“How do patients with a repaired Tetralogy of Fallot or a...

“How do patients with a repaired Tetralogy of

Fallot or a Fontan circulation correspond to

normal children and to each other when it comes

to exercise and recovery?”

Name : Eshuis, G.

Student nr. : 1959026.

Supervisors : Dr. B. Bartelds en prof. dr. R.M.F. Berger.

Location : Department of paediatric cardiology of the

Beatrix children’s hospital in Groningen.

Date : 2nd

of May 2014

1

– Abstract –

Introduction

Improved survival rates in congenital heart diseases (CHD) lead to an increased morbidity in

adult life. Morbidity is monitored by cardiopulmonary exercise testing (CPET). Particularly

two patient groups are at risk for early exercise impairment: repaired tetralogy of Fallot (TOF)

patients and Fontan patients.

Aim

To identify and describe maximal exercise capacity in children with repaired TOF and Fontan

circulations. To assess whether the possible limitations are correlated to residual lesions, such

as ventricular or valvular insufficiency.

Materials and methods

All participants (n = 87) underwent a maximal CPET in the period 2011-2013 in the

University Medical Centre of Groningen. Seven patients were excluded due to submaximal

exercise. The study population consisted of 11 healthy controls, 28 TOF patients and 41

Fontan patients. Cardiac function at rest was examined by echo and MRI assessments

performed by medical experts. CPET protocol was a steep RAMP protocol on a cycle-

ergometer. Exercise performance is defined as workload and maximum oxygen uptake (VO2

peak). Additional factors were monitored continuously: heart rate, ventilation, oxygen pulse,

blood pressure and transcutaneous saturation.

Results

Exercise performance was significantly decreased in Fontan patients and seemed lower in

TOF as compared to the control group. In Fontan and TOF maximal heart rate (HR max),

chronotropic response to exercise, ventilation and ventilator efficiency were lower than in the

controls. The oxygen pulse at peak exercise was also lower in the Fontan. Correlations

between VO2 peak and BMI are found in both patients groups. In the Fontan group cardiac

response to exercise was correlated to workload and VO2 peak. In the TOF children no

additional parameters were correlated to exercise performance. Unexpectedly residual lesions

and ventricular function was neither correlated to exercise capacity.

Conclusion

Fontan children are early impaired in their exercise performance, possibly due to reduced

cardiac response to exercise. TOF children have a mildly reduced exercise capacity, although

not yet explainable. Further studies are necessary to explain the role of heart rate recovery,

ventilation capacity and muscle strength factors.

2

– Samenvatting –

Introductie

Toegenomen overlevingskans in patiënten met aangeboren hartafwijkingen heeft geleid tot

meer morbiditeit in volwassenen met aangeboren afwijkingen. Om deze morbiditeit te

monitoren worden inspanningstesten gebruikt. Twee patiëntgroepen hebben een verhoogd

risico op een afgenomen inspanningscapaciteit op jonge leeftijd: tetralogie van Fallot

patiënten en Fontan patiënten.

Doel

Het identificeren en beschrijven van de maximale inspanningscapaciteit bij kinderen met een

gecorrigeerde tetralogie van Fallot en kinderen met een Fontan circulatie. Beoordelen of een

eventuele inspanningsbeperking is geassocieerd met restafwijkingen, zoals pulmonalisklep

insufficiëntie of ventrikelfalen.

Materiaal en methoden

Alle kinderen (N = 87) hebben een maximale inspanningstest gedaan in het Universitair

Medisch Centrum in Groningen in de periode 2011-2013. Zeven patiënten zijn geëxcludeerd

vanwege een submaximale inspanningtest (RER < 1,03). De populatie bestond uit 11 gezonde

controles, 28 tetralogie van Fallot patiënten en 41 Fontan patiënten. De cardiale functie in rust

is beoordeeld door een medisch specialist middels echo en MRI. Het inspanningsprotocol was

een RAMP-protocol op een fietsergometer. Inspanningscapaciteit is gedefinieerd als workload

en maximale zuurstof opname capaciteit (VO2 peak). Additionele parameters zijn continu

geregistreerd, deze factoren zijn onder andere: hartslag, bloeddruk, ventilatie (L/min),

zuurstofpuls (O2 per hartslag per kg) en transcutane zuurstofsaturatie.

