Pediatr Cardiol
DOI 10.1007/s00246-016-1501-9
ORIGINAL ARTICLE
Home Exercise Training in Children and Adolescents
with Pulmonary Arterial Hypertension: A Pilot Study
David Zoller1 Jannos Siaplaouras1 Anita Apitz1 Peter Bride1 Michael Kaestner1
Heiner Latus2 Dietmar Schranz2 Christian Apitz1
Received: 11 April 2016 / Accepted: 25 October 2016
Springer Science+Business Media New York 2016
Abstract Pulmonary arterial hypertension (PAH) is often
associated with impaired exercise capacity. It has been
shown that supervised training can improve exercise
capacity in adult patients with PAH. The objective of this
prospective study was to assess the feasibility of a home
exercise training program in children with PAH. Nine
children and adolescents (mean age 15.2 3.8 years) with
low-risk PAH (defined as mean pulmonary to systemic
arterial pressure ratio \0.75; WHO functional class I and
II) performed home-based exercise training for 16 weeks.
Cardiopulmonary exercise testing and health-related qual-
ity of life was evaluated before and after 16 weeks of
training. The amount of training at home and patients
well-being was supervised by periodical phone calls and
online-questionnaires. Home exercise training was well
tolerated in all patients, and no adverse events occurred.
After 16 weeks of training, patients significantly improved
their exercise capacity [treadmill running distance
increased from 589.5 153.9 to 747.9 209.2 m
(p = 0.036)]. Oxygen consumption at the anaerobic
threshold increased from 1307.8 (417) to 1406.4
(418) ml (p = 0.028). Chronotropic index improved
from 0.77 0.12 to 0.82 0.11 (p = 0.004) and was
slightly related to the increase in running distance
(r = 0.62; p = 0.07). Home exercise training is feasible in
David Zoller and Jannos Siaplaouras contributed equally to this
manuscript.
& Christian Apitz
Capitz@aol.com
1
Department of Pediatric Cardiology, University Childrens
Hospital Ulm, Eythstr. 24, 89075 Ulm, Germany
2
Pediatric Heart Center, University of Giessen, Giessen,
Germany
children and adolescents with low-risk PAH, and the pre-
liminary results of this pilot study indicate beneficial
effects. The observed increase in exercise capacity was
accompanied by an improved chronotropic competence
and increased oxygen consumption at the anaerobic
threshold. Future research is needed to investigate the
safety and efficacy of home exercise training in a larger
population of children with PAH including also patients in
WHO functional class III or IV.
Keywords Heart rate variability
Pediatric cardiology

Exercise training
Congenital heart disease
Pulmonary
hypertension
Introduction
Pulmonary arterial hypertension (PAH) is a rare disease
with an incidence of 23 per million and a prevalence of
2550 per million [1]. Although recent developments of
PAH-targeted therapies resulted in an improvement of
prognosis, morbidity and mortality is still high in children
and adolescents [26]. Thus, pediatric patients with PAH
urgently need additional therapeutic tools.
Specific treatment goals in children include exercise
capacity assessed by six minute walking distance or alter-
natively by cardiopulmonary exercise testing (CPET) [7].
Although exercise testing can usually be performed safely
in a clinical outpatient setting [8], it is rather unclear
whether and to which extent children and adolescents with
PAH should perform sports or exercise training on a reg-
ular basis at home. Recently, there is growing evidence that
in adults with idiopathic PAH (IPAH) and different forms
of associated PAH (APAH), an individualized and super-
vised exercise training as add-on to optimized medical
123

