Pediatr Cardiol (2017) 38:1342–1349
DOI 10.1007/s00246-017-1667-9
ORIGINAL ARTICLE
Hemodynamic Evaluation of Children with Persistent
or Recurrent Pulmonary Arterial Hypertension Following
Complete Repair of Congenital Heart Disease
Heiner Latus1 • Inken Wagner1 • Stefan Ostermayer1 • Gunter Kerst1
Joachim Kreuder1 • Dietmar Schranz1 • Christian Apitz1,2
Received: 28 January 2017 / Accepted: 19 June 2017 / Published online: 5 July 2017
Ó Springer Science+Business Media, LLC 2017
Abstract Persistent or recurrent pulmonary arterial hyper-
tension (PAH) following complete surgical repair of congen-
ital heart disease (CHD) represents one of the largest group of
PAH associated with CHD (PAH-CHD) in recent registry
studies and seems to have a particularly poor prognosis.
However, little is known about this fourth clinical subclass of
PAH-CHD, especially in children. The purpose of this study
was to assess specific characteristics of invasive hemody-
namics of this disease in children, including acute vasodilator
testing (AVT) and pulmonary endothelial function (PEF) and
to compare to patients with idiopathic PAH (IPAH), who
usually present with a similar fatal clinical course. Thirty-two
children with PAH were included in the study, twelve of these
patients had PAH-CHD subclass 4 (mean age 8.0 ± 3.4 years)
and twenty children had IPAH (mean age 8.6 ± 4.4 years).
Cardiac catheterization was performed in all children,
including AVT and PEF. PEF was assessed by changes in
pulmonary blood flow in response to acetylcholine (Ach) using
Doppler flow measurements. Pulmonary flow reserve (PFR)
was calculated as the ratio of pulmonary blood flow velocity in
response to Ach relative to baseline values. At baseline, the
ratio of mean PA pressure to mean systemic arterial pressure
(mPAP/mSAP) was comparably high in both groups
(0.78 ± 0.32 vs. 0.80 ± 0.22), while the indexed pulmonary
vascular resistance (PVRI) was significantly lower in the PAH-
& Heiner Latus
heiner.latus@googlemail.com
& Christian Apitz
christian.apitz@uniklinik-ulm.de
1
Pediatric Heart Center, Justus-Liebig-University Giessen,
Feulgenstr. 10-12, 35392 Giessen, Germany
2
Division of Pediatric Cardiology, University Children’s
Hospital Ulm, Eythstr. 24, 89075 Ulm, Germany
123
•
CHD group (12.6 ± 6.8 WUxm2) compared to IPAH patients
(19.9 ± 10.6 WUxm2) (p = 0.04). Cardiac index was sig-
nificantly higher in the PAH-CHD group (4.19 ± 1.09 l/min/
m2 vs. 3.23 ± 0.76) (p = 0.017). However, AVT revealed a
significantly larger maximum response (percentage of fall of
PVR/SVR ratio during AVT) in the IPAH group (37 ± 22%)
compared to the PAH-CHD group (13 ± 23%) (p = 0.017).
PEF showed no significant difference between both patient
groups (PFR 1.69 ± 0.71 vs. 1.73 ± 0.68) (p = 0.76). Our
study demonstrates significant pulmonary vascular disease in
children with persistent or recurrent PAH following complete
surgical repair of CHD similar to IPAH patients. Although
baseline measures appeared to be more favorable, pulmonary
vasoreactivity was markedly impaired in PAH-CHD subclass
4, which may contribute to its negative impact on the long-term
outcome of this patient group.