Resultaten

Inspanningscapaciteit is duidelijk beperkt in the Fontan patiënten en lijkt lager in the TOF

kinderen vergeleken met de controle groep. In beide patiënten groepen zijn de maximale

hartfrequentie (HR max), chronotrope response, ventilatie en efficiëntie van de ventilatie lager

dan in de gezonde leeftijdsgenoten. Zuurstofpuls ten tijde van de piekinspanning is

afgenomen in de Fontan. Correlaties tussen VO2 piek en BMI worden gevonden in beide

groepen. In de Fontan kinderen kan de cardiale respons geassocieerd worden met de VO2

piek. In de TOF kinderen zijn er geen additionele factoren die correleren met

inspanningscapaciteit gevonden. Een onverwachte bevinding was dat restafwijkingen en

ventriculaire functie niet gecorreleerd zijn met inspanningsperformance.

Conclusie

Fontan kinderen zijn op vroege leeftijd al beperkt in hun inspanningsvermogen, mogelijk door

een verminderde cardiale reactie op inspanning. TOF kinderen zijn matig beperkt in hun

inspanningscapaciteit, dit kan niet worden verklaard door de additionele parameters die in

deze studie zijn onderzocht. Verder onderzoek zal de rol van herstel van de hartslag, ventilatie

capaciteit en spierkracht factoren moeten uitwijzen.

3

– List of abbreviations –

∆VO2/∆WL : Flow or utilization of oxygen in the exercising tissues

AI : Aortic valve insufficiency

AI LVOT : Aortic valve insufficiency with Left Ventricular Outflow Tract

Ao : Aorta

AS : Aotric valve stenosis

AVI : Atrioventricular insufficiency, defined as mitral valve insufficiency

BCPC : Bidirectional Cavo Pulmonary Connection

BMI : Body Mass Index

BR : Breathing rate

BSA : Body Surface Index

BT-shunt : Blalock-Taussing shunt

CHD : Congenital heart disease

CPET : Cardiopulmonary exercise test

CRE : Chronotropic response to exercise, defined as HRmax – HR rest

ECG : Electrocardiogram

ECHO : Echocardiografie

EDV : End diastolic volume

EF% : Ejection fraction

ESV : End systolic volume

HR : Heart rate

HR max : Maximum heart rate during the test

HR x min : Heart rate at x minutes after cessation of the test (recovery phase)

HRR% : Heart rate reserve as percentage of the predicted heart rate, defined as

(predicted heart rate – heart rate in rest)/predicted heart rate

MI : Mitral valve insufficiency

MRI : Magnetic Resonance Imagery

O2-pulse : Oxygen pulse, defined as oxygen per heart beat per kg

PA : Pulmonary artery

PAB : Pulmonary Artery Banding

PI : Pulmonary valve insufficiency

PS : Pulmonary valve stenosis

RER : Respiratory Expiratory Ratio

RF% : Regurgitation fraction

RVOTO : Right ventricular outflow obstruction

SpO2 : Transcutaneous oxygen saturation (%)

SV : Stroke volume

TAP : Trans annular patch

TAPSE : Tricuspid Annulus Plane Systolic Excursion

TCPC : Total Cavo Pulmonary Connection (Fontan)

TOF : Tetralogy of Fallot

Ve : Ventilation (L/min)

Ve/VCO2 : Ventilation efficiency

VO2 peak : Maximum oxygen uptake during the test, defined as the mean of the two

highest values achieved within 20s (mL/min/kg)

VO2max : Maximal exercise test

VSD : Ventricular septum defect

W : Watt

WL : Maximum achieved workload during the test (W)