treatment may be able to increase exercise capacity, quality
of life, peak oxygen consumption, and WHO functional
class [916]. It is unclear whether these results are repro-
ducible also in children and adolescents with PAH.
Therefore, the aim of this pilot study was to prospec-
tively assess the feasibility of exercise training and its
effects on safety and prognostic relevant factors such as
exercise capacity and quality of life in pediatric patients
with low-risk PAH in an outpatient setting.
Methods
Study Population and Design
Children ([8 years of age) and adolescents with low-risk
PAH (defined as mean pulmonary to systemic arterial
pressure ratio \0.75; WHO functional class I and II) [17]
were offered to participate in this prospective pilot study at
our tertiary referral center. Patients had to be stable under
optimized advanced PAH-specific therapy for a minimum
of 3 months before entering the study and medication
remained unchanged during the complete study period. For
each patient, the diagnosis was previously established by
cardiac catheterization including testing for pulmonary
vasoreactivity prior to the study. The study protocol con-
forms to the ethical guidelines of the 1975 Declaration of
Helsinki and was approved by the local ethics committee.
Each patient gave written informed consent prior to the
inclusion in the study, as well as the caregivers if the
patient was below 18 years of age.
To assess the effects of the individual training program,
clinical assessment, cardiopulmonary exercise testing, and
the evaluation of health-related quality of life were per-
formed at baseline and after 16 weeks of training in all
patients.
Cardiopulmonary Exercise Testing
Cardiopulmonary exercise testing was performed on a
treadmill (CareFusion MasterScreen CPX, Hochberg,
Germany) according to a modified Bruce protocol as
described previously [18]. All subjects were encouraged
to exercise until exhaustion regardless of the maximal
heart rate achieved. Ventilation, oxygen uptake, and car-
bon dioxide production were measured continuously.
Heart rate was assessed by continuous electrocardiogra-
phy. Resting heart rate was measured after at least 2 min
in an upright position, and peak heart rate was defined as
the maximal heart rate achieved during exercise. Anaer-
obic threshold has been determined manually as described
previously.
123
Pediatr Cardiol
Calculation of Heart Rate Reserve
and Chronotropic Index
Heart rate reserve was calculated as the difference between
peak and resting heart rates. The chronotropic index, (peak
heart rate - resting heart rate)/(220 - age - resting heart
rate) [19], is derived by applying the chronotropic meta-
bolic relationship concept introduced by Wilkoff et al. [20]
to a symptom-limited exercise test as described previously
[21]. This allows definition of the normal chronotropic
response independently of age, resting heart rate, and
functional state [20]. In a group of 410 healthy adults,
Wilkoff et al. [20] reported 95% limits of normality of
chronotropic index to be 0.81.3. Based on this finding,
chronotropic incompetence is usually defined as failure to
achieve a chronotropic index of 0.8 (i.e., falling below
97.5% of healthy adults).
Calculation of Heart Rate Recovery
Heart rate was also recorded 1, 2, 3, and 4 min after the
cessation of exercise, and heart rate recovery was calcu-
lated as the difference between peak heart rate and the
heart rate at these recovery time points. In addition, the
relative decrement in heart rate was calculated as heart rate
recovery divided by the heart rate at peak exercise.
Health-Related Quality of Life
We used the 12-item Short Form Survey (SF-12) to assess
quality of life at baseline and after 16 weeks [22, 23]. The
questionnaires were completed by the patient (if C16 years
and capable to do) or by both, parents and children (if
\16 years). The questionnaire provides a physical com-
ponent summary (PCS) score and mental component
summary (MCS) score. Both scores range from 0 to 100.
Higher scores indicate a better self-reported health status.
Normal mean values of German children and adolescents
aged between 14 and 20 years are PCS = 52.99 and
MCS = 49.63 [24].
Exercise Training
For a total of 16 weeks, patients performed home exercise
training consisting of two components with target on
endurance training (bicycle ergometer) and activities
focusing on muscle tone (theraband). All patients received
an individualized training manual and arranged to receive a
bicycle ergometer and therabands for use at home.
In detail, the training consisted of a heart rate controlled
bicycle ergometer training, performed twice a week,
starting with a low workload (2025 W) for 2025 min per
day, achieving approximately 6070% of the heart rate