Keywords Idiopathic pulmonary arterial hypertension

Pulmonary arterial hypertension associated with congenital
heart disease
Endothelial dysfunction
Pulmonary flow
reserve
Introduction
Pulmonary arterial hypertension (PAH) is a disease of the
small pulmonary arteries characterized by a progressive
increase in pulmonary vascular resistance leading to right
ventricular failure and ultimately death [1]. Persistent or
recurrent pulmonary arterial hypertension (PAH) following
complete surgical repair of congenital heart disease (CHD)
represents one of the largest group of PAH patients in
recent registry studies and seems to have a particularly
poor prognosis [2]. Prior to surgical closure, enhanced
pulmonary blood flow in the presence of pre- or post-
Pediatr Cardiol (2017) 38:1342–1349
tricuspid shunt defects may lead to structural and func-
tional changes in pulmonary vessels which can contribute
to the increase in pulmonary arterial pressure. Pulmonary
vascular endothelial dysfunction is an important mecha-
nism involved in the pathophysiology of pulmonary
hypertension. Impairment in vasorelaxation properties due
to alterations in the nitric oxide pathway acts as a major
contributor to pulmonary hypertension. There are sparse
data on the reason for the initiation and progression of PAH
after defect closure; a delayed correction of the defects has
been discussed especially if the pulmonary vascular disease
had already developed [2]. Although no specific recom-
mendations exist, diagnostic and drug treatment strategies
in patients with PAH-CHD subgroup 4 currently follow the
same algorithms as established for patients with idiopathic
PAH (IPAH). This is due to the fact that both entities have
a comparable fatal course, even if PAH-CHD subgroup 4
appears to be more progressive. Remarkably, recently
published randomized controlled studies (PATENT, SER-
APHIN, GRIPHON) also included patients with PAH-
CHD subgroup 4 and were able to confirm similar bene-
ficial treatment effects consistent with the effects in each of
the entire study cohort [3–7]. However, whether these two
disease entities (IPAH and PAH-CHD subgroup 4) share
comparable hemodynamic characteristics and response to
pulmonary vasodilators is still unknown.
Accordingly, the purpose of this study was to assess
specific characteristics of invasive hemodynamics of this
disease in children, including acute vasodilator testing
(AVT) and assessment of pulmonary endothelial function
(PEF) in comparison to patients with IPAH.
Methods
We included children and adolescents with IPAH and PAH-
CHD after previous surgical/interventional shunt closure
who had undergone cardiac catheterization at our tertiary
referral center from 2001 to 2014 to assess pulmonary
hypertension (defined as mean pulmonary arterial pressure
(mPAP) greater than 25 mmHg and/or pulmonary vascular
resistance (PVR) greater than 3 Wood units x m2 body sur-
face area). Global and local vasoreactivity testing were
standard part of our routine invasive hemodynamic assess-
ment. Informed written consent was obtained from the par-
ents of the patients. The study protocol was approved by the
Institutional Committee on Ethical Practice.
Protocol for Testing of the Acute Vasodilator
Response
Testing of the acute vasodilator response was done
according to a systematic protocol as previously published
1343
[8]. PAH-specific drug therapy was suspended at least 12 h
before catheterization. Patients were only moderately
sedated while spontaneously breathing, allowing normal gas
exchange, and adequate systemic vascular resistance (SVR)
and systemic arterial pressure (SAP). Hemodynamic and
oxygen transport measurements were made at stable base-
line conditions (at ‘usual’ FiO2) and then the vasoreactivity
was tested as the effects of inhaled nitric oxide (NO) at 20 to
40 ppm for 10 min on mean and diastolic PAP, SAP, and
PVR/SVR ratio. Thereafter, the effects of the additional
application of oxygen with fractional inspired oxygen
(FiO2) * 0.8 (if possible) was assessed. During close
observation for possible rebound phenomena, NO ? O2
was discontinued and new baseline hemodynamic parame-
ters were obtained after 10 min. Subsequently, the effects of
aerosolized Iloprost (0.3–0.5 lg/kg) administered by a
specific applicator were assessed; thereafter, if not con-
traindicated, NO ? O2 was inhaled again to define the
hemodynamic effects of combined cyclic adenosine
monophosphate (cAMP), cyclic guanosine monophosphate
(cGMP), and oxygen-dependent pulmonary vasodilator
effects. Acute response to global vasoreactivity testing
(AVT) was defined as a[20% fall in the ratio of PVRi/SVRi
without a decrease in cardiac output.
