
==== Front
Open Heart
Open Heart
openhrt
openhrt
Open Heart
2053-3624
BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR

39160087
10.1136/openhrt-2024-002820
openhrt-2024-002820
Original Research
Congenital Heart Disease
1506
Prognostic value of cardiopulmonary exercise test in children with congenital heart defects
http://orcid.org/0000-0001-8880-1192
Terol Covadonga 1covatem@gmail.com

Hagen Juliette 1jhagen@live.nl

Rammeloo Lukas 2l.rammeloo@amsterdamumc.nl

Kuipers Irene M 2i.m.kuipers@amsterdamumc.nl

Blom Nicolaas A 12n.a.blom@amsterdamumc.nl

ten Harkel Arend DJ 1a.d.j.ten_harkel@lumc.nl

1 Department of Paediatrics, Division of Paediatric Cardiology, LUMC, Leiden, The Netherlands
2 Department of Paediatrics, Division of Paediatric Cardiology, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

Additional supplemental material is published online only. To view, please visit the journal online (https://doi.org/10.1136/openhrt-2024-002820).

None declared.

DrNicolaas ABlom; n.a.blom@amsterdamumc.nl
2024
19 8 2024
11 2 e00282002 7 2024
12 7 2024
Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.
2024
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

Abstract

Background

Cardiopulmonary exercise testing (CPET) has an important prognostic value in adults with different congenital heart defects (CHDs) and is a useful tool for risk stratification and clinical decision-making. In this retrospective study, we studied the prognostic value of CPET in paediatric patients with CHD.

Methods

411 CPET performed by paediatric patients with different CHDs were evaluated in this retrospective study. Medical records were reviewed to determine the presence of cardiac events. Participants were classified using the 2018 AHA/ACC guideline for the management of adults with CHD that combines anatomical complexity and current physiological stage.

Results

411 patients with a median age at test of 12 years, 51 patients with simple CHD, 170 patients with moderate complexity CHD and 190 with high complexity CHD underwent CPET. Overall, CPET parameters were lower than the reference values (%predicted VO2peak=75% and %predicted oxygen uptake efficiency slope (OUES)=79%), showing worst exercise capacity in the most complex types of CHD (Group III: %predicted VO2peak=72% and %predicted OUES=75%). Seventy-one patients presented with cardiac events at a median time from CPET to first event of 28 months. Patients with cardiac events had lower exercise performance as compared with patients without cardiac events as determined by the submaximal variables (%predicted OUES: HR=2.6 (1.5–4.4), p<0.001 and VE/VCO2: HR=2.2 (1.4–3.5), p=0.001).

Conclusion

Reduced exercise capacity at young age is related to a higher probability of future cardiovascular events in paediatric patients with CHD. Submaximal exercise variables can be used instead when maximal exercise cannot be achieved.

heart defects, congenital
echocardiography
congenital abnormalities
==== Body
pmcWHAT IS ALREADY KNOWN ON THIS TOPIC

The prognostic value of cardiopulmonary exercise tests (CPET) in paediatric patients with different congenital heart defects (CHDs) is not well known, whereas in adults it is a useful tool for risk stratification.

WHAT THIS STUDY ADDS

In this retrospective study, we reviewed 411 CPET performed by children with very diverse types of CHD and we found a reduction in exercise capacity in this group of patients. In addition, a lower %predicted value of oxygen uptake efficiency slope and higher value of minute ventilation (VE)/carbon dioxide production (VCO2) were related to higher probability of cardiac events at a median time of follow-up of 28 months; 81% of the events consisted of the need of reoperation or reintervention of residual lesions.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

The results of this study highlight the need to routinely perform CPET in paediatric patients with different types of CHDs and provide new perspectives in the decision-making process for reintervention of residual lesions.

Introduction

The prevalence of congenital heart defects (CHDs) in children is 9.1 per 1000 live births, amounting to approximately 1.35 million newborns with CHD annually.1 CHD encompasses a spectrum from mild to critical malformations, often requiring early surgical intervention, though advancements in diagnosis and treatment have significantly reduced mortality and morbidity.2 3 As more patients with CHD reach adolescence and adulthood, optimising quality of life and decision-making regarding reinterventions, such as through assessing exercise capacity, becomes increasingly important.

Cardiopulmonary exercise testing (CPET) is frequently used in patients with CHD as it can objectively evaluate the functional cardiovascular capacity and haemodynamic status of these patients. Several variables obtained by CPET have demonstrated to have an important prognostic value in adults with different CHDs47 and is emerging as a potential tool for risk stratification and clinical decision-making in assessing prognosis and planning interventions.8 However, the prognostic value of exercise variables in the paediatric age group is as yet unclear.

In this retrospective study, we aimed to determine the role of CPET in predicting major cardiovascular events (MACEs) in children with different types and degrees of complexity of CHD. We hypothesised that as in adults CPET results in children may help to predict future outcome.

