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Citation: Vecchiato, M.; Ermolao, A.;
Zanardo, E.; Battista, F.; Ruvoletto, G.;
Palermi, S.; Quinto, G.; Degano, G.;
Gasperetti, A.; Padalino, M.A.; et al.
Overshoot of the Respiratory
Exchange Ratio during Recovery
from Maximal Exercise Testing in
Young Patients with Congenital
Heart Disease. Children 2023,10, 521.
https://doi.org/10.3390/
children10030521
Academic Editors: P. Syamasundar
Rao, Arpit Agarwal and Harinder
R. Singh
Received: 31 December 2022
Revised: 2 March 2023
Accepted: 4 March 2023
Published: 7 March 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
children
Article
Overshoot of the Respiratory Exchange Ratio during Recovery
from Maximal Exercise Testing in Young Patients with
Congenital Heart Disease
Marco Vecchiato 1,2 , Andrea Ermolao 1,2 , Emanuele Zanardo 1,2, Francesca Battista 1,2 ,* , Giacomo Ruvoletto 1,
Stefano Palermi 3, Giulia Quinto 1,2 , Gino Degano 1,2, Andrea Gasperetti 1,2, Massimo A. Padalino 4,
Giovanni Di Salvo 5and Daniel Neunhaeuserer 1,2
1Sports and Exercise Medicine Division, Department of Medicine, University of Padova, 35128 Padova, Italy
2Clinical Network of Sports and Exercise Medicine of the Veneto Region, 35131 Padova, Italy
3Public Health Department, University of Naples Federico II, 80131 Naples, Italy
4Pediatric and Congenital Cardiac Surgery Unit, Department of Cardiac, Thoracic, Vascular Sciences and
Public Health, University of Padova, 35128 Padova, Italy
5Pediatric and Congenital Cardiology Unit, Department for Women’s and Children’s Health,
University of Padova, 35128 Padova, Italy
*Correspondence: francesca.battista@unipd.it
Abstract:
Introduction: The overshoot of the respiratory exchange ratio (RER) after exercise is
reduced in patients with heart failure. Aim: The present study aimed to investigate the presence
of this phenomenon in young patients with congenital heart disease (CHD), who generally present
reduced cardiorespiratory fitness. Methods: In this retrospective study, patients with CHD underwent
a maximal cardiopulmonary exercise testing (CPET) assessing the RER recovery parameters: the
RER at peak exercise, the maximum RER value reached during recovery, the magnitude of the RER
overshoot and the linear slope of the RER increase after the end of the exercise. Results: In total,
117 patients were included in this study. Of these, there were 24 healthy age-matched control subjects
and 93 young patients with CHD (transposition of great arteries, Fontan procedure, aortic coarctation
and tetralogy of Fallot). All patients presented a RER overshoot during recovery. Patients with
CHD showed reduced aerobic capacity and cardiorespiratory efficiency during exercise, as well
as a lower RER overshoot when compared to controls. RER magnitude was higher in the controls
and patients with aortic coarctation when compared to those with transposition of great arteries,
previous Fontan procedure, and tetralogy of Fallot. The RER magnitude was found to be correlated
with the most relevant cardiorespiratory fitness and efficiency indices. Conclusions: The present
study proposes new recovery indices for functional evaluation in patients with CHD. Thus, the
RER recovery overshoots analysis should be part of routine CPET evaluation to further improve
prognostic risk stratifications in patients with CHD.
Keywords:
cardiopulmonary exercise test; CHD; RER; Fontan; Fallot; coarctation; transposition;
functional evaluation
1. Introduction
Congenital heart disease (CHD) accounts for nearly one-third of all major congenital
anomalies and its birth prevalence worldwide is suggested to vary [
1
]. Recent data extracted
from the European Surveillance of Congenital Anomalies estimated the average total
prevalence of CHD in Europe is around 8.0 per 1000 births [
2
]. In this patient population,
long-term survival is decreased [
3
], with lesion severity and repair status as major risk
factors for excess mortality [
4
]. However, due to improvements in medical, surgical, and
intensive care interventions, the life expectancy of patients born with CHD has been rising
over time [3].
Children 2023,10, 521. https://doi.org/10.3390/children10030521 https://www.mdpi.com/journal/children
Children 2023,10, 521 2 of 15
Cardiorespiratory fitness was found to be highly heterogeneous both within and
between individuals with CHD diagnoses [
5
]. In this context, cardiopulmonary exercise
testing (CPET) has emerged as an important tool for risk stratification and may guide
clinicians in assessing prognosis and planning interventions in CHD patients [
6
,
7
]. CPET
may also be useful for diagnostic purposes as well as for decision-making making.
Most of the studies about CPET have focused on the cardiopulmonary response
during exercise; however, there is less evidence about the respiratory gas indices during
recovery with most studies focusing only on oxygen uptake (VO
2
) kinetics [
8
,
9
]. Most
studies on the recovery phase of patients with heart disease are on adult patients with
heart failure (HF) [
10
–
12
]. These studies demonstrated that patients with HF exhibit an
increased VO
2
delay during the recovery phase after maximal CPET compared to controls
and this delay is associated with the severity of diseases [
13
]. Recently, the transient
increase, defined as overshoot, of some CPET parameters during the recovery phase, such
as the respiratory exchange ratio (RER), has aroused scientific and clinical interest [
12
]. The
magnitudes of these parameters have been compared between HF patients and healthy
subjects, demonstrating that overshoots tended to be more pronounced in subjects with
better cardiopulmonary function during exercise [12].
Cardiovascular recovery after exercise appears to be faster in children than in
adults [14,15]
,
but data about the recovery after CPET in young patients with CHD is limited. VO
2
recovery kinetics and heart rate (HR) recovery are prolonged in patients with different
types of CHD [
16
,
17
] but little is known about the prognostic and diagnostic value of this
data and how it can guide clinical decision-making [18,19].
Therefore, the present study aimed to evaluate the behavior of the respiratory gas
exchange indices during recovery in young patients with CHD, assessing the impact of
different conditions compared with an age-matched healthy control group. Furthermore,
it will be discussed how these recovery parameters might be used for prognostic risk
stratification in clinical routine.