4

– Table of contents –

– INTRODUCTION – 5

– MATERIALS AND METHODS – 8

PATIENTS 8

ECHO AND MRI 9

EXERCISE PROTOCOL 10

CALCULATIONS 11

STATISTICS 11

– RESULTS – 12

EXERCISE PERFORMANCE 14

RECOVERY 15

EXPLANATORY FACTORS 16

– DISCUSSION – 27

CONCLUSIONS 30

– REFERENCES – 31

5

– Introduction –

Over the last three decades congenital heart diseases (CHD) are treated with increased

success(1,2). As a result, mean survival rates of patients with CHD have increased rapidly

over the last three decades. This improved survival has led to an increased morbidity in adult

life, such as heart failure, exercise impairment and arrhythmias(3,4). This increase calls for a

shift in treatment focus. Preventing mortality is the main focus, however an adjustment

towards reducing morbidity and improving quality of life is required. Although there are

many studies about morbidity in adulthood(5-7), there remains uncertainty regarding

morbidity in childhood.

Early detection of alterations in functional parameters influences treatment choices

and adequate therapy may lower morbidity. An evident method to detect morbidity is the

cardiopulmonary exercise test (CPET). In adults with heart failure the CPET is used to predict

outcome, determine target therapy and detect problems(8-10). Exercise induces physiological

changes in both cardiovascular and respiratory systems. Gas exchange in the lungs is

increased by a higher perfusion rate due to a decrement of the pulmonary resistance.

Ventilation is increased by heightened respiratory frequency. The CO2-concentration in the

bloodstream raises during exercise and therefore causes vessel dilatation and more efficient

gas exchange in the small vessels (Bohr-effect). In addition to the pulmonary changes, the

cardiac system needs to react too. Heart minute volume is increased by 5-6 liter. This is

independent of age, weight, physical condition and active muscle mass. An important factor

in increasing the volume is the pump function of the heart. The heart rate is controlled by two

nerves: nervus vagus and nervus accelerantus. During rest the nervus vagus is overactive and

during exercise the nervus accelerantus is activated by the effect of adrenaline and other

hormones. Stimulation of the nervus accerlantes causes the heart rate to increase. Besides

activation of the cardiopulmonary system, exercise performance requires muscle activation

and muscle strength. Skeletal muscles are necessary to transfer resistance and intercostal

muscles are essential for an appropriate respiratory response to exercise. During CPET the

cardiopulmonary system is challenged. Pulmonary and cardiac restrictions may be detected

prior to actual symptoms in rest develop, because of a decrease in exercise performance(8,11).

6

Figure 1: Left – normal heart. LA left atrium, LV left ventricle, RV right

ventricle, PV pulmonary valve, AoV aortic valve, MV mitral valve, TV tricuspid

valve, MPA main pulmonary artery, Ao aorta, SVC superior vena cava, IVC

inferior vena cava.

Right – preoperative heart of a TOF patient. 1. left atrium, 2 left ventricle, 3 right

atrium, 4 hypertrofic right ventricle, 5 pulmonary valve with subvalvular

obstruction, 6 overriding aorta, 7 pulmonary artery, 8 aorta.

Maximum achieved workload (WL) and maximum oxygen uptake (VO2 peak) are used to

determine exercise performance. Other factors describe the nature of the CPET, such as

ventilation parameters (ventilation in L/min (Ve) and ventilation efficiency (Ve/VCO2)),

cardiac parameters (O2-pulse, used as a surrogate for cardiac output, defined as oxygen uptake

per heart beat per kg) and heart rate dynamics during exercise(8,9,11,12). Research in adults

with heart failure has revealed that heart rate recovery at two minutes after cessation of the

CPET is an essential predictor of mortality (13-15). Although the value of CPET in adults

with ischemic heart disease is established, it’s role in children with CHD is less clear.

Particularly two patient groups are at risk for exercise impairment in early childhood.

These groups are repaired Tetralogy of Fallot children (TOF) and children with a Fontan

circulation. Both patient groups may develop a diminished ventricular function and/or a

diminished pulmonary blood flow that may affect CPET results(16-18).