Vasodilator Response to Acetylcholine
Before vasoreactivity testing was performed with the
above-mentioned protocol, pulmonary endothelial function
was assessed by vasodilator response to Acetylcholine
(Ach). Dependent on the patient size, a 4F or 5F multi-
purpose catheter was inserted into the left or right lower
lobe pulmonary artery (Fig. 1). A 0.014 inch pulsed Dop-
pler wire (Volcano Corporation, Rancho Cordova, CA,
USA) was positioned through the multipurpose catheter
into a straight segment of the medial or posterior branch of
the lower lobe pulmonary artery with a diameter of
3–5 mm. Position of the Doppler wire in the center of this
vessel was confirmed by a hand injection of contrast
through a Tuohy-Borst adapter (‘‘sighting’’ angiography),
and a stable flow velocity signal with minimal noise. Then,
serial infusions were made via the multipurpose catheter
into the segmental pulmonary artery using an infusion
pump with Ach-concentrations of 10-6 and 10-5 M,
respectively. Changes in pulmonary blood flow in response
to Ach were assessed using intravascular Doppler blood
flow velocity measurements. Pulmonary flow reserve
(PFR) was calculated as the ratio of pulmonary blood flow
velocity in response to Ach relative to baseline values. This
optional measurement may add additional information
regarding the etiology and stage of pulmonary vascular
disease, treatment strategy, and prognosis in children with
PAH [9–11].
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Fig. 1 a Sighting angiography by hand injection of contrast through
a Tuohy-Borst adapter to confirm position of the Doppler wire in the
center of the vessel in anteroposterior projection. The wire was
Statistical Analysis
Continuous variables were tested for normality using the
D’Agostino-Pearson omnibus test and are presented as
mean with standard deviation or median and range. Com-
parisons between the IPAH and PAH-CHD group were
made with the Student t test, the Mann–Whitney U test, or
the Fisher’s exact test, as appropriate. Hemodynamic
changes during acute vasodilator testing were assessed by
paired t-test. Spearman’s rank correlation coefficient was
used to analyze simple linear relationships between dif-
ferent variables. Kaplan–Meier survival analysis was con-
ducted with the definition of end point as the composite of
all-cause mortality, lung/heart–lung transplantation, and
creation of a Potts shunt. A log-rank test was conducted to
determine the difference between the PH groups. Analysis
was performed using GraphPad statistical software package
(San Diego, California, USA). A p value B0.05 was con-
sidered statistically significant.
Results
Patient Characteristics
Thirty-two children with PAH were included in the study,
twenty children had IPAH (mean age 8.6 ± 4.4 years),
and twelve patients (mean age 8.0 ± 3.4 years) had
PAH-CHD subclass 4 with previously closed shunt
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Pediatr Cardiol (2017) 38:1342–1349
inserted via a multipurpose catheter into the left lower lobe
pulmonary artery. b Doppler flow signal at baseline (upper panel)
and in response to local application of Ach (lower panel)
defects (mean time between shunt closure and cardiac
catheterization 4.7 ± 3.5 years) (Table 1). Of those, two
patients had previous closure of an atrial septal defect
(interventional and surgical closure in one patient,
respectively, age at closure 0.4 and 2.0 years), five
patients had undergone patch closure of ventricular septal
defects (initial pulmonary artery banding in one patient,
age at repair 2.0 (0.3–6.5) years), three patients had
corrected complete atrioventricular septal defects (all
trisomy 21 patients, median age at repair 1.8
(0.3–2.0) years, the oldest one had previously undergone
pulmonary artery banding) and two patients were previ-
ously diagnosed with a persistent arterial duct (one
patient with trisomy 21, age at interventional closure 6.3
and 9.6 years). In one patient after ASD closure, partial
anomalous pulmonary venous return of the right superior
pulmonary vein to the superior vena cava was present at
the time of catheterization and was corrected surgically at
follow-up. Two patients (one ASD and one VSD patient)
were previous preterm infants (born at 31th and 35th
weeks of gestation). One patient in the PAH-CHD group
underwent atrial septostomy during surgical VSD patch
closure (as pop-off) while another patient with a PDA
had initial atrial septostomy in the neonatal period as
interventional treatment of severe PAH and cardiac
decompensation. In the IPAH group, one patient under-
went atrial septostomy prior to transplantation. In all
other patients no residual left-to-right shunts were present
at the time of the present catheterization.