Materials and methods

Study population

All patients with a CHD who performed a CPET at the Leiden University Medical Centre (LUMC) between December 2010 and September 2022 and were aged less than 18 years were included in this retrospective study. If patients performed more than one CPET the first available test was used for analysis. The study was approved by the institutional review board and the need for individual consent for this retrospective study was waived.

Follow-up data were collected until November 2022. The medical records were reviewed to determine cardiac events. Cardiac events were defined as overall mortality, the need for heart transplantation, all cardiac-related hospitalisations (including medical management of heart failure, arrhythmia therapies, protein losing enteropathy or plastic bronchitis) and surgical or catheter-based interventions.

To classify the different CHDs in a systematic way, the classification scheme proposed in the 2018 AHA/ACC guideline for the management of adults with CHD9 was used. This classification combines anatomical complexity and current physiological stage of the patient to group them in different risk categories and it has shown to improve prediction for cardiac mortality over 15 years in adults as compared with anatomical classification only.10 Patients were first classified according to anatomical complexity into low complexity I (eg, atrial and ventricular septal defects or patent ductus arteriosus), moderate complexity II (eg, congenital valve diseases, repaired tetralogy of Fallot or auriculoventricular septal defect) and high complexity III (eg, transposition of the great arteries, valvular atresia or Fontan procedure); and subsequently they were subclassified into four subcategories (A, B, C, D) depending on the physiological stage at the time the CPET was performed. The physiological stage was evaluated reviewing the clinical records of the patients and only information that was within a reasonable period from the CPET was considered.

Exercise protocol

All patients performed a progressive CPET on an electronically braked cycle ergometer (GE Healthcare eBike Comfort, Freiburg, Germany) connected to a facemask (Hans Rudolph, Kansas City, Missouri, USA) with a flowmeter (Triple V volume transducer) and a computerised gas analyzer (Jaeger MasterScreen CPX, CareFusion GmbH, Hoechberg, Germany; or Vyntus CPX, Vyaire Medical GmbH, Hoechberg, Germany). A breath-by-breath minute ventilation (VE), oxygen uptake (VO2), carbon dioxide production (VCO2) and respiratory exchange ratio (RER) in 10-s intervals were measured. A 12-lead ECG continuously monitored the heart rate (HR) and blood pressure was determined every 2 min by a sphygmomanometer. A 3-min warm-up phase (unloaded cycling) followed by a continuous incremental bicycle protocol with a work rate increment of 10, 15 or 20 W/min depending on the height (<125 cm, 125–150 cm or >150 cm) according to the Godfrey protocol11 was used. The patients had to maintain a pedalling rate between 60 and 80 revolutions/min and were encouraged to perform to exhaustion unless the patient experienced discomfort, changes in the ECG, excessive breathing pattern or otherwise.

RER was defined as the ratio of VCO2/VO2 and the RER peak (RERpeak) was calculated as the average of the two highest consecutively achieved RER values in 10 s during peak work rate. An RERpeak >1.00 was considered as maximal exercise. The WR peak (WRpeak) was defined as the maximum work rate achieved and finished (1 min completed) and the %predicted value was calculated.12 HR at rest was measured after at least 3 min in a seated position and HR peak (HRpeak) was calculated as the highest value achieved during at least 10 s in WRpeak. Then the %predicted value was calculated and ≤90% was considered abnormal.13 HR reserve was defined as HR peak minus HR rest.

With the linear regression of VE and VCO2 during the entire period of the test the VE/VCO2 slope (ventilatory efficiency) and the %predicted values were calculated based on the published reference values.12 An absolute value ≥34 was considered abnormal.1315

Oxygen uptake efficiency slope (OUES) was calculated by the linear least squares regression of the VO2 on the common logarithm of the VE by the equation VO2=alog (VE)+b, where the constant ‘a’ is the regression coefficient OUES.16 Absolute values, %predicted values and values per body weight were represented. The %predicted (OUES%) was determined using the previous described formulas based on reference normal values adjusted for age and sex.17

The maximal oxygen consumption (VO2peak), measured in mL/min, was calculated as the average of two highest consecutive achieved VO2 values in 10 s during WRpeak. Reference values were used for calculating the %predicted value (VO2peak%) and ≤84% was considered abnormal.18 The O2pulse is the VO2 divided by HR and the maximal O2pulse (O2pulsemax) was calculated as the average of the highest two consecutive O2pulse values during WRpeak. The data of Ten Harkel et al12 were used to calculate the %predicted values and ≤80% were considered abnormal.13 Both VO2peak and O2pulsemax were measured only in patients who achieved RER >1.

Data analysis

Data analysis was performed using SPSS Statistics software (V.29.0.0.0 IBM SPSS, Chicago, Illinois, USA). Variables were tested for normal distribution using the Kolmogorov-Smirnov or Shapiro-Wilk test when suitable and data were expressed as mean±SD, if normally distributed or as median and IQR if not normally distributed. The exercise test results were expressed relatively to the reference values as % of predicted value (100% would mean equal to reference value) and represented as mean with 95% CI.