TOF is the most common cyanotic CHD, about 3-5% of all infants born with a CHD is

diagnosed with TOF. The defect entails a ventricle septal defect, an overriding aorta, a right

ventricle outflow obstruction and a right ventricle hypertrophy (Figure 1). If a distinction is

made in pulmonary anatomy, 80% of all patients has a pulmonary stenosis, the remaining

20% has pulmonary atresia. A common observation in TOF patients is valve dysmorphology

with a small annulus of the pulmonary valve. The right ventricle outflow obstruction causes

lower blood flow of a partially obstructed pulmonary system, which results in cyanosis. The

clinical (cyanotic) image of the child is dependent on the grade of right outflow obstruction.

Due to functional reserves, symptoms usually arise when the cardiovascular system is

stressed, e.g. during exercise. The purpose of the therapy is to close the VSD and to relieve

the right outflow obstruction. At the age of 3-6 months the corrective surgery takes place.

(1,18-20). If there is a small annulus of the pulmonary valve, a transannular patch (TAP) can

be used to correct this. In this procedure the annulus is cut open, the diameter of the annulus is

expanded and closure is achieved by placing a patch. Pulmonary valve insufficiency has been

reported as a complication of a TAP procedure (21). Residual stenosis or insufficiency leads

to right heart failure based on right ventricular dilation. This is associated with exercise

intolerance in the third and fourth decades of life. There is a lack of studies which describe the

value of CPET in younger patients(22,23).

7

Fontan circulation

In complex cardiac malformations, normal anatomy may be severely compromised, resulting

in absence of one of the pumping chambers of the heart. This occurs for example in tricuspid

atresia of hypoplastic left heart syndrome. These pathological circulations result in

disadvantages such as, arterial desaturation in rest and during exercise and chronic volume

overload of the ventricle. That leads to congestive heart failure in the future(16,24). A strategy

to approach this problem is given by Francis Fontan in 1971. He separated the two systems by

connecting the venous return directly to the pulmonary arteries (TCPC). With this approach

all shunts on venous, atrial, ventricular and arterial levels are interrupted. This leads to

normalization of the arterial saturation and abolishment of the chronic volume overload.

However, disadvantages of this procedure consist of chronic hypertension and congestion of

the systemic veins(17).

The Fontan circulation lacks a right ventricle that supports the pulmonary blood flow.

Without this ventricle to actively pump the blood into the pulmonary circulation, pulmonary

blood flow is compromised(17). Preferably the TCPC is achieved in a staged approach. First

the caval veins are connected to the pulmonary system bypassing the right side of the heart.

Then the superior caval vein is connected to the pulmonary artery (BCPC) and the inferior

vein is connected using a lateral tunnel, right auricle tunnel or an extra cardiac conduit. The

right auricle tunnel is a local approach to make an intercaval tunnel, which has more grow

potential than a lateral tunnel, is not as close to the sinus node and avoids the use of prosthetic

material(25). In high risk patients a small fenestration is created between the tunnel conduit

and the pulmonary atrium, this allows a right-to-left shunt and provides an increased preload

of the systemic ventricle. However it also causes lower saturated blood flowing into the

systemic circulation, for this reason patients are impaired in their exercise capacity(10,24,26).

Research questions

Our research questions are: (1) are TOF and Fontan patients limited in their exercise

performance? If so, (2) what are the best parameters to describe this limitation? And (3) do

these limitations correspond to residual lesions, such as ventricle or valve insufficiency? To

answer these questions we will perform a retrospective analysis of the CPET performance in

children with TOF or Fontan circulations.

Figure 2: Left – BCPC, hemi-Fontan. Middle – Lateral tunnel Fontan. Right – Extracardiac Fontan. SVC superior

vena cava, IVC inferior vena cava, RPA right pulmonary artery, RA right atrium, LA left atrum.

8

– Materials and methods –

The retrospective cohort study from 2010-2013 is part of the research line on healthy aging

with congenital heart disease. This research line focuses on right ventricular and pulmonary

adaptation to abnormal loading conditions in CHDs throughout life. The approach is

translational; knowledge obtained from the bench is applied to the patient population. For that

reason there is a close collaboration with several clinical departments.