Pediatr Cardiol
they had reached during peak oxygen uptake at the initial
exercise test. The training intensity was increased (e.g., up
to a maximum of 70 W) with respect to the individual
tolerability and improvement. Training intensity was lim-
ited by peak heart rate (not more than 150 bpm) and sub-
jective physical exertion. Furthermore, a set of seven
different theraband workouts have been performed on two
separate days apart from the bicycle training twice a week.
All patients were advised to avoid heavy exercise. Thera-
band workouts have been practiced with support of local
physiotherapists and further assisted by web-based training
films. During the home-based exercise training, all patients
were asked to keep in close contact with the physicians of
the training program and to complete a short online-ques-
tionnaire at each training day. Furthermore, the amount of
training at home and patients well-being was supervised
by phone at least every 2 weeks by members of the study
team.
Statistical Analysis
All values are given as mean SD. Comparison between
pre- and post-training was made using paired t test. Cor-
relations were tested using linear regression analysis.
Analysis was performed using GraphPad statistical soft-
ware package (San Diego, CA, USA). p values B0.05 were
considered statistically significant.
Results
Study Population
The study group consisted of nine children and adolescents
with PAH (six female, mean age 15.2 3.8 years).
Baseline characteristics of the patients including demo-
graphic data, diagnosis, PAH-specific medical therapy, and
hemodynamic data are displayed in Table 1. None of the
patients received supplemental oxygen. According to the
WHO functional classification, all patients were in func-
tional class I and II.
Effects of Exercise Training
All patients tolerated the exercise training well without
severe adverse events, especially no syncope or presyncope
occurred. Each patient reported that exercise training
improved the awareness of physical abilities and limita-
tions and was overall satisfied with the training program.
After 16 weeks of home-based training, patients sig-
nificantly improved their exercise capacity. All except two
patients improved in running distance compared to base-
line. Loading time improved significantly by 16.7%
(absolute 01:39 01:58), treadmill distance increased
even by 30.6% (absolute 158.4 189.3) (Table 2; Fig. 1).
The reason for nonresponse to exercise training in 2 of the
9 patients was noncompliance in one patient due to a
depressive episode following separation of her boyfriend,
and in the second patient limited intellectual and motoric
ability to comply with the protocol due to young age, as the
patient was 8 years old.
There was no significant change in peak oxygen con-
sumption [peak VO2 at baseline 1682.3 (569), after
training 1692.3 (505) ml (p = 0.84)], while oxygen
consumption at the anaerobic threshold improved by 8.1%
from 1307.8 (417) to 1406.4 (418) ml (p = 0.028)
(Fig. 2a).
Exercise training had remarkable effects on chrono-
tropic competence (Table 2). Maximum heart rate
increased significantly from 177.6 (13.6) to 184.4
(11.2) beats per minute (p = 0.009) (Fig. 2b), and
chronotropic index increased from 0.77 (0.12) to 0.82
(0.11) (p = 0.004) (Fig. 3). As in six of 9 patients, the
chronotropic index was below 0.8 before training, in all
except one patient an improvement of chronotropic index
could be detected after 16 weeks of training (Fig. 3). As
Fig. 4 demonstrates, heart rate recovery did not change
significantly (Fig. 4).
Interestingly, change in chronotropic index was slightly
related to change in treadmill running distance (r = 0.62;
p = 0.07). However, there was no correlation between
peak VO2 and change in chronotropic index or change in
running distance.
Quality of Life
Physical component summary (PCS) score showed an
increase after exercise training of 14.9% (absolute
5.5 8.2) and reached almost age-related normal levels.
Mental component summary (MCS) score was already at a
normal level before training and even slightly improved
after the training by 6.9% (absolute 2.5 6.4) (Fig. 5).
Discussion
This pilot study presents for the first time promising effects
of exercise training as add-on to PAH-targeted medication
in a population of children and adolescents with PAH,
thereby confirming data previously reported in adult
patients with PAH [916]. Mean walking distance signifi-
cantly improved by more than 30% after 16 weeks of
exercise training. Taking into consideration that patients
with PAH usually have limitations of their exercise
capacity, and reduced walking distance is one of the main
predictors of mortality in patients with PAH [25],
123
 Pediatr Cardiol