Pediatr Cardiol (2017) 38:1342–1349 1345

Table 1 Demographic and clinical data of the study population Outcome

Variable IPAH PAH-CHD p value
The mean follow-up was 7.4 ± 5.5 years in the IPAH
Patients (n) 20 12 group and 6.5 ± 4.3 years in the PAH-CHD group. In the
Female/male 11/9 9/3 0.46 IPAH group, one patient underwent combined heart–lung
Age at study (years) 8.6 ± 4.4 8.0 ± 3.4 0.89 transplantation 11 months after cardiac catheterization and
Height (cm) 129 ± 27 118 ± 25 0.20 one patient died 10 months after catheterization. Two
Weight (kg) 31 ± 16 22 ± 10 0.13 patients in the PAH-CHD group died 3 and 6 years after
BSA (m2) 1.05 ± 0.38 0.85 ± 0.29 0.14 invasive assessment and one patient underwent implanta-
WHO class I/II/III/IV, n 5/11/4/0 2/7/3/0 0.84 tion of a Potts shunt 9 years after catheterization but died in
Age at defect closure (years) – 3.3 ± 3.0 the early postoperative period due to low-cardiac output.
Oxygen saturation (%) 97 ± 4 96 ± 5 0.67 Although Kaplan–Meier analysis showed no significant
Treatment, n (%) 0.94 difference, there was a trend to a worse outcome in the
Sildenafil 13 (65) 9 (75) group with PAH-CHD (subclass 4) (Fig. 2). The 3-year
CCB 9 (45) 6 (50) mortality in the IPAH group was 10% and then remained
Bosentan 7 (35) 3 (25) stable for the next 7 years whereas the 3-, 5-, and 10-year
Prostanoids 6 (30) 4 (33) mortality in PAH-CHD (subclass 4) patients was 8, 16, and
25%, respectively (p = 0.23).
IPAH idiopathic pulmonary arterial hypertension, PAH-CHD pul-
monary arterial hypertension associated with congenital heart disease,
WHO world health organization, CCB calcium channel blocker; data
presented as mean ± 1 SD Discussion

This study provides specific characteristics of invasive

Invasive Hemodynamic Data
At baseline, the ratio of mean PA pressure to mean systemic
arterial pressure (mPAP/mSAP) was comparably high in
both groups (0.78 ± 0.32 vs. 0.80 ± 0.22) (Table 2).
Indexed pulmonary vascular resistance (PVRI) was signifi-
cantly lower in the PAH-CHD group (12.6 ± 6.8 WUxm2)
compared to IPAH patients (19.9 ± 10.6 WUxm2)
(p = 0.04) while cardiac index was significantly higher in
the PAH-CHD group (4.19 ± 1.09 l/min/m2 vs.
3.23 ± 0.76 l/min/m2) (p = 0.017). Fourteen of the 20
IPAH (70%) and five of the 12 PAH-CHD patients (42%)
showed an acute response to global acute vasoreactivity
testing (AVT). AVT revealed a significantly larger maxi-
mum response (percentage of fall of PVR/SVR ratio during
AVT) in the IPAH group (37 ± 22%) compared to the PAH-
CHD group (13 ± 23%) (p = 0.017).
