig. 2) and after adjustment for potential confound-
ing variables, plasma CRP predicted mortality of all PAH,
IPAH, and treatment-naive PAH patients (Table 2). Inde-
pendent of the other covariates, a doubling of the plasma
CRP level was associated with a 41% (95% CI: 9% to 81%,
p ? 0.008) increase in the risk for a fatal event. The
corresponding hazard ratios for IPAH and treatment-naive
PAH patients were 100% (95% CI: 6% to 290%, p ? 0.033)
and 48% (95% CI: 10% to 99%, p ? 0.009), respectively
(Table 2). CRP levels did not correlate with the elapsed
time since the onset of symptoms or since diagnosis. In
CTEPH patients, PAP was predictive for adverse outcome
(hazard ratio: 1.05, 95% CI: 1.01 to 1.10, p ? 0.02),
whereas CRP was not.
Effect of medical treatment in PAH. A second evaluation
was performed in 24 PAH patients, mean 28 months (range
1 to 82 months) after start of disease-specific medication. In
33 of the 37 PAH patients who were already treated at
inclusion, the baseline evaluation was retrospectively re-
trieved from the reference center database. In the whole
group of 57 PAH patients, an average period of 40-month
treatment (range 9 to 82 months) resulted in significant
decreases in PVR (?134 ? 397 dyn·s·cm?5, p ? 0.003) and
NYHA functional class (?0.3 ? 0.8, p ? 0.01) and increase
in cardiac index (0.38 ? 0.97 l·min?1·m2, p ? 0.0001),
without any significant change in RAP, PAP, 6MWD, and
CRP levels. However, when patients were stratified accord-
ing to treatment effect on CRP levels, patients normalizing
CRP levels under ULN (responders, n ? 29, ?3.7 ? 6.8,
p ? 0.0001) displayed a concomitant decrease in NYHA
functional class (?0.3 ? 0.8, p ? 0.05) and increase in
cardiac index (0.29 ? 0.78 l·min?1·m2, p ? 0.002). Survival
Kaplan-Meier analysis showed that responders had a higher
survival rate (84% vs. 61% at 3 years, p ? 0.05) (Fig. 3).
Twenty-nine PAH patients were treated with endothelin
receptor antagonists, 17 with prostacyclin analogues, 5 with
phosphodiesterase-5 inhibitors, 5 with a combination of 2
of them, and 1 with calcium-channel blockers. The propor-
tion of patients receiving prostacyclin analogues was signif-
icantly higher among the responders compared with the
nonresponders (55% vs. 17%, p ? 0.002). Patients receiving
prostacyclin analogues displayed significantly lower CRP
levels (2.7 mg·l?1, 95% CI: 1.8 to 3.9 mg·l?1vs. 5.1 mg·l?1,
95% CI: 3.5 to 7.4 mg·l?1; p ? 0.01).
Effect of surgical treatment in CTEPH. A second eval-
uation was performed in 23 CTEPH patients, mean 12
months (range 2 to 22 months) after PEA. Circulating CRP
levels were significantly decreased (4.0 mg·l?1, 95% CI: 2.8
to 5.8 mg·l?1vs. 5.1 mg·l?1, 95% CI: 3.5 to 7.4 mg·l?1;
p ? 0.004) (Fig. 4), with concomitant decreases in RAP
(?3.1 ? 5.4 mm Hg, p ? 0.01), PAP (?15 ? 12 mm Hg,
p ? 0.0001), PVR (?522 ? 433 dyn·s·cm?5, p ? 0.0001),
and NYHA functional class (?0.9 ? 1.0, p ? 0.0002) and
increase in cardiac index (0.59 ? 0.55 min?1·m2, p ?
0.0002) and 6MWD (95 ? 99 m, p ? 0.0003).