One-way analysis of variance with Bonferroni post hoc correction if normally distributed or Kruskal-Wallis test adjusted by the Bonferroni correction for multiple test if not normally distributed were used to assess the differences in CPET variables between the three anatomical and physiological classification groups. The independent-samples t-test or the Mann-Whitney U test, in case of non-normality, were used to assess differences between patients with or without cardiac events.

Kaplan-Meier survival curves and a cox regression, to calculate the HR with the 95% CI, were performed to determine the predictive value of the different CPET variables for cardiac events in the overall group and per anatomical classification group. P values <0.05 were accepted as statistically significant.

Results

Four hundred and eleven patients were included in the study with a median (Q1–Q3) age at test of 12 (10–15) years; 43% were female. Figure 1 (and table 1) shows the distribution of the patients with different CHDs according to the 2018 AHA/ACC guideline risk classification. Most of the 51 patients included in the first anatomical group had a good physiological status (A), whereas most of the 170 patients of group II and the 190 patients of group III were in physiological stages B or C (online supplemental table S1). In none of the three anatomical categories were patients in physiological stage D. The clinical assessment to determine the physiological stages of the patients could be assessed at the same time of the CPET in 61%, within 2 months in 29% and within 5 months in 9%. Four patients with an analysis outside this range were excluded. There were no differences in age, sex and size between the three anatomical groups (table 2).

Figure 1 Anatomical and physiological classification according to the 2018 AHA/ACC guideline of the different congenital heart diseases. Classification of patients according to anatomical complexity into three categories: low complexity I, moderate complexity II and high complexity III and subsequently they were subclassified into four subcategories (A in green, B in blue, C in yellow, D not represented as there were no patients in this category) depending on the physiological stage at the time the cardiopulmonary exercise testing was performed.

Table 1 Types of CHDs according to the 2018 AHA/ACC guideline for the management of adults with CHD

Group I (51 patients)	Group II (170 patients)	Group III (190 patients)	
Mild pulmonary stenosis: 3 patients

ASD: 10 patients

VSD: 38 patients

	Tetralogy of Fallot: 40 patients

Coarctation of the aorta: 35 patients (3 with VSD)

Congenital aortic valve disease: 22 patients

AVSD: 16 patients (7 partial and 9 complete)

Pulmonary valve stenosis: 13 patients

VSD with associated abnormality and/or moderate or greater shunt: 9 patients

Anomalous pulmonary venous connection: 7 patients (3 partial and 4 total)

Ebstein anomaly: 7 patients

Subvalvular aortic stenosis: 5 patients

Shone syndrome: 4 patients

Anomalous origin of coronary arteries: 4 patients

Congenital mitral valve disease: 3 patients

Moderate shunt after repaired secundum ASD: 1 patient

Absent of pulmonary valve: 1 patient

Pulmonary veins stenosis: 1 patient

Severe dysplastic tricuspid valve: 1 patient

	Fontan procedure (all types): 93 patients

TGA (all types): 65 patients

Double-outlet ventricle (with biventricular repair): 12 patients

Pulmonary atresia (with biventricular repair): 8 patients

Truncus arteriosus: 8 patients

Cyanotic congenital heart defects: PHT with multiple ASDs: 1 patient

Pulmonary stenosis with 1 ½ repair: 3 patients

	
ASDatrial septal defectAVSDatrioventricular septal defectCHDscongenital heart defectsPHpulmonary hypertensionTGAtransposition of the great arteriesVSDventricular septal defect