The mean baseline flow velocity in the segmental pul-
monary artery was comparable between the two groups
(IPAH 18.5 (7–50) cm/s vs PAH-CHD 16.5 (5–32) cm/s,
p = 0.42). During Ach infusion the flow velocity increased
to 27.0 (7.3–110.0) cm/s in the IPAH group (p = 0.002)
and to 23.0 (10.0–74.0) cm/s in the PAH-CHD group
(p = 0.01). The resulting mean pulmonary flow reserve
(PFR) showed no significant difference between both
groups (1.69 ± 0.71 vs. 1.73 ± 0.68; p = 0.76). In all
PAH patients, PFR was related to the percentage of fall of
PVR/SVR ratio during AVT (r = 0.37, p = 0.03).
hemodynamics of children with persistent or recurrent
PAH following complete surgical repair of CHD, including
AVT and assessment of PEF in comparison to patients with
IPAH, as the latter entity is regarded as very similar to
PAH-CHD subgroup 4 in regard to its clinical course and
response to treatment [6].
Our study demonstrates marked pulmonary vascular
disease in children with persistent or recurrent PAH fol-
lowing complete surgical repair of CHD on a similar level
as usually seen in IPAH patients. Although baseline mea-
sures appeared to be more favorable, pulmonary vasore-
activity was markedly impaired in PAH-CHD subclass 4,
which may contribute to its negative impact on the long-
term outcome of this patient group. The estimated 20-year
survival rate in recent registry data is 36% and is signifi-
cantly worse than the survival rates in other PAH-CHD
subclasses, especially patients with the Eisenmenger syn-
drome. The reasons for the worse prognosis of these
patients are unclear and may include the lack of a possible
pulmonary-to-systemic shunt in the case of elevation of
PVR or impaired adaptation of the right ventricle to an
increasing afterload when this starts after the first months/
years of life. An increase in mortality rate in patients with
postoperative PAH compared with Eisenmenger Syndrome
patients has also been reported in the pediatric age group
[12, 13]. In our series, PAH was likely to be a relatively
early complication after cardiac defect repair (average age
of children was 8.0 years) compared with reported adult
populations in which PAH was detected very late after
defect correction [2]. Data regarding this PAH subgroup

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1346 Pediatr Cardiol (2017) 38:1342–1349

Table 2 Hemodynamic data of

Variable IPAH PAH-CHD p value
the two groups including results
of acute vasoreactivity testing Baseline
(maximal response) and
assessment of pulmonary mPAP 64 ± 20 59 ± 22 0.42
endothelial function by local mSAP 79 ± 10 77 ± 10 0.32
response to acetylcholine mPAP/mSAP 0.80 ± 0.22 0.78 ± 0.32 0.56
CI (l/min/m2) 3.23 ± 0.76 4.19 ± 1.09 0.017
2
PVRi (WUxm ) 19.9 ± 10.6 12.6 ± 6.8 0.04
Rp/Rs 0.79 ± 0.27 0.69 ± 0.35 0.24
RAP (mmHg) 7±2 5±2 0.13
Maximal response
mPAP 45 ± 22 53 ± 27 0.50
mSAP 79 ± 11 74 ± 11 0.28
mPAP/mSAP 0.58 ± 0.26 0.70 ± 0.34 0.30
CI (l/min/m2) 3.9 (2.4–7.9) 4.5 (3.0–8.6) 0.21
PVRi (WUxm2) 10.7 (3.4–31.1) 6.7 (2.6–34.3) 0.47
Rp/Rs 0.52 ± 0.29 0.60 ± 0.36 0.56
Fall in Rp/Rs (%) 37 ± 22 13 ± 23 0.017
Acetylcholine
APV baseline (cm/s) 18.5 (7–50) 16.5 (5–32) 0.42
APV max (cm/s) 27.0 (7.3–110.0) 23.0 (10.0–74.0) 0.76
PFR 1.69 ± 0.71 1.73 ± 0.68 0.76
Bold values indicate statistical significance (p B 0.05)
IPAH idiopathic pulmonary arterial hypertension, PAH-CHD pulmonary arterial hypertension associated
with congenital heart disease, mPAP mean pulmonary artery pressure, mSAP mean systemic artery pres-
sure, CI cardiac index, PVRi indexed pulmonary vascular resistance, RAP right atrial pressure, Rp/Rs ratio
of pulmonary-to-systemic vascular resistance, APV average peak velocity, PFR pulmonary flow reserve;
data presented as mean ± 1 SD

pulmonary vasodilators. In a study from the Dutch cohort

Fig. 2 Kaplan–Meier curve of the IPAH (idiopathic pulmonary
hypertension) and PAH-CHD (pulmonary arterial hypertension asso-
ciated with congenital heart disease) group for the composite endpoint
consisted of all-cause mortality, heart–lung transplantation, and
implantation of a Potts shunt (p = 0.23). Displayed on the x-axis is
the time that has passed since invasive hemodynamic assessment
presenting at a younger age are scarce and little is known
about the potential differences in circulatory characteristics
and pulmonary vascular remodeling including response to
overall survival of patients with PAH-CHD was better than
for IPAH [14]. However, pediatric PAH-CHD represents a
very heterogenous group with highly variable clinical
courses. Van Loon et al. [14] showed very detailedly that
specific PAH-CHD subgroups (i.e., after shunt closure)
showed worse survival compared to IPAH, and is therefore
quite in line with our results. Similar to our patients, van
Loon et al. described that syndromes were frequently
present, especially in patients with progressive PAH-CHD
which might be an important contributing factor for the
worse survival.