2. Materials and Methods
2.1. Study Design and Population Characteristics
This was a retrospective observational cross-sectional study that included all young
patients with CHD (aged between 7 and 20 years) who were evaluated at our Sports and
Exercise Medicine Division between 2018 and 2021 for cardiovascular screening/follow-up,
sports eligibility assessment, and/or exercise prescription [
20
]. Patients with different CHD
were compared to highlight any functional and prognostic differences between their CPET
exercise and recovery parameters. The selected CHD were the 4 most represented within
our population: transposition of great arteries (TGA), patients with univentricular CHD
who underwent Fontan procedure (Fon), aortic coarctation (CoA), and tetralogy of Fallot
(ToF). Other or complex CHD, as well as all patients with beta-blocker therapy and/or
pacemaker, were excluded from this study. The other exclusion criteria were related to
absolute contraindications to CPET evaluation, as well as musculoskeletal disease that
would impede maximal exercise testing. Moreover, tests with gas monitoring of fewer than
four minutes during the recovery phase were excluded.
A control group of apparently healthy subjects was added, consisting of children who
were referred for pre-participation screening or for minor complaints during exercise, such
as chest pain, palpitations or breathing difficulties, but were declared negative after the
diagnostic process. The control group was selected to match the patient study population
with regard to gender, age, and body mass index (BMI).
In accordance with legal regulations, the Code of Medical Ethics and the Declaration
of Helsinki, subjects were duly informed of the risks, benefits, and stress deriving from the
study protocol and signed a written informed consent form. This study was approved by
the local Ethics Committee for Clinical Research (protocol code 302n/AO/22).
Children 2023,10, 521 3 of 15
2.2. Cardiopulmonary Exercise Testing
For each patient, personal history was collected and a physical examination was
conducted. Each subject underwent a standardized, incremental, maximal 12-leads ECG-
monitored CPET (Masterscreen CPX system Jaeger, Carefusion, Hoechberg, Germany)
using a treadmill (T170 DE-med, h/p/cosmos, Nussdorf-Traunstein, Germany) until a
rating of perceived exertion (RPE)
≥
18/20 of Borg Scale was reached and metabolic,
cardiovascular, or ventilatory signs of exhaustion appeared. Blood pressure was measured
both at rest and during CPET and its recovery phase. The age-predicted heart rate (HR)
was calculated with the following formula: (220-age) bpm. The respiratory gas exchange
(VO
2
, VCO
2
) and ventilation (VE) were monitored through the breath-by-breath mode
and at least until the fourth minute of recovery. The first ventilatory threshold (VT) was
identified through the V-slope method. When the VT was not clearly identifiable, it was
determined by the consensus of two physicians within the following group (A.E., G.D.,
A.G., or D.N.). The respiratory compensation point (RCP) was determined with the same
principle considering the ventilatory equivalents and the partial pressure of end-tidal
carbon dioxide (PETCO
2
). The VE/VCO
2
slope was calculated as the coefficient of linear
regression from the beginning of the exercise (removing possible initial hyperventilation)
to the RCP. The oxygen uptake efficiency slope (OUES) was determined by the slope of the
regression line between VO2and the logarithm of VE [21,22].
2.3. Overshoot Analyses
The RER overshoot was analyzed by assessing five parameters (Figure 1):
Children 2023, 10, x FOR PEER REVIEW 3 of 17
In accordance with legal regulations, the Code of Medical Ethics and the Declaration
of Helsinki, subjects were duly informed of the risks, benefits, and stress deriving from
the study protocol and signed a written informed consent form. This study was approved
by the local Ethics Committee for Clinical Research (protocol code 302n/AO/22).
2.2. Cardiopulmonary Exercise Testing
For each patient, personal history was collected and a physical examination was con-
ducted. Each subject underwent a standardized, incremental, maximal 12-leads ECG-
monitored CPET (Masterscreen CPX system Jaeger, Carefusion, Hoechberg, Germany) us-
ing a treadmill (T170 DE-med, h/p/cosmos, Nussdorf-Traunstein, Germany) until a rating
of perceived exertion (RPE) ≥ 18/20 of Borg Scale was reached and metabolic, cardiovas-
cular, or ventilatory signs of exhaustion appeared. Blood pressure was measured both at
rest and during CPET and its recovery phase. The age-predicted heart rate (HR) was cal-
culated with the following formula: (220-age) bpm. The respiratory gas exchange (VO2,
VCO2) and ventilation (VE) were monitored through the breath-by-breath mode and at
least until the fourth minute of recovery. The first ventilatory threshold (VT) was identi-
fied through the V-slope method. When the VT was not clearly identifiable, it was deter-
mined by the consensus of two physicians within the following group (A.E., G.D., A.G.,
or D.N.). The respiratory compensation point (RCP) was determined with the same prin-
ciple considering the ventilatory equivalents and the partial pressure of end-tidal carbon
dioxide (PETCO2). The VE/VCO2 slope was calculated as the coefficient of linear regres-
sion from the beginning of the exercise (removing possible initial hyperventilation) to the
RCP. The oxygen uptake efficiency slope (OUES) was determined by the slope of the re-
gression line between VO2 and the logarithm of VE [21,22].
2.3. Overshoot Analyses
The RER overshoot was analyzed by assessing five parameters (Figure 1):
Figure 1. The respiratory exchange ratio (RER) recovery parameters in a healthy subject.
• the RER at peak exercise (RER peak) was defined as the highest value of the RER
reached during exercise;
• the highest RER value reached during the recovery phase (RER max);
• the difference between RER max and RER peak, calculated as the percentual increase
during the recovery phase; i.e., RER magnitude (RER mag);
Figure 1. The respiratory exchange ratio (RER) recovery parameters in a healthy subject.
•
the RER at peak exercise (RER peak) was defined as the highest value of the RER
reached during exercise;
•the highest RER value reached during the recovery phase (RER max);
•
the difference between RER max and RER peak, calculated as the percentual increase
during the recovery phase; i.e., RER magnitude (RER mag);
•
the slope of the RER calculated by linearly regressing the RER data between RER peak
and RER max during the recovery phase (RER slope);
•the time between RER peak and RER max (Time to RER max) [12].
Children 2023,10, 521 4 of 15
2.4. Ventricular Function Assessment
Furthermore, all subjects were assessed to obtain data regarding ventricular systolic
function. Data regarding ventricular systolic function were obtained by echocardiographic
evaluations, which have been performed in the context of the routine follow-up of these
patients at the Department of Women’s and Children’s Health of University of Padova.
The parameter chosen to quantify the systolic function of the left ventricle is the ejection
fraction (LVEF), which indicates the ratio (expressed as a percentage) between the volume
of blood expelled during systole from the left ventricle and the end-diastolic volume. For
the systolic function of the right ventricle, on the other hand, tricuspid annular plane
systolic excursion (TAPSE), which is the displacement of the tricuspid valve plane towards
the cardiac apex during ventricular systole, as well as the fractional area change (FAC), as
shortening percentage of the right ventricle between systole and diastole, were evaluated.