Patients

The patient population consisted of patients in the age from 8-17 years old with a Fontan or a

repaired TOF circulation. They underwent a VO2max protocolled CPET at the University

Medical Centre of Groningen between 2011 and 2013. The CPET is considered part of routine

follow up. As patient data was collected in usual patient care and presented anonymously, no

patient or ethic committee approval was needed. All patients underwent a physical exam, rest

electrocardiogram (ECG), echocardiogram (echo), magnetic resonance imaging (MRI) and

CPET. The patients were then compared to each other and to healthy controls. The control

group consisted of children, who visited the hospital with complains of fatigue, palpitations or

dizziness. To exclude cardiopathology a rest ECG, an echo and a CPET are performed for this

control group. VO2 data were used only when there was no cardiopathology shown in the

echo or the ECG. Exclusion criteria were inability to perform exercise or compromising

factors for the CPET and cardiopathology in the control group.

Clinical data was extracted from patient’s medical records. This included age, surgical

history, (cardiac) medication and height, body weight, body mass index (BMI) and body

surface index (BSA). Diagnosis and details of the cardiac anatomy were based on echo and

MRI imagery, including residual lesions such as pulmonary stenosis, pulmonary insufficiency

and ventricular dysfunction. Surgical history was reported, for the Fontan group: first

palliation, pulmonary artery banding (PAB), performance of atrial septostomy, BT-shunt

(Blalock Taushing shunt), BCPC, type of TCPC and presence of an open fenestration at the

time of the CPET. For the TOF patients the first palliation, BT-shunt and TAP status were

reported

9

Echo and MRI

Echo and MRI were used to determine the residual lesions. To determine the degree of

valvular stenosis or insufficiency standard guidelines for adults as described in the textbook of

Pieper and Hamer(27) were used:

Table 1: Classification of valve insufficiency and stenosis

Mild Moderate Severe

Aortic

insufficiency

< 0.3 cm or < 25% 0.3-0.6 cm or 25-65% > 0.6 cm or > 65%

Aortic stenosis < 2.6-2.9 m/s

< 30 mmHg

Valve surface:

> 1.5 cm2 or

> 0.85 cm/m2

3-4 m/s

30-50 mmHg

Valve surface:

1-1.5 cm2 or

0.6-0.85 cm/m2

> 4 m/s

> 50 mmHg

Valve surface:

< 1 cm2 or

< 0.6 cm/m2

Pulmonary

insufficiency

< 50% of the annulus 50-70% of the annulus

PA flow > Ao flow

> 70% of the

annulus and diastolic

backflow

Pulmonary

stenosis

< 3 m/s

< 36 mmHg

3-4 m/s

36-64 mmHg

> 4 m/s

> 64 mmHg

Mitral valve

insufficiency

< 4 cm2 or < 20% 4-10 cm

2 or 20-40% > 10 cm

2 or >40%

Legend: AI – vena-contracta diameter (cm) and jet size AI/LVOT (%). AS – Vmax aorta-jet, mean gradient and valve

surface. PI – jet size/valve size on colour Doppler. PS – Doppler gradient across the pulmonary valve. MI – jet size as

percentage left atrium surface.

Ventricular function, particularly right ventricular function, was determined using the reports:

when the report showed no abnormalities, it was classified as normal. When the TAPSE was

lower than the ventricular function was classified as mildly impaired and when the report

states it is impaired than the ventricular function is moderately impaired. The TAPSE

(tricuspid annulus plane systolic excursion) is a measurement for right ventricular ejection

fraction.The classification of left ventricular function was extracted from the descriptions in

the report. We used cardiac MRI to determine the volumes of the ventricles at rest.

Volumetric analysis was performed using standard technique supervised by an expert

radiologist, dr. Willemse. We used these volumes to calculate stroke volume (SV = EDV-

ESV), ejection fraction (EF% = SV/EDV), regurgitation fraction (RF%) and to estimate the

right ventricular dilatation (EDV).