Table 1 Baseline
Study population Male/female 3/6
characteristics
Age (years) 15.2 3.8
Height (cm) 163.7 15.0
Weight (kg) 61.3 29.4
Diagnosis, no. (%) Idiopathic pulmonary arterial hypertension 8 (88.9%)
PAH associated with congenital heart disease 1 (11.1%)
Catheterization data Right arterial pressure (mmHg) 5.2 2.3
Mean pulmonary arterial pressure (mmHg) 43.8 19.7
Diastolic pulmonary arterial pressure (mmHg) 29.2 14.5
Mean systemic arterial pressure (mmHg) 87.7 13.9
mPAP/mSAP 0.5 0.2
Pulmonary arterial wedge pressure (mmHg) 8.2 2.8
Pulmonary vascular resistance index (WU 9 m2) 9.4 5.2
Time interval between Cath and Study (months) 33 21
PAH-targeted medication Endothelin receptor antagonists 4 (44.4%)
Phosphodiesterase-Type5-inhibitors 5 (55.6%)
Calcium channel blockers 5 (55.6%)
Combination therapy Monotherapy 4 (44.4%)
Dual therapy 5 (55.6%)
Values are mean SD
mPAP/mSAP ratio of mean pulmonary arterial pressure to systemic arterial pressure

Table 2 Training effects on

Baseline Post-training Absolute (percental) change p value
cardiopulmonary exercise
testing Cardiopulmonary exercise testing
Loading time (min) 10:42 01:47 12:21 02:11 01:39 01:58 (16.7%) 0.0359
Treadmill distance (m) 589.5 153.9 747.9 209.2 158.4 189.3 (30.6%) 0.0364
HR rest (L/min) 92.7 14.4 93.1 10.3 0.4 7.8 (1.5%) 0.8676
HR max (L/min) 177.6 13.6 184.4 11.2 6.9 6.0 (4.0%) 0.0090
HR reserve (L/min) 85.8 15.4 91.7 15.2 5.9 7.7 (7.4%) 0.0503
Chronotropic index 0.77 0.12 0.82 0.11 0.06 0.04 (7.9%) 0.0037
VO2@AT (mL/min) 1307.8 417.0 1406.4 417.9 98.7 110.5 (8.1%) 0.0280
VO2@AT/kg (mL/min/kg) 23.2 6.1 24.2 5.2 1.1 2.7 (5.9%) 0.2757
Peak VO2 (mL/min) 1682.3 568.7 1692.3 505.4 10.0 143.8 (1.62%) 0.8400
Peak VO2/kg (mL/min/kg) 29.7 7.2 29.2 6.3 -0.4 3.2 (-0.5%) 0.6888
Oxygen pulse (mL) 9.4 2.8 9.1 2.6 -0.3 0.7 (-2.3%) 0.3101
EqO2 37.8 7.7 40.1 7.0 2.3 5.1 (7.6%) 0.2081
EqCO2 34.9 7.2 35.1 5.7 0.2 4.3 (1.9%) 0.8872
RER (VCO2/VO2) 1.13 0.13 1.15 0.12 0.02 0.1 (2.46%) 0.5473
Values are mean SD. Percental change was calculated by averaging the individual percental change of
each patient
HR rest resting heart rate, HR max maximum heart rate, HR reserve heart rate reserve, VO2@AT oxygen
uptake at the anaerobic threshold, peak VO2 Peak oxygen uptake, EqO2 ventilatory equivalent for oxygen,
EqCO2 ventilatory equivalent for carbon dioxide, RER respiratory exchange rate

improvement of walking distance by exercise training as
reached in our study might be of important prognostic
relevance.
While in adult studies the improvement of exercise
capacity was frequently associated with an increase of peak
oxygen uptake, in our study peak oxygen uptake was
almost unchanged after 16 weeks of training, a result that
might be due to the study protocol, as a similar lacking
response on peak VO2 was also described by other authors
who performed exercise training in a similar outpatient

123
Pediatr Cardiol

600 a
mean increase: + 158.35 (meters) p=0.0364
2000
500 mean increase: + 98.67 (ml/min) p=0.0280
Change in running distance (meters)

1800
400
1600

300 1400

VO2@AT (ml/min)
1200
200
1000
100
800
0 600
1307.8 1406.4
-100 400 417.0 417.9
(ml/min) (ml/min)
200
-200
baseline 16 weeks 0
baseline 16 weeks
Fig. 1 Change in running distance. Change in running distance
(m) during cardiopulmonary exercise testing (CPET) at baseline and
after 16 weeks of training for each patient. CPET was performed on
b
200
mean increase: + 6.88 (1/min) p=0.0090
treadmill according to the modified Bruce treadmill protocol. After
16 weeks of supervised training, all except two patients improved in 195
running distance compared to baseline. Mean treadmill distance
190
Maximum heart rate (1/min)
increased from 589.5 (153.9) to 747.9 (209.2) m (p = 0.0364).
The reason for nonresponse to exercise training in 2 of the 9 patients 185
was noncompliance in one patient due to a depressive episode
following separation of her boyfriend, and in the second patient 180
limited intellectual and motoric ability to comply with the protocol
175
due to young age (8 years old)
170