2.5. Statistical Analyses
Data are expressed as a mean
±
the standard deviation. The normality was assessed
using the Shapiro–Wilk test. T-tests for the normally distributed variables and Mann–
Whitney U tests for the non-normally distributed variables were used. The various classes
of CHD were compared with each other and with controls by an ANOVA test for normally
distributed variables and with a non-parametric test for non-normally distributed variables.
Patients with CHD were further classified to investigate the RER recovery parameters
in subgroups with potential prognostic differences. Patients were grouped according
to the VE/VCO
2
slope into ventilatory classes: I (VE/VCO
2
slope < 30), II (VE/VCO
2
slope between 30 and 35.9), and III (VE/VCO
2
slope between 36 and 44.9); no patients
belonged to ventilatory class IV (VE/VCO
2
slope > 45). The correlations were evaluated
with Pearson’s index for normally distributed variables and with Spearman’s index for
non-normally distributed variables. The statistical analyses were executed with IBM SPSS
Statics software version 26. A statistical significance level of p≤0.05 was applied.
3. Results
3.1. Patients Selection
In total, 131 young subjects were initially recruited for the aim of the study, including
103 patients with CHD and 28 control subjects. In the CHD group, seven patients were
excluded from the study because it was not possible to clearly identify an RER max during
the time recorded; one patient was excluded due to a sampling error, and two patients
were excluded because they did not reach the criteria for metabolic exhaustion. Therefore,
the CHD study group was made up of 93 subjects: 23 TGA, 22 Fon, 24 CoA, and 24 ToF.
All patients with TGA correction underwent the arterial switch procedure. Moreover,
18 patients of the Fontan group presented a left dominant ventricle, whereas 7 had a right
dominant ventricle and 1 patient underwent a staged biventricular conversion. The degree
of pulmonary valve regurgitation and right ventricle outflow tract stenosis was rather
heterogeneous in the ToF group. In the control group, three patients were excluded because
it was not possible to clearly identify a RER max during the recovery phase, and one patient
because he was unable to reach the needed metabolic criteria for exhaustion. The control
group, therefore, was composed of 24 subjects.
3.2. Baseline Characteristics
The general anthropometric and clinical characteristics of the study participants are
represented in Table 1.
Children 2023,10, 521 5 of 15
Table 1.
Baseline characteristics of the healthy controls as well as of the patients with congenital heart
disease (CHD). Data are expressed as a mean
±
the standard deviation. BMI = body mass index;
SBP = systolic
blood pressure; DBP = diastolic blood pressure; TGA = transposition of great arteries;
Fon = Fontan procedure; CoA = aortic coarctation; ToF = tetralogy of Fallot.
Variables Controls (n = 24) CHD (n = 93) TGA (n = 23) Fon (n = 22) CoA (n = 24) ToF (n = 24)
Gender—females, n (%) 11 (46%) 34 (37%) 4 (17%) 9 (41%) 9 (38%) 12 (50%)
Age (years) 14.84 ±2.69 14.41 ±3.18 14.39 ±2.79 14.86 ±2.92 13.88 ±3.35 14.54 ±3.66
Height (cm) 156.00 ±14.60 161.50 ±13.51 164.80 ±10.53 161.82 ±14.90 159.30 ±13.80 160.25 ±14.65
BMI (kg/m2)19.55 ±2.64 20.70 ±4.38 22.52 ±5.23 19.06 ±2.42 20.45 ±4.41 20.69 ±4.46
SBP rest
(mmHg) 106.20 ±15.10 114.25 ±14.38 118.22 ±11.92 104.64 ±15.05 119.92 ±14.65 113.60 ±11.50
DBP rest
(mmHg) 53.80 ±9.50 64.92 ±9.80 63.35 ±10.30 63.60 ±8.61 66.12 ±9.64 66.50 ±10.65
Desaturation at rest, n (%)
0 (0%) 5 (5%) 0 (0%) 5 (23%) 0 (0%) 0 (0%)
Competitive sports, n (%) 23 (96%) 2 (2%) 0 (0%) 0 (0%) 2 (8%) 0 (0%)
Physical activity (h/week)
5.42 ±2.67 2.26 ±1.33 2.14 ±1.58 2.02 ±1.32 2.68 ±1.38 2.12 ±1.11
Cardio-Aspirine, n (%) 0 (0%) 72 (77%) 1 (4%) 18 (82%) 0 (0%) 2 (8%)
Anti-hypertensive drugs,
n (%) 0 (0%) 9 (10%) 1 (4%) 7 (32%) 1 (4%) 0 (0%)
Resting systolic and diastolic blood pressures were higher in CHD patients than in
healthy controls (p= 0.022 and p< 0.001, respectively). Moreover, statistically significant dif-
ferences were found between the 4 subgroups of CHD in systolic blood pressure
(p= 0.001
),
with patients with CoA having the highest mean resting SBP (119.92
±
14.65 mmHg). None
of the subjects included in the control group had a low blood oxygen saturation at rest,
while five patients with CHD (all belonging to the Fon group) desaturated at rest before
the exercise phase.
3.3. Cardiopulmonary Exercise Testing and Echocardiographic Assessments
All patients performed their respective maximal CPET with the same protocol (Bruce
Ramp) reaching a RPE
≥
18/20 on the Borg scale, with no reported symptoms. The results
of the CPET and the main indices of cardiac contractility analyzed with echocardiography
are shown in Table 2.
HR peak was lower in the CHD group than in the control group (p= 0.013). The
comparison of HR peak between the subgroups was also statistically significant (p= 0.001),
with patients with Fontan having the lowest median (176 bpm). Even the HR recovery after
one minute was lower in patients with CHD compared to controls (p= 0.007), with Fon
patients showing the slowest recovery. As for the oxygen pulse (O
2
pulse), an anomalous
behavior was recorded in 30% of patients with CHD, whereas all healthy controls had a
normal O
2
pulse behavior during the test. Patients with CHD showed lower values of the
O
2
pulse in terms of percentage of predicted, when compared to healthy controls (
p= 0.005
)
with still Fon patients presenting lower values compared to the other three CHD subgroups.
The analysis of peripheral saturation at peak exercise (SpO
2
peak) showed that 19 patients
with CHD desaturated at peak exercise (12 from the Fon group), while none of the healthy
controls had a lower-than-normal peripheral saturation.