Univariate and Multivariate Analysis Relating Survival to Selected Baseline Variables
Table 2Univariate and Multivariate Analysis Relating Survival to Selected Baseline Variables
Univariate AnalysisMultivariate Analysis
Variables Hazard Ratio 95% Confidence Intervalp ValueHazard Ratio95% Confidence Intervalp Value
PAH
Age1.0621.024–1.1000.0010———
Etiology1.2931.054–1.5870.01381.3541.085–1.6910.007
NYHA functional class0.0202———
II vs. I0.5750.252–1.3130.19———
III vs. I2.2031.102–4.4020.0254———
IV vs. I2.0350.813–5.0960.13———
6MWD0.9950.992–0.9970.00010.9960.993–0.9990.005
RAP1.1281.062–1.1980.00011.0681.000–1.1410.049
LogCRP3.8571.793–8.2980.00063.115 1.353–7.1720.008
IPAH
6MWD 0.9950.991–0.9990.0210.9950.990–0.9990.026
LogCRP6.374 1.616–25.1500.0082 10.6661.213–93.7470.033
PAH treatment naive
Age1.0481.002–1.0960.04———
Etiology1.1780.886–1.5680.261.4491.050–1.9990.024
6MWD0.9940.991–0.9980.00170.9930.989–0.9980.004
RAP1.158 1.074–1.2480.00011.1111.027–1.2010.008
LogCRP3.3361.387–8.235 0.0103.7161.386–9.9650.009
Etiology included IPAH, PAH associated to connective tissue disease, congenital heart disease, portal hypertension, myeloproliferative disorders, and pulmonary veno-occlusive disease. In multivariate
analysis, variables were selected by stepwise selection and reported if the value of p ? 0.10. NYHA functional class was coded as dummy variables in which class I was set as reference.
CRP ? C-reactive protein; IPAH ? idiopathic pulmonary arterial hypertension; other abbreviations as in Table 1.
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Discussion
The aim of the present study was to investigate a potential
role of CRP in predicting the outcome in patients with
PAH and CTEPH. The results revealed that CRP levels
were higher in patients with pulmonary hypertension com-
pared with those in control subjects. Severe pulmonary
hypertension was associated with increased circulating CRP
levels in PAH. CRP predicted mortality and clinical wors-
ening of PAH patients. An increase in CRP levels under
disease-specific medication also predicted mortality of PAH
patients. The novelty of the present study is a potential role
of CRP as a predictor of adverse outcome and response to
therapy in PAH.
Inflammation in PAH: circulating CRP as the main
indicator. Several studies have already argued for a role of
both systemic and local inflammation in PAH (3–6). This
fits with our findings demonstrating an increase in circulat-
ing CRP levels in PAH patients compared with those in
control subjects. Elevated levels of CRP predict the risk of
recurrent ischemia and death among patients with known
atherosclerotic disease. Elevated CRP has been recently
proposed as a predictor of pulmonary hypertension in
Gaucher disease (12). In chronic obstructive pulmonary
disease, also associated with systemic inflammation, CRP
has been identified as a marker of prognosis (13). Chronic
obstructive pulmonary disease patients with pulmonary
hypertension display higher plasma levels of CRP (14). The
present study is the first that evidenced circulating CRP as
an independent predictor of mortality and prognosis in
patients with PAH. In accordance, besides supranormal
CRP, poor survival was also associated with higher RAP
and NYHA functional class and lower 6MWD, known as
surrogate markers of survival in PAH (15,16). Nowadays,
NYHA functional class and 6MWD are widely recognized
as important and useful primary end points for clinical trials
(17,18). Our findings are even strengthened by the remain-
ing role of CRP as an independent risk factor in predicting
adverse outcome in more homogeneous groups of patients
like IPAH or PAH patients without any disease-specific
treatment.
The N-terminal fragment of brain natriuretic peptide
(NT-proBNP) is commonly used as a marker for diagnosis,
severity, and prognosis of patients with congestive heart
failure (19). NT-proBNP is so far the only biomarker
currently used in the practice as a prognostic parameter (20)
and to stratify disease severity (21) in patients with pulmo-
nary hypertension. According to our present findings, we
may consider including CRP as an additional biomarker in
the evaluation of PAH.
CRP and medical treatment in PAH. In accordance with
previous reports highlighting the importance of improve-
ment in exercise capacity, NYHA functional class, and
cardiac index in evaluating effects of treatment in PAH
(22,23), we have observed that a 40-month period of
specific disease treatment resulted in a decrease in PVR and
NYHA functional class and an increase in cardiac index.
Any association between the inflammation status of PAH
patients and treatment effect has been established so far.
Our present findings concerning 57 PAH-treated patients
highlight a potential role of CRP in predicting response to
therapy. In addition, the treated patients normalizing CRP
under ULN (5 mg·l?1) had a significantly better survival
accompanied by a decrease in NYHA functional class and
an increase in cardiac index. The better survival observed in
treated patients normalizing CRP under ULN was also
associated with a higher proportion under prostacyclin
analogues, in agreement with previous observations report-
ing an enhanced survival in patients under long-term
intravenous epoprostenol infusion (23,24).
NT-proBNP decreases together with an improvement in
hemodynamics in treated PAH patients (25). Consequently,
012345
0
20
40
60
80
100
120
p<0.05
Responders
Non-responders
Time (years)
Percent survival
Figure 3
Survival of Treated PAH Patients
According to the Change in CRP Levels
Kaplan-Meier curve comparing the survival rate of treated PAH patients (n ?