Table 2 CPET parameters in patients with different congenital heart diseases

	Overall group N=411	In=51 (12.5%)	II
n=170 (41.5%)	III n=190 (46%)	P value	P I vs II	P I vs III	P II vs III	
Age (years)	12 (10–15)	12 (9–14)	13 (10–15)	12 (10–14)	0.067	0.072	0.479	0.570	
Sex (male, %)	234 (57%)	30 (59%)	95 (56%)	109 (57%)	0.921	0.710	0.826	0.776	
Medication (yes, %)	113 (28%)	0 (0%)	16 (9%)	97 (51%)	<0.001	0.023	<0.001	<0.001	
Weight (kg)	44 (33–57)	43(32–55)	47(35–58)	42(32–55)	0.163	0.592	1	0.233	
Height (cm)	156(144–168)	154±15	158(146–169)	154(142–165)	0.167	0.637	1	0.230	
BSA (DuBuis)	1.41 (1.17–1.64)	1.38±0.27	1.45 (1.20–1.66)	1.37 (1.14–1.62)	0.149	0.578	1	0.209	
SBPbasal (mm Hg)	119 (110–134)	115 (108–132)	119 (110–133)	119 (108–134)	0.511	0.775	0.895	1	
SBPpeak (mm Hg)	164 (147–189)	172±26	163 (146–189)	167±30	0.430	0.656	0.667	1	
RERpeak	1.12±0.10	1.15±0.08	1.12±0.1	1.10±0.1	0.005	0.449	0.010	0.076	
RERpeak >1 n (%)	373 (91%)	51 (100%)	154 (91%)	168 (89%)	0.046	0.028	0.020	0.483	
WRpeak (W)	110 (80–160)	120(90–175)	120(90–166)	100 (75–135)	<0.001	1	0.015	<0.001	
%predicted	89 (81–97)	100 (95–106)	98 (78–117)	78 (74–81)	<0.001	0.006	<0.001	<0.001	
HRrest (bpm)	83±16	82±16.7	83.5±13.7	82±17.5	0.663	1	1	1	
HRpeak (bpm)	180 (165–189)	186 (176–193)	181(169–190)	173 (162–186)	<0.001	0.261	<0.001	<0.001	
%predicted	94 (93–95)	97 (95–99)	96 (94–97)	91 (90–93)	<0.001	0.472	<0.001	<0.001	
HRreserve (bpm)	95 (80–110)	108 (93–115)	95.6±17.7	88 (74.5–110)	<0.001	0.039	<0.001	0.057	
Submaximal effort parameters									
VE/VCO2	30.6 (27.3–34.6)	29.3±4.3	29.1 (26.5–32.1)	32.8 (28.3–37.4)	<0.001	1	<0.001	<0.001	
%predicted	105 (103–107)	96 (92–100)	100 (97–103)	112 (108–116)	<0.001	0.600	<0.001	<0.001	
OUES (mL/min/log(L/min))	1503 [1213–1876]	1502 [1273–1957]	1576 [1318–1998]	1450 [1156–1799]	0.012	1	0.342	0.004	
%predicted	79 (77–81)	86 (80–92)	80 (77–83)	75 (72–79)	0.004	0.794	0.013	0.031	
Maximal effort parameters									
VO2peak (mL/min)	1474 [1175–1936]	1639 [1194–2061]	1565 [1301–2034]	1323 [1102–1696]	0.118	0.779	1	1	
%predicted	75 (73–78)	83 (76–90)	76 (73–79)	72 (67–77)	<0.001	0.625	0.001	0.004	
O2pulsemax (mL/bpm)	8.7 [7.0–10.8]	8.9 [7.3–11.2]	9.1 [7.3–11.2]	8.2 [6.9–10.2]	0.049	1	0.321	0.066	
%predicted	70 (68–72)	78 (68–87)	70 (67–73)	67 (64–71)	0.004	0.476	0.008	0.068	
Data shown as mean±SD, median [IQR] or number (%).

The %predicted values are shown as mean (95% CI).

BSAbody surface areaCPETcardiopulmonary exercise testingHRpeakmaximal heart rate at peak exerciseHRreservemaximal heart rate-resting heart rateHRrestresting heart rateO2pulsemaxmaximal O2pulseOUESoxygen uptake efficiency slopeRERpeakrespiratory exchange ratio at peak exerciseSBPbasalsystolic blood pressure at restSBPpeaksystolic blood pressure at peak exerciseVE/VCO2ventilatory efficiencyVO2peakoxygen uptake at peak exerciseWRpeakpeak work rate

Of the 411 patients, 28% were receiving various medications, with Group III having the highest percentage (table 2). Specifically, 105 patients were on antithrombotic and/or anticoagulant medication. Additionally, nine patients were treated with ACE inhibitors (eight with enalapril and one with captopril). Five patients were on β-blockers (sotalol, labetalol, carvedilol and metoprolol). Two patients received medication to reduce pulmonary pressure (sildenafil and bosentan), and four were using diuretics. Lastly, one patient was treated with flecainide.

Overall, CPET variables in patients with different CHDs are lower than the reference values as demonstrated by the %predicted values (table 2: %predicted VO2peak=75% (73–78) and %predicted OUES=79% (77–81)). Group III, with the most complex types of CHDs, showed the worst exercise capacity, with all the %predicted variables lower than the other two anatomical groups (table 2). In groups I, II and III the maximum effort (RERpeak>1) was reached in 100%, 90% and 89% of patients, respectively. Also, the %predicted values of the WRpeak were different between groups, with lower values in patients with more complex CHDs (table 2). There were no other differences between groups I and II.

In groups II and III an analysis of the differences in CPET between the different physiological subgroups was performed (online supplemental table S2). The variables were lower in the subgroup with worst physiological classification in group II but those differences were not observed in group III. Group I was not included in the analysis as most of its patients were in physiological group A.