Pairwise comparisons between the various parameters are shown in Supplementary
Table S1. Most significant differences have been found between the Fontan group, which
had the greatest functional impairment, and the CoA and control groups. CoA patients
showed higher HR peak and HR peak (%) compared to ToF and Fon patients but similar
to TGA patients. Furthermore, aerobic capacity was significantly lower in patients with
CHD compared to healthy subjects; statistically significant differences were also displayed
between the four subgroups (in both cases p< 0.001) with Fon patients recording the lowest
VO2peak (32.05 ±5.90 mL/min/kg; 76.64 ±14.40% of predicted) and CoA patients with
the highest aerobic capacity (40.98 ±8.40 mL/min/kg; 99.00 ±17.10% of predicted).
Children 2023,10, 521 6 of 15
Table 2.
Cardiopulmonary test parameters of the healthy controls as well as of the patients with congenital heart disease (CHD). Normally distributed variables
are expressed with mean
±
standard deviation, non-normally distributed variables are expressed with median and confidence intervals; qualitative variables are
expressed with percentages of the total. Intergroup comparison was made between the four CHD subgroups and controls. HR = heart rate; HRRec 1 = heart rate
recovery after one minute; VO
2
= oxygen uptake; SBP = systolic blood pressure; DBP = diastolic blood pressure; SpO
2
= peripheral oxygen saturation; VE/VCO
2
slope = minute ventilation/carbon dioxide production slope; VT = Ventilatory Threshold; RCP = Respiratory Compensation Point; OUES = Oxygen Uptake Efficiency
Slope; METs = metabolic equivalents of task; LVEF = left ventricular ejection fraction; TAPSE = tricuspid annular plane systolic excursion; FAC = fractional area
change; * = 86 patients; ** = 64 patients; *** = 22 patients; TGA = transposition of great arteries; Fon = Fontan procedure; CoA = aortic coarctation; ToF = tetralogy
of Fallot.
Variables Controls (n = 24) CHD (n = 93) pTGA (n = 23) Fon (n = 22) CoA (n = 24) ToF (n = 24) p
HR peak (bpm) 190.00
(185.35–192.89)
184.00
(178.21–185.41) 0.013 187.00
(173.36–193.25)
176.00
(166.44–180.10)
190.00
(184.74–194.51)
182.50
(174.01–186.74) <0.001
HR peak (%) 91.00
(89.82–93.70)
90.00
(86.41–89.97) 0.042 92.00 (84.13–94.05) 85.50 (80.80–87.65) 92.00 (89.37–94.22) 89.00 (84.22–90.53) <0.001
HRRec 1
(-bpm)
−33.00
(−44.12/−30.84)
−26.00
(−31.03/−25.71) 0.007 −28.00
(−35.61–(−24.13))
−18.50
(−25.79–(−16.39))
−30.00
(−37.50–(−27.34))
−26.00
(−35.20–(−23.88)) 0.001
HR/VO2slope
(bpm/mL) 7.03 ±3.12 8.34 ±3.34 0.140 7.30 ±2.65 9.27 ±3.72 7.28 ±2.42 9.55 ±3.87 0.048
O2pulse (mL/bpm) 11.10
(10.45- 13.55)
10.20
(10.25–11.69) 0.174 11.10 (11.27–13.77) 8.85 (8.44–10.76) 10.85 (9.61–13.07) 9.05 (8.83–11.92) 0.004
O2pulse (%) 104.00
(100.93–118.19)
93.00
(91.02–99.63) 0.005
100.00 (90.19–109.38)
86.00 (76.20–96.98) 97.50 (92.38–108.70) 92.00 (86.76–100.91) 0.004
Oxygen Pulse
Behaviour
Normal:
24 (100%)
Normal: 65 (70%)
Early Plateau: 25
(27%)
Deflection: 3 (3%)
0.007
Normal: 15 (65%)
Early Plateau: 6
(26%)
Deflection: 2 (9%)
Normal: 16 (73%)
Early Plateau: 6
(27%)
Deflection: 0
Normal: 21 (87%)
Early Plateau: 3 (12%)
Deflection: 0
Normal: 13 (54%)
Early Plateau: 10
(42%)
Deflection: 1 (4%)
0.147
SBP peak (mmHg) 150.00
(140.60–157.00)
150.00
(143.9–153.40) 0.947 150.00
(142.77–157.66)
137.50
(130.25–147.02)
150.00
(146.54–168.88)
147.50
(136.69–157.89) 0.152
DBP peak (mmHg) 50.00
(45.48–56.12)
60.00
(58.29–64.40) <0.001 60.00 (55.90–69.75) 60.00 (54.24–65.77) 50.00 (52.37–65.55) 60.00 (57.27–69.81) 0.012
SpO2peak
(%)
99.00
(98.86–99.53)
96.00
(95.11–96.84) <0.001 98.00 (97.37–98.36) 92.00 (89.46–94.14) 98.00 (97.03–98.88) 97.50 (93.85–97.42) <0.001
Desaturation at peak,
n (%) 0 (0%) 19 (21%) 0.012 0 (0%) 12 (60%) 1 (4%) 6 (27%) <0.001
VE/VCO2slope 27.93
(26.36–29.35)
29.14
(28.73–30.61) 0.102 28.25 (27.14–30.72) 31.06 (29.10–33.20) 28.17 (26.47–30.47) 28.68 (28.28–32.17) 0.120
Children 2023,10, 521 7 of 15
Table 2. Cont.