setting, although in an adult population [15, 26, 27].
However, it may also be a more typical finding in pediatric
and adolescent patients, since in previous studies in a
healthy population of children and adolescents it has been
demonstrated that the magnitude of training-induced
changes in peak VO2 may be smaller than that seen in
adults, possibly also due to lower compliance in this pop-
ulation [28, 29].
Interestingly, oxygen consumption at the anaerobic
threshold did improve in our study, which can be explained
by the fact that the patients did their training at a sub-
maximal level, where preferably changes of oxygen con-
sumption at the anaerobic threshold might be expected.
Thus, the used exercise protocol might have been not fre-
quent enough, intense enough, nor long enough to elicit
changes in peak VO2.
Remarkably, the increased exercise capacity found in
our study was accompanied by a significant improvement
of chronotropic competence. A lack of chronotropic com-
petence, i.e., a blunted increase in heart rate during exer-
cise, is an established predictor of mortality in patients with
coronary artery disease, adults with congenital heart dis-
ease and in healthy populations [19, 21, 30]. Little is
known about its prevalence and prognostic implication in
children with PAH. We found that patients with increased
165
160 177.6 184.4
13.6 11.2
155
(1/min) (1/min)
baseline 16 weeks
Fig. 2 a Change in oxygen consumption at the anaerobic threshold.
Change in oxygen consumption at the anaerobic threshold
[VO2@AT] during cardiopulmonary exercise testing (CPET) at
baseline and after 16 weeks. CPET was performed on treadmill
according to the modified Bruce treadmill protocol. Oxygen con-
sumption at the anaerobic threshold improved from 1307.8 (417) at
baseline to 1406.4 (418) ml after 16 weeks of training (p = 0.028).
b Change in maximum heart rate. Change in maximum heart rate
[beats per minute] during cardiopulmonary exercise testing (CPET) at
baseline and after 16 weeks. CPET was performed on treadmill
according to the modified Bruce treadmill protocol. Maximum heart
rate increased significantly from 177.6 (13.6) at baseline to 184.4
(11.2) beats per minute after 16 weeks of training (p = 0.009)
chronotropic competence had improved exercise capacity
as result of their training program.
Underlying mechanisms responsible for chronotropic
incompetence in PAH patients are not fully understood. It
appears likely that chronotropic incompetence is a multi-
factorial phenomenon resulting from the confluence of
several factors which themselves are associated with poor
prognosis. Colluci et al. [31] reported that impaired

123
 Pediatr Cardiol

1.0 55
baseline 16 weeks p=0.0785 p=0.2788
chronotropic index

50 51.88
1 51.27

SF-12-Score
49.42

0.8 45
45.75

p=0.0037
40
0.6

Physical component summary score Mental component summary score

1 2
Fig. 3 Training effects on chronotropic index. Changes in chrono-
tropic index (peak heart rate - resting heart rate)/(220 - age - rest-
ing heart rate) for each patient. This index allows definition of the
normal chronotropic response independently of age, resting heart rate,
and functional state [20]. Chronotropic incompetence is usually
defined as a chronotropic index below 0.8 (dotted line). The mean
chronotropic index increased significantly from 0.77 (0.12) at
baseline to 0.82 (0.11) after 16 weeks of training (p = 0.0037)
peak of excercise
Heart rate as percentage of peak exercise value
3 4 5 6 7 8 9 mean
value baseline 16 weeks
patients
Fig. 5 Training effects on quality of life (SF-12). Training effects on
quality of life assessed by the SF-12 questionnaire. The questionnaire
provides a physical component summary (PCS) score and mental
component summary (MCS) score. Both scores range from 0 to 100.
Higher scores indicate a better self-reported health status. Normal
mean values of Caucasian children and adolescents aged between 14
and 20 years are PCS = 52.99 and MCS = 49.63. PCS score showed
an increase after exercise training toward normal levels although the
change did not reach significance [45.75 (7.5) and 51.3 (5.8),
respectively; p = 0.079]. MCS score was at a normal level before
training and even slightly improved after the training [49.4 (8.4) and
51.9 (6.8), respectively; p = 0.279]