Cardiac events

In table 3, the differences in CPET variables between patients who had a cardiac event and those who did not are depicted. Only 13 patients were lost to follow-up (seven from group I, three from group II and three from group III) and 72 patients presented cardiac events; 40 patients in group III, 32 patients in group II and none in group I; with a median time to first event of 28 [11–52] months. In table 4, the different types of cardiac events are depicted. Overall, 30 (42% of the total number of interventions) patients needed a catheter-based intervention and 28 (39%) patients needed cardiac surgery.

Table 3 Differences in CPET parameters between patients with cardiac and no cardiac events

	Overall	Group II	Group III	
Overall	No events n=326	Events n=72	P value	No events n=135	Events n=32	P value	No events n=147	Events n=40	P value	
HRpeak (bpm)	180 (165–189)	173 (162–187)	0.033	181 (168–190)	178 (167–187)	0.262	175 (162–186)	168±21	0.186	
%predicted	94 (93–95)	91 (89–94)	0.027	96 (94–97)	94 (91–97)	0.281	92 (90–93)	90 (85–93)	0.144	
HRreserve (bpm)	95 (81–110)	89±23	0.079	96±17	93±20	0.427	90 (76–110)	85±25	0.230	
Submaximal effort										
VE/VCO2	30.2 [27.0–34.1]	32.0 [28.8–37.5]	0.001	29.4±4.2	30.7 [28.0–36.0]	0.080	32.7±6.5	34.6 [29.6–41.7]	0.028	
%predicted	103 (101–105)	114 (106–122)	0.004	99 (96–1001)	105 (95–115)	0.200	109 (106–113)	121 (110–132)	0.061	
OUES (mL/min/log(L/min))	1537 [1241–1950]	1416±504	0.001	1615 [1335–2030]	1471 [1149–1779]	0.078	1478 [1198–1876]	1320±429	0.014	
%predicted	80 (78–83)	71 (66–76)	0.001	82 (78–85)	74 (67–82)	0.058	77 (74–81)	69 (62–75)	0.051	
Maximal effort	n=300	n=60		n=125	n=26		n=131	n=34		
VO2peak (mL/min)	1531 [1215–19865]	1259 [1023–1635]	0.009	1568 [1335–2044]	1594±590	0.239	1427 [1121–1843]	1202 [952–1437]	0.003	
%predicted	76 (73–78)	69 (64–74)	0.056	77 (73–80)	73 (67–79)	0.243	71 (68–75)	66 (59–73)	0.258	
O2pulsemax (mL/bpm)	8.7 [7.2–10.9]	8.2±3.0	0.007	9.2 [7.5–11.2]	8.7±3.6	0.177	8.4 [7.0–10.8]	7.5±2.0	0.006	
O2 %predicted	72 (69–74)	62 (60–66)	0.009	71 (68–75)	66 (56–75)	0.271	69 (65–73)	58 (54–63)	0.011	
Data shown as mean ± SD, median [IQR] or number (%).

The %predicted values are shown as mean (95% CI).

CPETcardiopulmonary exercise testingHRpeakmaximal heart rate at peak exerciseHRreservemaximal heart rate-resting heart rateO2pulsemaxmaximal O2pulseOUESoxygen uptake efficiency slope;VE/VCO2ventilatory efficiencyVO2peakoxygen uptake at peak exercise

Table 4 Types of first cardiac events after CPET

Catheter-based interventions (30 patients 42%)	
Melody implantation (3 cases)

Stent placement: pulmonary valve and arteries, descending aorta, Fontan tunnel or homograft (13 cases)

Balloon dilation: pulmonary valve and arteries, pulmonary veins or descending aorta (8 cases)

Vascular plug: collaterals in univentricular patients (12 cases)

Closure of Fontan fenestration (3 cases)

	
Surgery (28 patients 39%)	
Homograft implantation (14 cases)

Contegra change (1 case)

Ross procedure (1 case)

RVOT obstruction repair (1 case)

Sutureless repair of pulmonary veins (2 cases)

Cone procedure (2 cases)

Replacement of Fontan (1 case)

Subaortic valve obstruction repair (1 case)

Aortic root replacement (1 case)

Closure of ASD II (1 case)

	
Rhythm disorders (10 patients 14%)	
Catheter ablation (7 cases)

Implantable cardioverter defibrillator (3 cases)

Pacemaker (2 cases)

	
Others	
Endocarditis (1 case)

Pleural-pericardial effusion that needed drainage (1 case)

Death (1 case)

	
Note: In some procedures more than one intervention on was performed (eg, stent implantation and close of a collateral or catheter ablation and implantable cardioverter defibrillator placement).

CPETcardiopulmonary exercise testing

Exercise performance was reduced in the group of patients who presented cardiac events in the follow-up period, with lower absolute values and %predicted values of VE/VCO2, OUES and O2pulse (table 3). There were no differences in group II and in group III only the absolute values were lower in the event group but not the %predicted values (except the O2pulse). In the survival analysis (figure 2), %predicted OUES and VO2peak values ≤84% and VE/VCO2 ≥34 were related to higher probability of having cardiac events over time (HR=2.6 [1.5–4.4], p<0.001; HR=2.1 [1.2–3.7], p=0.009 and HR=2.2 [1.4–3.5], p=0.001, respectively). In the group analysis, only in group III this association persisted but not in group II.