10

Exercise protocol

Participants performed a cycling VO2max test on a Jaëger Oxycom Pro System, with a breath-

by-breath mask, a 12-lead ECG, finger pulsoximeter and blood pressure bandage. The

exercise laboratory had a strictly controlled temperature and humidity(28). The test started

with two minutes of rest, then three minutes of warming-up with or without 20 Watts (W)

resistance depending on the protocol. Next the workload was increased with 10-25 W per

minute. The majority of the participants (60%) performed a 20 W/min increment protocol, the

other 25% underwent a 15 W/min increment and 10 and 25 W/min protocol was used in eight

respectively four participants. The speed at which the resistance was increased was dependent

on the height of the children(29). During the test participants were asked to peddle in a 60-80

rotations per minute rhythm. The duration of the test was 8-12 minutes and the test ended

when the participants were not able to hold the rhythm any longer. Important was that

participants were encouraged to perform until exhaustion. To guarantee the quality of the

VO2max protocol, the respiratory coefficient (RER) was used. A RER over 1.03 was

sufficient for maximum effort. After peak exercise, the recovery period started and the

participants were allowed to slow down to 40 rotations per minute against a resistance of 20

W.

Outcome parameters

Exercise performance was defined by oxygen uptake (VO2) and workload. Chronotrope

response (heart rate course, heart rate reserve and recovery), ventilation response to carbion

dioxide (Ve/VCO2), oxygen pulse per kg, ventilation capacity and breathing rate were used to

describe the nature of the CPET (8,9,11). During the test all parameters were registrated

continiously, but they were included in different timeframes (rest, warming-up, peak exercise,

the mean of the two highest VO2 values within 20s, at maximum VO2 achieved and recovery

1, 2, 3, 4 minutes). The peak values toke place at peak exercise and the maximal values are

those at highest VO2 achieved. All variables are displayed as mean of the two values closest

to the timepoint, except for the maximal VO2 and the maximal heart rate. These were the

highest values achieved during the test. The resting heart rate (HR) was either measured

before the CPET, while the patient was in the resting period or during physical exam in case

of absence of the resting period(12).

We used serveral timepoints in our study, but to provide a dataset where comparison

with the liturature is possible, we chose to use the mean of the two highest VO2 values

displayed as VO2 peak and for that same reason we used the highest achieved heartrate

(HRmax)(30).

11

Calculations

Predicted values for the VO2 peak and workload were based on Cooper(8), expected HR is

185 beat per minute(12). ∆VO2/∆WL was defined as the VO2 (ml/min) per watt and was

calculated as (VO2peak-VO2 warming-up)/(WLpeak-WLwarming-up). The heart rate course

during exercise is clarified in different ways, first is the chronotropic response to exercise

(CRE) defined as maximal heart rate – heart rate at rest. Second, the heart rate reserve

(HRR%) defined as predicted maximum HR – HRmax/ predicted HR. The recovery values

were displayed as discrete and cummulative decrement percentages of the CRE. The discrete

values were calculated by (HRmax-HR 1 min)/CRE(30), (HR 1 min – HR 2 min)/CRE and

the cummunaltive values were calculated by (HRmax – HR recovery timepoint)/CRE.

Cardiac output is the product of HR and stroke volume (SV). Oxygen pulse is the amount of

oxygen consumed per heartbeat(12). A reduced oxygen pulse may indicate reduced oxygen

extraction at the cellular level or a lower SV. Therefore oxygen pulse was used as a surrograte

for SV during exercise. Pulmonary factors were assessed using the ventilation capacity per

minute (Ve), the breathing rate (BR) and the ventilation efficiency (Ve/VCO2). The Ve/VCO2

was obtained using linear regression analysis of the data acquird throughout the period of

exercise(9,12).

Statistics

We used SPSS 20 to analyse the data. Continuous values were displayed in median (IQR) or

mean ± standard deviation as appropriate. We utilised the Kruskal Wallis test with post-hoc

Mann Whitney U to display the differences between the groups. To show correlation between

descriptive factors and exercise performance we used a Spearmann’s test. Correlations were

not described for the control group, due to the small number of participants. Seven out of 87

patients did not reach the RER > 1.03 goal.(31).

12

– Results –

A total of 87 patients had undergone a CPET in the period between 2011 and 2013. Seven of

the Fontan patients were excluded due to submaximal effort, these patients did not reach a

RER > 1,03. The remaining 80 patients formed the study, subdivided in 3 groups: 11 controls,

28 TOF patients and 41 Fontan patients. There were no major differences in group

characteristics, except for lower transcutaneous oxygen saturation in rest in the Fontan group.