Variables Controls (n = 24) CHD (n = 93) pTGA (n = 23) Fon (n = 22) CoA (n = 24) ToF (n = 24) p
OUES (mL/logL) 1849.19
(1739.05–2281.50)
1784.00
(1739.96–1994.13) 0.365 1990.00
(1804.69–2220.96)
1613.50
(1460.38–1949.52)
1887.50
(1695.67–2342.09)
1565.50
(1475.68–1972.49) 0.087
VO2peak
(mL/min/kg) 43.72 ±6.13 36.27 ±8.33 <0.001 36.83 ±8.70 32.05 ±5.90 40.98 ±8.40 34.90 ±7.85 <0.001
VO2peak (%) 108.84 ±15.82 86.70 ±17.90 <0.001 83.30 ±15.80 76.64 ±14.40 99.00 ±17.10 86.92 ±17.10 <0.001
VO2at VT
(mL/Kg/min)
23.90
(22.34–26.22)
22.80
(21.81–24.50) 0.229 22.80 (21.11–24.22) 21.40 (19.47–22.89) 25.60 (22.82–26.26) 21.60 (19.19–29.06) 0.085
VO2at RCP
(mL/Kg/min)
34.50
(32.28–38.89)
28.200
(27.69–30.57) <0.001 28.80 (25.93–31.63) 25.10 (23.52–28.75) 31.45 (29.83–36.15) 28.00 (25.50–30.76) <0.001
METs 16.76 ±2.09 15.03 ±2.48 0.001 15.00 ±2.61 14.72 ±1.95 15.65 ±2.80 14.75 ±2.52 0.040
LVEF * (%) - 64.00 (60.00–70.00) - 63.00 (61.25–69.00) 58.00 (50.47–63.24) 68.00 (64.51–70.93) 66.00 (61.08–68.52) 0.002
TAPSE ** (mm) - 19.00 (16.40–22.10) - 17.00 (15.21–18.10) 12.60 (9.15–18.59) 25.10 (22.24–27.10) 19.00 (16.67–20.59) <0.001
FAC *** (%) - 44.50 (40.00–48.00) - 40.50 (34.15–46.85) 48.00 (33.63–55.17) 42.50 (37.60–47.40) 44.00 (38.89–46.66) 0.392
Children 2023,10, 521 8 of 15
3.4. Overshoot Analysis
Table 3shows the comparison between the parameters concerning the phenomenon
of RER overshoot during the recovery phase between study groups. All included patients
showed an increase, defined as an overshoot of the RER after exercise. Although during
exercise patients with CHD and controls showed a similar RER peak, the behavior of the
RER during recovery was significantly different. Moreover, RER max, RER mag, and RER
slope revealed a lower RER overshoot for patients with CHD when compared to the healthy
controls (Figure 2). However, no statistically significant difference was found for the RER
peak, RER max, RER slope and Time to RER max parameters when CHD subgroups were
compared. Only the RER mag was higher in the controls and patients with CoA when
compared with the Fon, ToF, and TGA groups.
Table 3.
Respiratory exchange ratio (RER) recovery parameters of the healthy controls as well as
of the patients with congenital heart disease (CHD). Normally distributed variables are expressed
with mean
±
standard deviation and non-normally distributed variables are expressed with median
and confidence intervals. Intergroup comparison was made between the four CHD subgroups and
controls. TGA = transposition of great arteries; Fon = Fontan procedure; CoA = aortic coarctation;
ToF = tetralogy of Fallot.
Variables Controls (n = 24) CHD (n = 93) pTGA (n = 23) Fon (n = 22) CoA (n = 24) ToF (n = 24) p
RER peak 1.22 ±0.11 1.23 ±0.12 0.819 1.24 ±0.14 1.22 ±0.11 1.20 ±0.12 1.24 ±0.10 0.902
RER max 1.94 ±0.28 1.77 ±0.23 0.010 1.80 ±0.25 1.74 ±0.24 1.80 ±0.21 1.75 ±0.24 0.076
RER mag
(%) 58.54 ±14.72 44.41 ±14.75 0.010 43.74 ±13.81 42.31 ±13.10 49.95 ±15.23 41.42 ±15.94 0.001
RER slope 34.40 ±16.50 27.63 ±13.52 0.037 29.81 ±15.40 23.12 ±10.84 28.80 ±13.70 28.50 ±13.60 0.207
Time to RER
max (s)
146.00
(126.31–164.17)
139.00
(129.47–151.50) 0.403 130.00
(107.60–151.87)
151.50
(137.58–186.60)
145.00
(119.90–170.51)
119.00
(108.58–143.92) 0.136
Children 2023, 10, x FOR PEER REVIEW 9 of 17
Figure 2. Example of two patients (a healthy subject in blue and a patient with CHD in red) present-
ing the same respiratory exchange ratio at peak exercise (RER peak) but different maximal values
of respiratory exchange ratio during the recovery phase (RER max).
The correlations between RER overshoot parameters during the recovery phase and
some of the main cardiorespiratory fitness and efficiency indices were assessed (Table 4).
Table 4. Correlations between the respiratory exchange ratio (RER) recovery parameters and cardi-
opulmonary/echocardiographic functional indices, expressed as Pearson’s or Spearman’s indices.
Variables RER Peak RER Max RER Mag RER Slope
Time to RER
Max
Age
(years)
0.428 (p = 0.001)
0.277 (p = 0.007)
−0.034 (p =
0.744)
−0.085 (p =
0.418)
0.174 (p = 0.095)
HR peak
(bpm)
0.227 (p = 0.021)
0.323 (p = 0.001)
0.366 (p = 0.001)
0.297 (p = 0.004)
−0.042 (p =
0.692)
HR/VO
2
slope
(bpm/mL)
0.059 (p = 0.581)
−0.135 (p =
0.103)
−0.232 (p =
0.004)
−0.154 (p =
0.418)
−0.095 (p =
0.089)
HRRec 1
(-bpm)
0.412 (p < 0.001)
0.253 (p = 0.014)
−0.042 (p =
0.687)
0.122 (p = 0.242)
0.006 (p = 0.950)
VE/VCO2 slope
−0.429 (p =
0.001)
−0.343 (p =
0.001)
−0.100 (p =
0.334)
−0.201 (p =
0.054)
−0.021 (p =
0.840)
VO
2
at VT
(ml/kg/min)
−0.265 (p =
0.008)
−0.115 (p =
0.274)
0.100 (p = 0.343)
0.123 (p = 0.245)
−0.060 (p =
0.573)
VO
2
peak
(ml/kg/min)
−0.100 (p =
0.314)
0.212 (p = 0.040)
0.393 (p = 0.001)
0.297 (p = 0.004)
−0.048 (p =
0.650)
OUES (ml/logL)
0.213 (p = 0.031)
0.370 (p = 0.001)
0.311 (p = 0.002)
0.137 (p = 0.191)
0.143 (p = 0.170)
LVEF
(%)
0.056 (p = 0.608)
−0.003 (p =
0.975)
0.002 (p = 0.989)
0.083 (p = 0.449)
−0.072 (p =
0.510)
TAPSE (mm) 0.241 (p = 0.057)
0.312 (p = 0.012)
0.151 (p = 0.234)
−0.083 (p =
0.516)
0.192 (p = 0.132)
FAC
(%)
0.199 (p = 0.365)
−0.068 (p =
0.764)
−0.065 (p =
0.772)
0.035 (p = 0.877)
−0.090 (p =
0.692)
HR peak showed significant correlations with both RER max (ρ = 0.323; p < 0.001) and
RER mag (r = 0.366; p < 0.001). A significant negative correlation between RER mag and
HR/VO2 slope was displayed, as well as a positive correlation between RER max and
HRRec after one minute. Although the time to RER max and the RER slope showed slight
Figure 2.