The largest published pediatric cohort so far (TOPP
registry [1]) reported hemodynamic data of 45 patients
with repaired shunts diagnosed at a similar age as in our
study (age 7.4 (5.8–8.9) years). Main difference to our
study is that it was not detailed in the TOPP data whether a
residual shunt was present in some of the patients. How-
ever, most of the invasive data were on a similar level as in
our study (i.e., mPAP/mSAP ratio; PVRI). About one-third
of the patients with repaired shunts in the TOPP registry
showed positive response during vasoreactivity testing
which is quite in line with our results. Interestingly, the
TOPP data also showed higher response rate in the IPAH

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group (38 vs. 33%) and also higher CI in the repaired shunt
group, although these differences seem to be only
moderate.
The responder rate in our IPAH group was rather high,
which might be explained by the used responder criteria.
There are no established responder criteria for children
with PAH, and the criteria in our protocol (so-called Barst
criteria) are the commonly used criteria in childhood.
However, recent data from the TOPP registry [13] were
able to show that more strict criteria (Sitbon criteria) may
result in a reduction of the rate of responders and thus
might improve the reliability of the vasoreactivity test.
Consequently, identifying AVT responders largely depends
not only on the used criteria but also on patients’ age and
diagnosis groups [13]. Supporting our results, a previous
study by Douwes and colleagues reported a lower number
of AVT responders in patients with PAH-CHD compared
to patients with IPAH/HPAH [15]. Although the CHD
group investigated in this study was very heterogenous
regarding the underlying diagnoses and age (adults and
children), these findings must be considered with regards to
the mentioned poor outcome in this PAH subgroup.
Notably, despite similar elevation of pulmonary artery
pressure, the CHD subgroup in our study had a higher
cardiac output with subsequent lower PVR resulting in
more favorable baseline hemodynamics. This finding may
be related to differences in the onset and progression of the
disease as well as potential differences in right heart
adaption to chronic pressure overload when the adaptation
process starts soon after birth as in our patients with
hemodynamically relevant shunts before closure. However,
the maximum response during AVT was markedly
impaired in CHD patients while pulmonary endothelial
function was equally affected in both groups. The reason
for these findings remains speculative but may be related to
similarities in pulmonary vascular disease characteristics
and/or in pulmonary circulatory physiology between these
two disease entities. After birth, the unique ultrastructural
appearance of neonatal pulmonary smooth muscle cells
makes the pulmonary vasculature susceptible to any toxic
factor. In neonates and infants with large left-to-right shunt
lesions increased pulmonary blood flow ultimately leads to
pulmonary vascular obstructive disease [16, 17]. Depend-
ing on the type of congenital abnormality and the patient’s
age, the rate of progression of these pulmonary vascular
changes is variable and even after closure of the defect,
chronic pulmonary vascular disease may be present early
after repair or even reoccur later in life after initial post-
operative normalization [18, 19]. However, even when the
lesion is corrected at an early age, the vasoreactivity of the
pulmonary vascular bed may be abnormal making it prone
to factors that trigger any form of PAH. In addition, genetic
syndromes, for example Trisomy 21, and prematurity (as
1347
also presented in our patient cohort) can also contribute to
the development or progression of pulmonary vascular
disease. Thus, the mechanisms and underlying factors
causing a progression of chronic postoperative pulmonary
vascular disease are obviously very heterogenous and still
not completely understood.