The patients in the TOF and Fontan group appeared to have a lower body weight than the

controls, although this difference was not statistically relevant (Table 2).

Table 2: Population characteristics

Control TOF Fontan P-value

N N N

Age at test (years) 11 13.9 (13.1-15.4) 28 13.9 (10.6-15.5) 41 13.9 (11.4-15.6) 0.823

Female (%) 11 6 (55) 28 15 (54) 41 14 (34)

Heigth (m) 11 166 (158-172) 28 158 (148-170) 41 162 (144-170) 0.247

Weigth (kg) 11 60.2 (50.4-68.0) 28 47.3 (33.6-57.0) 41 50.0 (33.0-56.6) 0.079

BMI (kg/m2) 11 21.6 (17.6-25.5) 28 18.3 (15.8-20.8) 41 17.8 (16.0-20.6) 0.100

z-score BMI 11 0.92 (-0.49-1.81) 28 0.14 (-0.60-1.06) 41 -0.19 (-0.79-0.88) 0.141

BSA (m2) 11 1.68 (1.56-1.87) 28 1.50 (1.18-1.68) 41 1.55 (1.21-1.68) 0.079

BP systolic

(mmHg) 10 117 (110-123) 24 111 (103-118) 38 115 (100-125) 0.234

BP diastolic

(mmHg) 10 66 (59-73) 24 71 (59-76) 38 70 (65-78) 0.199

SaO2 (%) 7 99 (98-100) 16 98 (98-99) 30 95 (92-97) *† <0.001

Beta-blocker 11 0 28 0 41 4

Pacemaker 11 0 28 0 41 3

Legend: Continuous data is presented as median (IQR) and frequencies are displayed as number (percentage). Differences are

based on a Kruskal Wallis test with post-hoc Mann Whitney U p = 0.05. * = post-hoc significant difference compared to

control group. † = significant difference between the patient groups.

13

Surgical history

TOF: 54% of the TOF patients had undergone a corrective surgery with a TAP, resulting in

greater risk of developing pulmonary insufficiency. 38% had a BT-shunt prior to the surgery.

The median age at first surgery is 0.35 (0.10-1.00) and the median age at corrective surgery

was 1.05 (0.90-1.40) (Table 3).

Fontan: this patient group is relatively older at completion of TCPC. The median age

is 4.7 (3.8-8.1). Within this group three patients did not have a BCPC, 21 patients had a BT-

shunt and 14 a PAB prior to the TCPC. Of those 41 patients 24 patients had an extra cardiac

conduit, nine a right auricle tunnel and eight patients had a lateral tunnel. At the time of the

CPET four (10%) patients had a fenestration allowing right-to-left shunt. 68% of the Fontan

patients had a left ventricular morphology (Table 3). There were four patients on beta-

blockade and three patients were dependent on a pacemaker, probably affecting their heart

rate dynamics during exercise (table 2).

Table 3: Surgical history of the patient groups

Fontan TOF

Number 41 28

Age at first OK 0.10 (0.00-0.75) 0.35 (0.10-1.00)

Age at correction 4.70 (3.80-8.15) 1.05 (0.90-1.40)

Number BT-shunt (%) 21 (53) 11 (38)

TOF with TAP (%) 15 (54)

Number PAB (%) 14 (34)

Number of septectomy (%) 10 (25)

BCPC (%) 38 (93)

TCPC

Lateral tunnel

Right auricle tunnel

Extra cardiac conduit

41 (100)

8 (20)

9 (22)

24 (58)

Left ventricular morphology (%) 28 (68)

Fenestration (%) 4 (10) Legend: Age is expressed median (IQR) in years. Other values are displayed as number (percentage).