Example of two patients (a healthy subject in blue and a patient with CHD in red) presenting
the same respiratory exchange ratio at peak exercise (RER peak) but different maximal values of
respiratory exchange ratio during the recovery phase (RER max).
The correlations between RER overshoot parameters during the recovery phase and
some of the main cardiorespiratory fitness and efficiency indices were assessed (Table 4).
HR peak showed significant correlations with both RER max (
$
= 0.323; p< 0.001)
and RER mag (r = 0.366; p< 0.001). A significant negative correlation between RER mag
and HR/VO
2
slope was displayed, as well as a positive correlation between RER max
and HRRec after one minute. Although the time to RER max and the RER slope showed
slight correlations with the principal CPET parameters, RER max and RER mag were
significantly correlated with important cardiorespiratory fitness and efficiency indices,
Children 2023,10, 521 9 of 15
such as VO
2
peak and OUES. Moreover, when grouped by ventilatory classes, the RER
recovery parameters, except for time to RER max, were significantly higher in patients
of ventilatory class I compared with patients belonging to ventilatory classes II and III
(Figure 3). No statistically significant correlations between the RER recovery parameters
and resting echocardiographic data were found, except between RER max and TAPSE.
Table 4.
Correlations between the respiratory exchange ratio (RER) recovery parameters and car-
diopulmonary/echocardiographic functional indices, expressed as Pearson’s or Spearman’s indices.
Variables RER Peak RER Max RER Mag RER Slope Time to RER Max
Age
(years) 0.428 (p= 0.001) 0.277 (p= 0.007) −0.034 (p= 0.744) −0.085 (p= 0.418) 0.174 (p= 0.095)
HR peak
(bpm) 0.227 (p= 0.021) 0.323 (p= 0.001) 0.366 (p= 0.001) 0.297 (p= 0.004) −0.042 (p= 0.692)
HR/VO2slope
(bpm/mL) 0.059 (p= 0.581) −0.135 (p= 0.103) −0.232 (p= 0.004) −0.154 (p= 0.418) −0.095 (p= 0.089)
HRRec 1
(-bpm) 0.412 (p< 0.001) 0.253 (p= 0.014) −0.042 (p= 0.687) 0.122 (p= 0.242) 0.006 (p= 0.950)
VE/VCO2slope −0.429 (p= 0.001) −0.343 (p= 0.001) −0.100 (p= 0.334) −0.201 (p= 0.054) −0.021 (p= 0.840)
VO2at VT
(ml/kg/min) −0.265 (p= 0.008) −0.115 (p= 0.274) 0.100 (p= 0.343) 0.123 (p= 0.245) −0.060 (p= 0.573)
VO2peak
(ml/kg/min) −0.100 (p= 0.314) 0.212 (p= 0.040) 0.393 (p= 0.001) 0.297 (p= 0.004) −0.048 (p= 0.650)
OUES (ml/logL) 0.213 (p= 0.031) 0.370 (p= 0.001) 0.311 (p= 0.002) 0.137 (p= 0.191) 0.143 (p= 0.170)
LVEF
(%) 0.056 (p= 0.608) −0.003 (p= 0.975) 0.002 (p= 0.989) 0.083 (p= 0.449) −0.072 (p= 0.510)
TAPSE (mm) 0.241 (p= 0.057) 0.312 (p= 0.012) 0.151 (p= 0.234) −0.083 (p= 0.516) 0.192 (p= 0.132)
FAC
(%) 0.199 (p= 0.365) −0.068 (p= 0.764) −0.065 (p= 0.772) 0.035 (p= 0.877) −0.090 (p= 0.692)
Children 2023, 10, x FOR PEER REVIEW 10 of 17
correlations with the principal CPET parameters, RER max and RER mag were signifi-
cantly correlated with important cardiorespiratory fitness and efficiency indices, such as
VO2 peak and OUES. Moreover, when grouped by ventilatory classes, the RER recovery
parameters, except for time to RER max, were significantly higher in patients of ventila-
tory class I compared with patients belonging to ventilatory classes II and III (Figure 3).
No statistically significant correlations between the RER recovery parameters and resting
echocardiographic data were found, except between RER max and TAPSE.
Figure 3. The RER overshoot parameters (RER max, RER mag, RER slope and Time to RER max)
between patients of different ventilatory classes. VC= ventilatory class.
4. Discussion
To the best of the authors’ knowledge, this is the first study evaluating the overshoot
parameters of the respiratory gas exchange and specifically the behavior of the RER dur-
ing recovery from maximal CPET in young patients with CHD. The main results of the
present study are the following:
• All patients with CHD presented an overshoot of the RER during recovery after max-
imal CPET.
• Patients with CHD showed reduced RER recovery overshoot compared to healthy
subjects.
• Although there are significant differences regarding the cardiopulmonary response
during exercise between the subgroups of CHD, no differences in the RER recovery
parameters were evident.
Figure 3.
The RER overshoot parameters (RER max, RER mag, RER slope and Time to RER max)
between patients of different ventilatory classes. VC= ventilatory class.
Children 2023,10, 521 10 of 15
4. Discussion
To the best of the authors’ knowledge, this is the first study evaluating the overshoot
parameters of the respiratory gas exchange and specifically the behavior of the RER during
recovery from maximal CPET in young patients with CHD. The main results of the present
study are the following:
•
All patients with CHD presented an overshoot of the RER during recovery after
maximal CPET.
•
Patients with CHD showed reduced RER recovery overshoot compared to healthy
subjects.
•
Although there are significant differences regarding the cardiopulmonary response
during exercise between the subgroups of CHD, no differences in the RER recovery
parameters were evident.
•
RER recovery parameters significantly correlated with the most important cardiores-
piratory fitness and efficiency indices, independently from the RER peak reached
during exercise.
4.1. Why Is the CPET Recovery Phase Relevant in Patients with CHD?
Currently, the cardiopulmonary response during exercise has been widely studied
in different populations but there is still little evidence of the CPET parameters’ behavior
during the recovery phase [
8
]. Some authors described delayed kinetics of VO
2
recovery in
patients with HF after maximal and submaximal incremental exercise testing compared
to healthy subjects [
13
,
23
,
24
], showing that these findings were associated with a worse
prognosis in these patients [
24
,
25
]. Slow recovery of energy stores in skeletal muscles was
deemed to be responsible for the delayed VO
2
recovery [
26
]. In addition, in patients with
HF, a delayed recovery of VE and VCO
2
was also found. This phenomenon has been
attributed to the retention of CO
2
in the muscles after exercise, justifying the consequent
increase in ventilation to maintain a state of eucapnia [
24
]. In this regard, it is noteworthy to
underline that parameters describing the recovery phase seemed to have a more significant
correlation than peak values with muscle strength in both healthy controls and patients
with HF [27].