100%
baseline 16 weeks

p=0.4468 present in children and adolescents with PAH and might be

90%
p=0.8067
80%
70%
0 1
Time into recovery (minutes)
Fig. 4 Heart rate recovery. Heart rate was recorded at maximum
exercise and 1, 2, 3, and 4 min after the cessation of exercise. Heart
rate recovery was calculated as the difference between peak heart rate
and the heart rate at these recovery time points. In addition, the
relative decrement in heart rate was calculated as heart rate recovery
divided by the heart rate at peak exercise. There was no significant
change of mean heart rate recovery between baseline CPET and after
16 weeks of training
chronotropic response to exercise in patients with chronic
heart failure is, at least in part, due to postsynaptic
desensitization of beta-adrenergic receptors.
Attenuation of heart rate recovery, i.e., the rate of
decrease in heart rate after cessation of exercise, also is
associated with increased mortality in patients being
assessed for coronary artery disease [32]. Since cardiac
autonomic dysfunction is not uncommon in PAH patients
[33], which may also be related to disease severity and
prognosis [34, 35], our preliminary results suggest that
abnormal heart rate response to exercise also appears to be
improved by exercise training.
Although children and adolescents with PAH frequently
p=0.1658
are severely affected with reduced exercise capacity
p=0.1257
especially in psychosocial aspects, quality of life parame-
ters seems to be less impaired as in adult IPAH patients
[36]. This might be due to the fact that pediatric PAH
patients live with the disease often from early childhood on
2 3 4 and might be better adapted to exercise limitations. In our
study, the SF-12 subscale physical component summary
(PCS) improved by exercise training consistently with
improved exercise capacity.
While the effects of training may vary between different
exercise programs and settings, the promising results of
this pilot study suggest that, in experienced hands, exercise
training may be an important add-on therapy also in chil-
dren and adolescents with PAH, especially in regard of
their impaired exercise capacity and may be able to
improve clinically relevant parameters.
Although no severe adverse effects occurred during the
home-based exercise training program of this pilot study, in
our opinion these programs should be closely monitored by
PAH experts. Exercise training in children and adolescents
with PAH seems to be an effective add-on therapy, but it is
not completely harmless. In particular in children, it has to
address special needs and pathophysiological
circumstances.
As previously described, an in-hospital start of the
rehabilitation program may have the advantage of a closely
supervised setting which might be beneficial especially in
young patients with PAH, since they may tend to

123
Pediatr Cardiol
overestimate their exercise capacity. In the presented study
on a low-risk pulmonary hypertension population, we were
able to show that an exclusively home-based exercise
training can also be performed safely by keeping in close
online and phone contact with the physicians or study
nurses of the training program and with additional support
of local physiotherapists. In subjects who are more severely
limited (WHO functional class III or IV), an inpatient and/
or careful outpatient initiation under close observation and
monitoring might be essential. Nonetheless, our presented
data represent an important first step in understanding the
impact of regular exercise in young patients with PAH.
The results of this prospective pilot study are limited by
the small number of patients. Because of this, the observed
effects have to be interpreted with caution; studies with
larger patient populations are clearly needed. Another
limitation is the lack of randomization. Because of this,
there could be a referral bias that patients doing well have
been selected. The patients that were enrolled elected to
participate in the study and may have represented
patients/families that are healthier, more active, or more
motivated than the general pulmonary hypertension popu-
lation. Nevertheless, the study provides a good rationale for
future randomized controlled studies.
Conclusions
A 16-week exercise training in children and adolescents
with low-risk PAH as add-on to optimized medical therapy
was feasible and resulted in an improvement of exercise