Figure 2 Cardiovascular event-free survival curves. Kaplan-Meier curves for different exercise test parameters in the entire group, group II and group III and their hazard ratios. The analysis was performed using as cut-off points the published reference values (see Material and methods section) and the values considered abnormal were: VE/VCO2 >34, %predicted OUES ≤84%, %predicted VO2peak ≤84% and %predicted O2pulse ≤80%. O2pulsemax, maximal O2pulse; OUES, oxygen uptake efficiency slope; VO2peak oxygen uptake at peak exercise.

Discussion

In the present study, maximal and submaximal exercise capacity were reduced in patients with CHD and this was most prominent in patients with more severe CHD. Lower exercise capacity was associated with a higher likelihood of future cardiovascular events.

CPET tests the integrity of cardiopulmonary, skeletal and autonomic function. Impairment in either of these systems will result in a reduced exercise capacity. In the present study, we found a reduction in the %predicted maximal (VO2peak) and submaximal (OUES and VE/VCO2) variables. Other studies in patients with CHD with specific cardiac lesions, varying in complexity, also demonstrated reduced exercise capacity in the majority of patients. Even patients after relatively simple CHD surgery, such as coarctation repair, with good long-term outcome show reduced CPET results.19 Also patients after surgical VSD closure show reduced exercise capacity as compared with healthy controls, with further deterioration with advancing age.20 21 More severely reduced exercise capacity usually is found in the univentricular patients after completion of the Fontan circulation.6 22

To compare patient groups with different levels of CHD several classification systems have been developed. The most widely used system is the New York Heart Association (NYHA) classification, that classifies the stages of heart failure in patients with any type of cardiovascular disease ranging from I to IV. A more anatomically based classification is the RACHS-I classification.23 This is developed as a perioperative classification especially used for operative mortality. The new classification combining the anatomical and functional characteristics used in adults with CHD9 has shown in a group of 629 adult patients that the addition of the physiological stage to the anatomical complexity improved the prediction for cardiac mortality over 15 years.10 Although our patients were much younger, to our opinion this classification may be useful in young patients as well as it combines the physiological status of the patients with the anatomical classification. Surprisingly, our study found that CPET variables differed between physiological subgroups only in group II. In contrast, in the group with more severe CHD, CPET variables were similar regardless of physiological status. However, this may have been influenced by the uneven distribution of physiological subtypes within the anatomical groups.

To our knowledge this is the largest group of children with a wide variety of CHD studied with CPET. In such a diverse group we have found that reduced exercise capacity determined by the %predicted values of VE/VCO2 and OUES is related to cardiac events (mostly cardiac interventions) irrespectively of the complexity of the CHD. CPET has been extensively used as a predictive tool in adults with different cardiovascular diseases and specifically, in adult patients with CHD.7 8 24 In a recent meta-analysis several maximal and submaximal CPET variables have shown to predict MACEs in adults with different CHDs.4 Moreover, Wikner et al have demonstrated that exercise capacity and diverse group of adults CHD complexity are independently associated with all-cause mortality in patients with CHD.25 Data about the prognostic value of CPET in children with CHD are as yet scarce. In Fontan patients’ reduced exercise capacity predicts cardiovascular events after 8 years of follow-up.6 Also, Lytrivi et al showed that children with CHD and biventricular circulation, exercise testing during heart transplant evaluation identified patients at higher risk of death or earlier clinical deterioration.26

In adult’s studies, as mentioned before, CPET can predict MACEs. This term is increasingly been used as outcome in adult studies but its definition is unclear, and includes different endpoints such as cardiovascular death, acute myocardial infarction and stroke and also transplant, initiation of ventricular assist device and cardiac and/or unscheduled hospitalisation.27 In the present study, we found that reduced exercise capacity in an unselected population of paediatric patients with CHD also predicts future cardiovascular events, mostly the need of reintervention/reoperation of residual lesion, which opens new perspectives. If exercise capacity is impaired, detailed investigation about underlying mechanisms should be performed, including residual defect, and if possible, they should be treated. This finding also underscores the necessity to evaluate exercise capacity on a regular basis in children with CHD as it can help in the decision-making process for reintervention of residual lesions.