In the latter, the phenomenon of VO
2
overshoot during the first part of the recovery
phase has also been described: it is defined by a further VO
2
growth compared to the
peak values [
28
]. This overshoot has been found in some cardiac patients and it seems
to be associated with a worse prognosis [
29
]. Other authors also found a paradoxical
increase in cardiac output in the recovery phase after CPET [
11
], which may explain VO
2
overshoot. This increase in cardiac output would be attributable to a reduction of peripheral
vascular resistances at the end of the exercise but also to the contribution of skeletal muscles
to repay the oxygen debt or to a relatively slower decline in the blood concentration of
catecholamines during recovery [11,30].
More recently, the overshoot phenomenon of gas exchange indices, such as RER
and VE/VO
2
during the recovery phase after maximal CPET, has been described [
12
].
Takayanagi et al. identified an attenuation of this phenomenon in patients with HF when
compared to healthy subjects [
12
]. The overshoot of gas exchange indices seems to be a
direct consequence of VE and VCO
2
returning to normal more slowly than VO
2
, due to the
carbon dioxide deposits produced by the anaerobic metabolism during exercise [12].
Some authors reported a delay in gas exchange recovery in patients with different
types of CHD, but they mainly focused on the VO
2
recovery kinetics [
16
,
17
]. Since most of
the literature concerning the evaluation of CHD by CPET focuses on the exercise phase, this
study aimed to analyze the behavior of the main cardiopulmonary indices during recovery
in a population of young patients with CHD and to compare it with an age-matched
healthy population. The RER was chosen as the most suitable parameter to be evaluated
as it reflects simultaneously both the VO
2
and VCO
2
trend, with possibly slowed kinetics
during the recovery phase [16,17,31].
Children 2023,10, 521 11 of 15
4.2. Exercise Phase
Patients with CHD are subjects who, despite the improvement in medical and surgical
therapies that occurred over the last decades, are still forced to live their whole life with
the pathophysiological alterations due to their disease and to the sequelae of surgical
interventions. These alterations mainly involve the cardiovascular system with consequent
functional limitations, but, in complex CHD the whole oxygen transport system might be
affected [
32
,
33
]. Therefore, a comprehensive functional evaluation with maximal CPET
is strongly recommended in current guidelines [
34
]. Patients with CHD have reduced
cardiorespiratory fitness and efficiency during exercise when compared to healthy con-
trols. This is widely demonstrated in the literature and confirms the possible presence of
cardiogenic limitations to exercise in patients with CHD [
35
]. Indeed, children and adults
with CHD, in particular after surgical repair, have lower maximal aerobic and functional
capacity compared to controls [
36
,
37
]. A recent systematic review and meta-analysis in-
vestigating children and adolescents with CHD reported a lower exercise capacity and
cardiorespiratory efficiency compared with healthy controls as shown by worse VO
2
peak,
maximal power, VE/VCO2slope, O2pulse, and HR max [38].
Moreover, exercise capacity differs significantly across the spectrum of CHD [
35
].
Simple CHD present usually better exercise parameters compared to complex CHD. In our
study, CoA patients had a higher HR peak compared to ToF and Fon patients. Moreover,
Fon patients presented mild chronotropic incompetence compared to other CHD subgroups,
probably related to an abnormal cardiac filling rather than sinoatrial node dysfunction.
In accordance with previous studies, patients with complex CHD, in particular patients
with univentricular circulation who underwent a Fontan procedure, presented the lowest
VO
2
peak and highest VE/VCO
2
slope values [
39
]. On the other hand, patients with CoA
and patients with TGA, in particular those who received an arterial switch operation,
were found to have the highest VO
2
peak and lowest VE/VCO
2
slope values [
40
]. Our
work confirms this previous evidence with Fon patients presenting the lowest maximal and
submaximal cardiorespiratory fitness during exercise. Indeed, a proportion of them showed
desaturation at rest and during exercise, with the worst values for aerobic capacity and
ventilatory efficiency among the CHD groups investigated. Moreover, despite patients with
TGA presenting a lesion with high complexity, restoring correct anatomy and physiology
during early life seem to ensure an almost normal exercise capacity and cardiorespiratory
fitness [35].
4.3. Recovery Phase
The focus of this study was related to the RER recovery parameters after maximal
CPET. Patients with CHD presented significantly reduced RER max, RER mag, and RER
slope compared to healthy controls, despite the RER peak value during exercise being
comparable between the two groups (1.22
±
0.11 vs. 1.23
±
0.12). These findings seem to
confirm that, in subjects with cardiogenic limitations to physical exercises, such as patients
with CHD, the RER overshoot phenomenon appears to be reduced [
12
]. Although the
included chronic conditions do not share the same pathophysiological mechanism, it is
possible that the underlying cardiac impairment leading to the reduced RER overshoot of
patients with CHD may be similar to what has been described in patients with HF [12].
A delay in VO
2
recovery kinetics and HR recovery has already been demonstrated
in young patients with different CHD [
16
]. An impaired right-sided hemodynamic and
central autonomic nervous activity may lead to a delay in recovery indices [
18
] with possible
implications also for clinical decision-making [
19
]. Most studies on patients with CHD
have focused on adult populations [
40
]. In one of the few works investigating the recovery
phase of a young population with CHD, patients with ToF presented diminished exercise
capacity and slower recovery of VO
2
and VCO
2
compared to healthy subjects. Those
patients with the worst exercise capacity also showed the slowest recovery indices [
31
].
This delay seemed to correlate to ventricular contractility indices, suggesting the crucial
role of ventricular function during the recovery after physical exercise [31].
Children 2023,10, 521 12 of 15
Interestingly, patients with different classes of CHD did not show significant variances
in RER recovery indices. This confirms previous studies on adults showing that gas
exchange recovery after exercise testing is prolonged in patients with CHD, independently
of the congenital heart lesion [
17
]. However, comparing our results with prior studies,
RER mag of young patients with CHD (44.4
±
14.8%) was higher compared to older
patients with HF, kidney transplant recipients but also healthy older subjects (21.4
±
12.4%,
28.4 ±12.7%
and 29.3
±
10%, respectively) [
12
,
41
]. These findings suggest that age appears
to be a crucial factor in determining this phenomenon in the recovery phase, as subjects
with the established cardiac disease show higher values than healthy older subjects, even
in CHD with the lowest cardiorespiratory fitness (RER mag in Fon group: 42.31
±
13.10%).