57) according to the change in CRP levels under therapy. Responders are
defined as patients normalizing their CRP values under the upper limits of nor-
mal. Abbreviations as in Figure 1.
pre PEA post PEA
1
10
100
p=0.004
-1)
Figure 4
Effect of Surgical Treatment
on CRP Levels in CTEPH Patients
CRP levels were measured in the plasma of CTEPH patients (n ? 23) before
and after pulmonary endarterectomy (PEA). Black lines represent geometric
mean. Abbreviations as in Figure 1.
1216Quarck et al.
CRP and Pulmonary Arterial Hypertension
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April 7, 2009:1211–8

Page 7

dosing NT-proBNP and CRP may help to orientate ther-
apeutic options.
CRP and surgical treatment in CTEPH. In our popula-
tion of CTEPH patients who underwent a PEA, a signif-
icantly decrease in circulating CRP levels has been observed
12 months after surgery, suggesting an improvement in
their inflammatory status. Similarly, Langer et al. (26) have
found elevated tumor necrosis factor-alpha levels in
CTEPH patients before PEA, which dropped after the
surgery. Besides the decrease in tumor necrosis factor-alpha
and CRP after surgical treatment in CTEPH, NT-
proBNP, also used as a noninvasive marker of the severity of
right ventricular dysfunction in CTEPH (27), is decreasing
under oral endothelin receptor antagonist (28) or subcuta-
neous prostacyclin analog therapy (29) in inoperable
CTEPH patients. Although CRP could not be identified as
a prognostic factor to predict adverse outcome of PEA in
our population of operated CTEPH patients, CRP may be
useful to evaluate both medical and surgical treatment
efficacy in CTEPH.
Relevance of the study. An interesting finding and unex-
plored aspect of the study is the predictive value of CRP for
the outcome of PAH patients and its sensitivity to disease-
specific medication. The noninvasive feature associated with
the low cost of the measurement of CRP minimizes risks for
the patients and deserves consideration to include it in the
evaluation of patients with pulmonary hypertension and to
orientate the therapeutic options.
Study limitations. The present study was exploratory and
performed on consecutive patients coming to the reference
center for right heart catheterization. At first line, our
prospective study only included 24 PAH patients who had
a second evaluation after an average period of 28 months
under disease-specific medication. In order to increase this
population and to strengthen our results, we have retrospec-
tively retrieved the baseline evaluation concerning 33 pa-
tients who were already treated at inclusion. To properly
evaluate the effect of treatment on inflammatory markers,
we should extend these measurements to a larger number of
patients evaluated at a fixed time after starting disease-
specific medications or PEA, although the present results
are promising.
ROC analysis indicated relatively low sensitivity and
specificity for CRP in predicting survival, compared with
NT-proBNP (20). However, we must emphasize that in
PAH: 1) ROC analysis has never been performed for
inflammatory biomarkers; and 2) we do not expect CRP to
be the unique predictor of death.
In the present study, CRP did not correlate strongly with
hemodynamics in PAH and CTEPH patients. Circulating
monocyte chemoattractant protein-1 has been found to
correlate with PVR in CTEPH patients (8), which we did
not confirm in our CTEPH population. A plausible expla-
nation could be that inflammation is not a linear evolving
process in the course of the disease (i.e., early peaks of
inflammation may occur without direct consequences on the
hemodynamics). However, we were not able to demonstrate
any relationship between the length of the disease and CRP.
Conclusions
The present study clearly shows that circulating CRP may
predict the severity and the outcome in PAH and that its
sensitivity to disease-specific medication may orientate thera-
peutic options.
Acknowledgments
The authors thank Peter Bynens, Viviane De Broyer, Lynn
Decoster, Frederick Guns, Petra Janssens, Pieter Kelber,
Erna Ruers, Hans Scheers, Evi Smeyers, Siska Van
Damme, Ellen Vandevelde, and Wim Wuyts for their
excellent logistical and technical support.
Reprint requests and correspondence: Dr. Marion Delcroix,
Department of Pneumology, Universitaire Ziekenhuizen Leuven,
Herestraat 49, B-3000 Leuven, Belgium. E-mail: marion.
delcroix@uzleuven.be.
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Key Words: pulmonary hypertension y inflammation y C-reactive
protein.
1218Quarck et al.
CRP and Pulmonary Arterial Hypertension
JACC Vol. 53, No. 14, 2009
April 7, 2009:1211–8