capacity, which was associated by improved chronotropic
competence. Chronotropic competence may therefore serve
as a physiologically important therapeutic target for train-
ing programs in children and adolescents with PAH
alongside the usual measurements of oxygen consumption.
Future research is needed to investigate the safety and
efficacy of home exercise training in a larger population of
children with PAH including also patients in WHO func-
tional class III or IV.
Acknowledgements We would like to thank all patients who par-
ticipated in this study for their high motivation and the parents for
their trust and support, as well as the local physiotherapists for their
highly appreciated collaboration.
Funding This work (D.Z., A.A., C.A.) was funded by grant support
of the Stiftung Kinderherz (2511-10-13-001). J.S. was supported
by a research grant of Actelion.
Compliance with Ethical Standards
Conflict of interest J.S. is director of SPORTICUM GmbH, a non-
profit-organization that supports children and adolescents with
chronic underlying medical conditions to practice sport. The other
authors (D.Z., A.A., P.B., M.K., H.L., D.S., and C.A.) declare that
they have no conflict of interest related to this manuscript.
References
1. Berger RMF, Beghetti M, Humpl T, Raskob GE, Ivy DD, Jing Z
et al (2012) Clinical features of paediatric pulmonary hyperten-
sion. A registry study. Lancet 379:537546. doi:10.1016/S0140-
6736(11)61621-8
2. Latus H, Delhaas T, Schranz D, Apitz C (2015) Treatment of
pulmonary arterial hypertension in children. Nat Rev Cardiol
12:244254. doi:10.1038/nrcardio.2015.6
3. Barst RJ, McGoon MD, Elliott CG, Foreman AJ, Miller DP, Ivy
DD (2012) Survival in childhood pulmonary arterial hyperten-
sion: insights from the registry to evaluate early and long-term
pulmonary arterial hypertension disease management. Circulation
125:113122. doi:10.1161/CIRCULATIONAHA.111.026591
4. Ivy DD, Rosenzweig EB, Lemarie J, Brand M, Rosenberg D,
Barst RJ (2010) Long-term outcomes in children with pulmonary
arterial hypertension treated with bosentan in real-world clinical
settings. Am J Cardiol 106:13321338. doi:10.1016/j.amjcard.
2010.06.064
5. van Loon RLE, Roofthooft MTR, Delhaas T, van Osch-Gevers
M, ten Harkel Arend DJ, Strengers JLM et al (2010) Outcome of
pediatric patients with pulmonary arterial hypertension in the era
of new medical therapies. Am J Cardiol 106:117124. doi:10.
1016/j.amjcard.2010.02.023
6. Haworth SG, Hislop AA (2009) Treatment and survival in chil-
dren with pulmonary arterial hypertension: the UK Pulmonary
Hypertension Service for Children 20012006. Heart
95:312317. doi:10.1136/hrt.2008.150086
7. Ploegstra M, Douwes JM, Roofthooft MTR, Zijlstra WMH,
Hillege HL, Berger RMF (2014) Identification of treatment goals
in paediatric pulmonary arterial hypertension. Eur Respir J
44:16161626. doi:10.1183/09031936.00030414
8. Smith G, Reyes JT, Russell JL, Humpl T (2009) Safety of
maximal cardiopulmonary exercise testing in pediatric patients
with pulmonary hypertension. Chest 135:12091214. doi:10.
1378/chest.08-1658
9. Ehlken N, Lichtblau M, Klose H, Weidenhammer J, Fischer C,
Nechwatal R et al (2016) Exercise training improves peak oxygen
consumption and haemodynamics in patients with severe pul-
monary arterial hypertension and inoperable chronic thrombo-
embolic pulmonary hypertension: a prospective, randomized,
controlled trial. Eur Heart J 37:3544. doi:10.1093/eurheartj/
ehv337
10. Becker-Grunig T, Klose H, Ehlken N, Lichtblau M, Nagel C,
Fischer C et al (2013) Efficacy of exercise training in pulmonary
arterial hypertension associated with congenital heart disease. Int
J Cardiol 168:375381. doi:10.1016/j.ijcard.2012.09.036
11. Chan L, Chin LMK, Kennedy M, Woolstenhulme JG, Nathan SD,
Weinstein AA et al (2013) Benefits of intensive treadmill exer-
cise training on cardiorespiratory function and quality of life in
patients with pulmonary hypertension. Chest 143:333343.
doi:10.1378/chest.12-0993
12. Fox BD, Kassirer M, Weiss I, Raviv Y, Peled N, Shitrit D et al
(2011) Ambulatory rehabilitation improves exercise capacity in
patients with pulmonary hypertension. J Card Fail 17:196200.
doi:10.1016/j.cardfail.2010.10.004
13. Grunig E, Lichtblau M, Ehlken N, Ghofrani HA, Reichenberger
F, Staehler G et al (2012) Safety and efficacy of exercise training
in various forms of pulmonary hypertension. Eur Respir J
40:8492. doi:10.1183/09031936.00123711
123