In CPET, the maximal oxygen consumption is usually seen as the gold standard. Most studies that investigate oxygen consumption during exercise use this maximal value. However, in a substantial number of patients a maximal exercise test cannot be performed because of psychological, medical or physical conditions.28 In the present study, on average 9% of the patients could not reach an RER >1.0, ranging from 0% in the patients with the simplest lesions up to 11% in the patients with the most severe lesions. Furthermore, in children with a Fontan circulation failure to reach an RER >1.0 can be as high as 20%.6 The maximally reached RER in a paediatric population is also age dependent which means a higher failure rate of reaching VO2peak in younger children.29 Therefore, submaximal exercise variables have been developed. The VE/VCO2 has shown to be a submaximal exercise variable related to mortality in adults with CHD.8 More recently the OUES has become more widespread in use,28 and has shown to have a good correlation with VO2peak and is a good prognostic marker.6 30 In our study, lower %predicted values of both OUES and higher VE/VCO2 were related to higher probability of having cardiac events over time. These findings underscore that not only maximal exercise variables have to be assessed but that also submaximal exercise variables have to be taken into account, especially in children and patients with severe underlying disease, in whom maximal effort is not always achieved.

Limitations

In this retrospective study, all CPET tests that were performed during a certain time period were taken into account. As no strict protocol about when and in which patients a CPET has to be performed was present during that time period, bias may have occurred as in which patients the CPET is performed. However, as the CPET results correlate well with those published in literature we do not think this have influenced our results significantly. While this single-centre design ensures consistency and reliability in the measurements, we recognise the potential limitation in generalisability to broader populations. Future multicentre studies could validate our findings across diverse settings.

The median follow-up period was 7 [3–8] years. If the same results will persist during long-term follow-up is as yet unknown. However, since the number of cardiovascular events increases during adult age it seems unlikely that the effect of previously reduced exercise capacity will disappear.

Most of the patients who underwent CPET were in NYHA classification I or II. If more patients with NYHA III or IV were included, it is likely that more cardiovascular events will be reported, and the prognostic significance of a CPET would probably have been increased.

Conclusions

Paediatric patients with CHD had overall lower CPET values compared with reference values. Those with the lowest CPET values are more likely to require cardiac interventions over time. When maximal exercise cannot be performed, submaximal exercise variables show similar results and can be used instead. These findings underscore the need to perform CPET on a regular basis in patients with CHD .

supplementary material

10.1136/openhrt-2024-002820 online supplemental file 1

Data availability statement

Data are available upon reasonable request.

Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Provenance and peer review: Not commissioned; externally peer reviewed.

Patient consent for publication: Not applicable.

Ethics approval: This study involves human participants and was approved by Medical Ethical Committee Leiden-Den Haag-Delft (number of the METC approval G17.084). The need for individual consent for this retrospective study was waived.

Data availability free text: Access to the database is currently restricted from public use. However, the data underlying this article will be shared on reasonable request.
==== Refs
References