In both flow-induced and idiopathic PAH, multiple
molecular and cellular events cause adverse pulmonary
vascular remodeling including smooth muscle cell hyper-
trophy [16, 17, 20, 21]. Accompanied by these histopatho-
logical changes, altered function of the pulmonary vascular
endothelium is considered to be an important factor in the
pathogenesis of PAH. Endothelial dysfunction affects the
production of vasoconstrictors (i.e., increases production of
endothelin I and thromboxane) and vasodilators (decreases
nitric oxide and prostacyclin), leading to pulmonary vaso-
constriction. Thus, assessment of pulmonary arterial
endothelial function may help to understand the progression
of pulmonary hypertensive vascular disease. Previously, we
were able to demonstrate the clinical and prognostic impli-
cations of pulmonary endothelial dysfunction by Ach-in-
duced regional vasoreactivity testing in children with IPAH
[10]. Our recent presented study showed that pulmonary
endothelial function was equally impaired in PAH-CHD
patients (subclass 4) compared to IPAH suggesting a similar
degree of adverse pulmonary vascular remodeling. Further
research on the mechanisms and underlying factors causing a
progression of chronic postoperative pulmonary vascular
disease is required with a special focus on pulmonary
endothelial function. By assessing both local and global
pulmonary vasodilation, differentiation between predomi-
nantly functional alterations of the endothelium and/or an
impaired vasomotor function of the vascular smooth muscle
cells is possible [22] and may give new insights into the
pathophysiologic changes in shunt-induced pulmonary vas-
cular disease.
According to our results, we postulate that PAH-CHD
patients (subclass 4) may show a similar response to pul-
monary vasodilators and thus may benefit from initiation of
targeted drug therapy especially considering the observed
more favorable baseline hemodynamic situation that may
indicate a reasonable response to PAH therapy when initiated
timely. With regards to the prognostic value of global AVT
and local PEF in children with IPAH, our findings therefore
support the current strategy to treat PAH-CHD patients with
persistent or recurrent PAH following complete surgical
repair of CHD according to a similar protocol as for IPAH.
Study Limitations
The results of our study are limited by the low number of
patients resulting in differences in demographic and clini-
cal characteristics (patients with Down’s syndrome were
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1348
included) as well as baseline hemodynamics. Furthermore,
invasive follow-up data were not available to assess long-
term pulmonary vascular remodeling and the prognostic
relevance of the detected differences. However, given the
natural rarity of childhood PAH, our study aimed to reveal
specific changes and differences of invasive indices of
adverse pulmonary vascular remodeling related to IPAH
and PAH-CHD. As most patients were already on targeted
PAH therapy at the time of cardiac catheterization, the
actual response and significance of AVT may be altered;
however, in order to minimize such effects, according to
our study protocol PAH-specific drug therapy was sus-
pended at least 12 h before catheterization.
Conclusions
Our study demonstrates significant pulmonary vascular
disease in children with persistent or recurrent PAH fol-
lowing complete surgical repair of CHD similar to IPAH
patients. Although baseline hemodynamics appeared more
favorable in the PAH-CHD group, pulmonary vasoreac-
tivity was markedly impaired in this group which may
contribute to its negative impact on the long-term outcome.
Compliance with Ethical Standards
Conflict of interest The authors declare that they have no conflict of
interest.
Ethical Approval All procedures performed in studies involving human
participants were in accordance with the ethical standards of the institu-
tional and/or national research committee and with the 1964 Helsinki
declaration and its later amendments or comparable ethical standards.
Informed Consent Informed consent was obtained from all indi-
vidual participants included in the study.
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