14. Grunig E, Maier F, Ehlken N, Fischer C, Lichtblau M, Blank N
et al (2012) Exercise training in pulmonary arterial hypertension
associated with connective tissue diseases. Arthritis Res Ther
14:R148. doi:10.1186/ar3883
15. de Man FS, Handoko ML, Groepenhoff H, vant Hul AJ, Abbink
J, Koppers RJH et al (2009) Effects of exercise training in
patients with idiopathic pulmonary arterial hypertension. Eur
Respir J 34:669675. doi:10.1183/09031936.00027909
16. Mereles D, Ehlken N, Kreuscher S, Ghofrani S, Hoeper MM,
Halank M et al (2006) Exercise and respiratory training improve
exercise capacity and quality of life in patients with severe
chronic pulmonary hypertension. Circulation 114:14821489.
doi:10.1161/CIRCULATIONAHA.106.618397
17. Ivy DD, Abman SH, Barst RJ, Berger RMF, Bonnet D, Fleming
TR et al (2013) Pediatric pulmonary hypertension. J Am Coll
Cardiol 62:D117D126. doi:10.1016/j.jacc.2013.10.028
18. Dubowy K, Baden W, Bernitzki S, Peters B (2008) A practical
and transferable new protocol for treadmill testing of children and
adults. Cardiol Young 18:615623. doi:10.1017/
S1047951108003181
19. Jouven X, Empana J, Schwartz PJ, Desnos M, Courbon D,
Ducimetiere P (2005) Heart-rate profile during exercise as a
predictor of sudden death. N Engl J Med 352:19511958. doi:10.
1056/NEJMoa043012
20. Wilkhoff BL, Corey J, Blackburn G (1989) A mathematical
model of the cardiac chronotropic response to exercise. J Elec-
trophysiol 3:176180. doi:10.1111/j.1540-8167.1989.tb01549.x
21. Lauer MS (1999) Impaired chronotropic response to exercise
stress testing as a predictor of mortality. JAMA 281:524. doi:10.
1001/jama.281.6.524
22. Jenkinson C, Layte R, Jenkinson D, Lawrence K, Petersen S,
Paice C et al (1997) A shorter form health survey: can the SF-12
replicate results from the SF-36 in longitudinal studies. J Public
Health Med 19:179186
23. Ware JE, Kosinski M, Keller S (1996) SF-12: an even shorter
health survey. Med Outcomes Trust Bull 4:2
24. Morfeld M, Kirchberger I, Bullinger M (2016) SF-36. Manual;
2011. http://www.testzentrale.de/programm/sf-36-fragebogen-
zum-gesundheitszustand.html. Accessed 10 Jan 2016
25. Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Fore-
man AJ, Coffey CS et al (2010) Predicting survival in pulmonary
arterial hypertension: insights from the Registry to Evaluate Early
and Long-Term Pulmonary Arterial Hypertension Disease Man-
agement (REVEAL). Circulation 122:164172. doi:10.1161/
CIRCULATIONAHA.109.898122
123
Pediatr Cardiol
26. Martnez-Quintana E, Miranda-Caldern G, Ugarte-Lopetegui A,
Rodrguez-Gonzalez F (2010) Rehabilitation program in adult
congenital heart disease patients with pulmonary hypertension.
Congenit Heart Dis 5:4450. doi:10.1111/j.1747-0803.2009.
00370.x
27. Boutet K, Garcia G, Degano B, Gonzalves-Tavares M, Tcher-
akian C, Jas X et al (2008) Results of a 12-week outpatient
cardiovascular rehabilitation in patients with idiopathic pul-
monary arterial hypertension (iPAH). Eur Respir J 32:240241
28. Mahon AD (2000) Exercise training. In: Armstrong N, Van
Mechelen W (eds) Paediatric exercise science and medicine.
Oxford University Press, Oxford, pp 201222
29. Stoedefalke K, Armstrong N, Kirby BJ, Welsman JR (2000)
Effect of training on peak oxygen uptake and blood lipids in 13 to
14-year-old girls. Acta Paediatr 89:12901294
30. Lauer MS, Okin PM, Larson MG, Evans JC, Levy D (1996)
Impaired heart rate response to graded exercise. Prognostic
implications of chronotropic incompetence in the Framingham
Heart Study. Circulation 93:15201526
31. Colucci WS, Ribeiro JP, Rocco MB, Quigg RJ, Creager MA,
Marsh JD et al (1989) Impaired chronotropic response to exercise
in patients with congestive heart failure. Role of postsynaptic
beta-adrenergic desensitization. Circulation 80:314323
32. Cole CR, Blackstone EH, Pashkow FJ, Snader CE, Lauer MS
(1999) Heart-rate recovery immediately after exercise as a pre-
dictor of mortality. N Engl J Med 341:13511357. doi:10.1056/
NEJM199910283411804
33. Wensel R, Jilek C, Dorr M, Francis DP, Stadler H, Lange T et al
(2009) Impaired cardiac autonomic control relates to disease
severity in pulmonary hypertension. Eur Respir J 34:895901.
doi:10.1183/09031936.00145708
34. Latus H, Bandorski D, Rink F, Tiede H, Siaplaouras J, Ghofrani
A et al (2015) Heart rate variability is related to disease severity
in children and young adults with pulmonary hypertension. Front
Pediatr 3:63. doi:10.3389/fped.2015.00063
35. Lammers AE, Munnery E, Hislop AA, Haworth SG (2010) Heart
rate variability predicts outcome in children with pulmonary
arterial hypertension. Int J Cardiol 142:159165. doi:10.1016/j.
ijcard.2008.12.087
36. Gratz A, Hess J, Hager A (2009) Self-estimated physical func-
tioning poorly predicts actual exercise capacity in adolescents
and adults with congenital heart disease. Eur Heart J 30:497504.
doi:10.1093/eurheartj/ehn531