4.4. RER Overshoot and Cardiorespiratory Fitness/Efficiency
The RER recovery indices showed interesting correlations with cardiorespiratory
efficiency even in CHD, corroborating that it is possible to implement the CPET evaluation
in this clinical population. HR/VO
2
slope describes the subject’s ability to adequately raise
HR to meet the increased metabolic demands during exercise, and it is a cardiocirculatory
efficiency index that has been poorly studied in the literature so far, particularly in patients
with CHD [
42
]. A significant negative correlation was found between RER mag and
HR/VO
2
slope (r =
−
0.232, p= 0.004). It could be hypothesized that patients with a
hyperkinetic response during exercise and thus lower cardiocirculatory efficiency have
also a reduced RER overshoot in the recovery phase, probably due to cardiac limitations.
Furthermore, patients with better exercise tolerance and thus higher HR peak have shown
a more significant RER overshoot. It needs to be investigated whether this observation
is due to cardiac limitations regarding the chronotropic response or simply due to lower
exercise tolerance.
The RER mag showed significant correlations with relevant indices of cardiorespiratory
fitness and efficiency such as VO
2
peak and OUES, which were comparable with those
previously described for patients with HF [
12
]. This shows how the overshoot phenomenon
is closely related to maximal and submaximal aerobic capacity. Different from previous
works, no correlation between RER mag and VE/VCO
2
slope was found [
12
,
41
]. This could
be explained by the fact that the population in this study was young and might not have
yet developed a relevant degree of ventilatory-perfusion mismatch. Alternatively, since
RER peak and RER max seem to negatively correlate with VE/VCO
2
slope, these data may
suggest that ventilatory-perfusion mismatch has a huger impact on exercise tolerance and
affects less the recovery phase [
43
]. To evaluate the potential clinical application of the RER
overshoot, patients with CHD were grouped according to their ventilatory classes, which
reflect the cardiorespiratory efficiency and a possible ventilation-perfusion mismatch during
exercise. Patients with better ventilatory classes showed higher RER recovery overshoots
compared with those belonging to worse ventilatory classes, similar to what was reported
about kidney transplant recipients [
41
]. Furthermore, a vigorous RER overshoot seems to
be an index of better cardiorespiratory performance and a better prognosis in patients with
CHD. This supports the proposal that the analysis of CPET metrics during recovery may
provide valid additional information for the test interpretation.
Finally, correlations between RER overshoot and resting biventricular function were
investigated. No significant correlations between RER mag and echocardiographic parame-
ters were found, as previously reported between RER mag and LVEF in patients with HF,
suggesting the absence of a direct relationship between RER overshoot and ventricular
function at rest [
12
]. However, there is still the need to study how limitations in the response
of cardiac output during exercise may influence the CPET overshoot recovery parameters.
In this regard, data from invasive and/or non-invasive measurements of cardiac output
during exercise could be useful to better understand the direct impact of cardiac limitations
on these recovery metrics.
Children 2023,10, 521 13 of 15
4.5. Limitations and Perspectives
This was a retrospective study assessing the recovery phase after maximal CPET
based on routinely performed clinical assessments. The sample size was limited because a
long-lasting evaluation of the recovery phase with gas exchange data was not routinely
performed in our laboratory before January 2018, when a dedicated recovery protocol
was created. A larger sample and specific trials are needed to investigate the impact of
ventricular function (during rest and exercise) on the RER recovery overshoot, as echocar-
diographic data have been assessed for clinical purposes and were thus not available for all
patients. Moreover, those patients with a peak RER < 1.1 were excluded from the study, for
consistency with previous literature and to avoid possible confounding in the assessment
of the recovery CPET parameters, especially RER.
The recovery phase after exercise has been poorly explored in pathological popu-
lations and often with heterogeneous methodologies. The present study could help to
highlight the possibility of incorporating and standardizing variables of the recovery phase
in CPET interpretation, aiming to improve the diagnostic and prognostic stratification of
these patients. Future trials should analyze the behavior of gas exchange indices after
maximal exercise testing in populations with different functional limitations, to improve
the understanding of the pathophysiological mechanisms that determine its behavior and
the clinical interpretation of this phenomenon. Finally, further studies are needed, aiming
to prospectively investigate the prognostic value of the RER overshoot parameters on hard
clinical endpoints.
5. Conclusions
The present study highlights the role of functional assessment in patients with CHD.
An overshoot of RER during recovery after maximal CPET is commonly observed in young
patients with CHD but this phenomenon appears to be lower compared to healthy controls,
suggesting a possible connection with cardiogenic limitations during exercise. Indeed,
RER mag was different in the study’s subgroups where healthy subjects and patients
with aortic coarctation showed a significantly higher RER overshoot compared to patients
with TGA, previous Fontan procedure, and ToF. RER recovery overshoots correlated with
prognostically relevant CPET indices of cardiorespiratory fitness and efficiency, showing
lower values in patients with significant ventilatory-perfusion mismatch. The evaluation
of CPET recovery parameters should be further investigated and implemented in clinical
settings to increase scientific evidence and provide additional information to improve risk
stratification in patients with CHD.
Supplementary Materials:
The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/children10030521/s1, Table S1. Pairwise comparisons between
four CHD groups and controls.
Author Contributions:
Conceptualization, M.V. and D.N.; methodology, M.V., F.B. and G.Q.; formal
analysis, M.V. and E.Z.; investigation, M.V., G.D. and A.G.; resources, M.V.; data curation, M.V., E.Z.
and G.R.; writing—original draft preparation, M.V., E.Z. and G.R.; writing—review and editing, M.V.,
F.B., S.P. and D.N.; visualization, M.V.; supervision, A.E., M.A.P. and G.D.S.; project administration,
A.E. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement:
Informed consent was obtained from all subjects involved in
the study
.
Data Availability Statement:
Data are available upon reasonable request to the
corresponding author.
Acknowledgments:
This research project is part of the Italian initiative of Exercise is Medicine.
Thanks to Irene Zago for her valuable support during data collection.
Conflicts of Interest: The authors declare no conflict of interest.
Children 2023,10, 521 14 of 15
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