1 van der Linde D Konings EEM Slager MA et al Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis J Am Coll Cardiol 2011 58 2241 7 10.1016/j.jacc.2011.08.025 22078432
2 Oster ME Lee KA Honein MA et al Temporal trends in survival among infants with critical congenital heart defects Pediatrics 2013 131 e1502 8 10.1542/peds.2012-3435 23610203
3 Downing KF Nembhard WN Rose CE et al Survival from birth until young adulthood among individuals with congenital heart defects: CH STRONG Circulation 2023 148 575 88 10.1161/CIRCULATIONAHA.123.064400 37401461
4 Wadey CA Weston ME Dorobantu DM et al The role of cardiopulmonary exercise testing in predicting mortality and morbidity in people with congenital heart disease: a systematic review and meta-analysis Eur J Prev Cardiol 2022 29 513 33 10.1093/eurjpc/zwab125 34405863
5 Udholm S Aldweib N Hjortdal VE et al Prognostic power of cardiopulmonary exercise testing in fontan patients: a systematic review Open Heart 2018 5 e000812 10.1136/openhrt-2018-000812 30057765
6 Terol Espinosa de los Monteros C Harteveld LM Kuipers IM et al Prognostic value of maximal and submaximal exercise performance in Fontan patients < 15 years of age Am J Cardiol 2021 154 92 8 10.1016/j.amjcard.2021.05.049 34233838
7 Diller G-P Dimopoulos K Okonko D et al Exercise intolerance in adult congenital heart disease: comparative severity, correlates, and prognostic implication Circulation 2005 112 828 35 10.1161/CIRCULATIONAHA.104.529800 16061735
8 Inuzuka R Diller G-P Borgia F et al Comprehensive use of cardiopulmonary exercise testing identifies adults with congenital heart disease at increased mortality risk in the medium term Circulation 2012 125 250 9 10.1161/CIRCULATIONAHA.111.058719 22147905
9 Stout KK Daniels CJ Aboulhosn JA et al 2018 AHA/ACC guideline for the management of adults with congenital heart disease: executivesummary: a report of the American college of cardiology/American heart association task force on clinical practice guidelines J Am Coll Cardiol 2019 73 1494 563 10.1016/j.jacc.2018.08.1028 30121240
10 Ombelet F Goossens E Van De Bruaene A et al Newly developed adult congenital heart disease anatomic and physiological classification: first predictive validity evaluation J Am Heart Assoc 2020 9 e014988 10.1161/JAHA.119.014988 32089057
11 Godfrey S Methods of measuring the response to exercise in children Exercise testing in children: applications in health and disease London W.B. Saunders Company Ltd 1974
12 Ten Harkel ADJ Takken T Van Osch-Gevers M et al Normal values for cardiopulmonary exercise testing in children Eur J Cardiovasc Prev Rehabil 2011 18 48 54 10.1097/HJR.0b013e32833cca4d 20595902
13 American Thoracic ATS/ACCP statement on cardiopulmonary exercise testing Am J Respir Crit Care Med 2003 167 211 77 10.1164/rccm.167.2.211 12524257
14 Chua TP Ponikowski P Harrington D et al Clinical correlates and prognostic significance of the ventilatory response to exercise in chronic heart failure J Am Coll Cardiol 1997 29 1585 90 10.1016/s0735-1097(97)00078-8 9180123
15 Ingle L Prognostic value and diagnostic potential of cardiopulmonary exercise testing in patients with chronic heart failure Eur J Heart Fail 2008 10 112 8 10.1016/j.ejheart.2007.12.011 18255336
16 Baba R Nagashima M Goto M et al Oxygen uptake efficiency slope: a new index of cardiorespiratory functional reserve derived from the relation between oxygen uptake and minute ventilation during incremental exercise J Am Coll Cardiol 1996 28 1567 72 10.1016/s0735-1097(96)00412-3 8917273
17 Bongers BC Hulzebos EH Helbing WA et al Response profiles of oxygen uptake efficiency during exercise in healthy children Eur J Prev Cardiol 2016 23 865 73 10.1177/2047487315611769 26464293
18 Mylius CF Krijnen WP van der Schans CP et al Peak oxygen uptake reference values for cycle ergometry for the healthy Dutch population: data from the lowlands fitness registry ERJ Open Res 2019 5 10.1183/23120541.00056-2018
19 Róg B Okólska M Weryński P et al Long-term observation of adults after successful repair of aortic coarctation Postepy Kardiol Interwencyjnej 2019 15 455 64 10.5114/aic.2019.90220 31933662
20 Maagaard M Eckerström F Boutrup N et al Functional capacity past age 40 in patients with congenital ventricular septal defects J Am Heart Assoc 2020 9 e015956 10.1161/JAHA.120.015956 32962479
21 Nederend I de Geus EJC Blom NA et al Long-term follow-up after ventricular septal defect repair in children: cardiac autonomic control, cardiac function and exercise capacity Eur J Cardiothorac Surg 2018 53 1082 8 10.1093/ejcts/ezx438 29253118
22 Harteveld LM Blom NA Terol Espinosa de Los Monteros C et al Determinants of exercise limitation in contemporary paediatric Fontan patients with an extra cardiac conduit Int J Cardiol 2021 341 31 8 10.1016/j.ijcard.2021.08.012 34375703
23 Jenkins KJ Gauvreau K Newburger JW et al Consensus-based method for risk adjustment for surgery for congenital heart disease J Thorac Cardiovasc Surg 2002 123 110 8 10.1067/mtc.2002.119064 11782764
24 Dimopoulos K Okonko DO Diller G-P et al Abnormal ventilatory response to exercise in adults with congenital heart disease relates to cyanosis and predicts survival Circulation 2006 113 2796 802 10.1161/CIRCULATIONAHA.105.594218 16769913
25 Wikner A Sandström A Rinnström D et al Impaired exercise capacity and mortality risk in adults with congenital heart disease JACC Adv 2023 2 100422 10.1016/j.jacadv.2023.100422 38938993
26 Lytrivi ID Blume ED Rhodes J et al Prognostic value of exercise testing during heart transplant evaluation in children Circ Heart Fail 2013 6 792 9 10.1161/CIRCHEARTFAILURE.112.000103 23580746
27 Bosco E Hsueh L McConeghy KW et al Major adverse cardiovascular event definitions used in observational analysis of administrative databases: a systematic review BMC Med Res Methodol 2021 21 241 10.1186/s12874-021-01440-5 34742250
28 Ten Harkel AD Takken T Oxygen uptake efficiency slope in children: its role in exercise testing Eur J Prev Cardiol 2019 26 171 3 10.1177/2047487318810872 30396296
29 Amedro P Matecki S Pereira Dos Santos T et al Reference values of cardiopulmonary exercise test parameters in the contemporary paediatric population Sports Med Open 2023 9 68 10.1186/s40798-023-00622-3 37528295
30 Terol Espinosa de Los Monteros C Van der Palen RLF Hazekamp MG et al Oxygen uptake efficiency slope is strongly correlated to VO2peak long-term after arterial switch operation Pediatr Cardiol 2021 42 866 74 10.1007/s00246-021-02554-9 33527171