14

Figure 3: the course of the VO2 in the separated groups,

displayed as median IQR

Legend: differences based on a Kruskal Wallis test with post-hoc Mann-Whitney U

p = 0.05. * significant difference between Fontan and the other groups. The time

points represent the measuring points during the CPET ( 1 = rest, 2 = warming-up,

3 = VO2 peak, 4 = HR 1 min, 5 = HR 2 min and 6 = HR 4 min)

Exercise performance

Exercise performance was decreased in Fontan patients. Although TOF patients did not

achieve a statistically significant difference compared to the control group, they seemed to

have a lower performance (Table 4). The VO2 peak was lower in both TOF and Fontan

patients, alhough there was no significant difference between TOF patients and controls

(Figure 3). The workload and peak VO2 as percentage of predicted were also lower in the

Fontan group. Unexpectedly, the VO2 at rest was higher in the Fontan group. The ∆VO2/∆WL

is lower in the patient groups and it is more in favour of the TOF patients.

Table 4: Exercise performance among the groups


Workload 190 (158-230) 140 (110-164) 118 (99-146)* † <0.001

Workload/kg 3.2 (2.9-3.8) 2.8 (2.4-3.2) 2.6 (2.2-2.9)* † 0.002

Workload as percentage of

predicted (%) 108 (84-114) 82 (75-94) 70 (63-84)* † <0.001

VO2 resta 6.1 (5.1-6.7) 6.8 (5.8-9.3) 7.9 (6.6-9.3)* 0.030

VO2 peak 38.0 (33.5-45.8) 35.0 (30.4-43.7) 30.5 (23.8-33.7)* † <0.001

VO2 as percentage pred (%) 111 (79-128) 92 (78-100) 69 (60-79)* † <0.001

∆VO2/∆WL 9.3 (8.7-10.6) 8.1 (7.3-9.3) 7.0 (5.8-8.5)* † <0.001 Legend: Values are displayed as median (IQR) and analysed by a Kruskal Wallis with post-hoc Mann Whitney U p = 0.05.

* = post-hoc significant difference compared to control group, † = significant difference between the patient groups.

Predictive values are based on Cooper 1984. a = values at rest have a smaller number because of missing data: controls 8,

TOF 25, Fontan 21.

15

Recovery

The HRmax during exercise is significantly lower in the patient groups. In the recovery period

were no major differences until the fourth minute. In general the heart rate decreased almost

equal in all groups until the third minute of recovery. Then the TOF and control group

recovered gradually and the Fontan group slowed down (Table 5, Figure 4). The TOF group

recovered the fastest (66% of the CRE after four minutes) and the Fontan group slowest (53%

of the CRE after four minutes), although this difference is not significant (Figure 5).

Table 5: Course of the recovery


Discrete decrement (%) N N N

1 minute after cessation 11 24 (18-29) 27 28 (18-33) 41 26 (20-35) 0.759



4 minute after cessation 10 10 (3-13) 25 8 (5-12)* 41 5 (1-8) 0.020

Cumulative decrement (%)




4 minute after cessation 10 61 (50-71) 25 66 (52-75) 41 53 (49-66) 0.093 Legend: Values are displayed as median (IQR) and analysed by a Kruskal Wallis with post-hoc Mann Whitney U p = 0.05.

* = post-hoc significant difference compared to controls, † = significant difference between the patient groups.

Figure 4: Discrete decrement of the heart

rate as % of the chronotropic response to

exercise

Figure 5: Cumulative decrement of the

heart rate as % of the chronotropic

response to exercise

Legend: differences based on a Kruskal Wallis test

with post-hoc Mann Whitney U p = 0.05. * significant

difference among TOF and the control group. The

time points represent the measuring points during the

recovery (1 = HR 1 min, 2 = HR 2 min, 3 = HR 3

min, 4 = HR 4 min).

Legend: differences based on a Kruskal Wallis test

with post-hoc Mann Whitney U p = 0.05. * significant

difference among TOF and the control group. The

time points represent the measuring points during the

recovery (1 = HR 1 min, 2 = HR 2 min, 3 = HR 3

min, 4 = HR 4 min).

*

16

The decrement in the first two minutes after exercise was correlated to the VO2 peak. Patients

with a lower VO2 peak had a delayed recovery. The TOF group did not show this correlation

(Figure 6 and 7).

Explanatory factors

The differences in workload and VO2 peak may be due to limitations in heart rate, changed

ventricular function, blood pressure abnormalities, residual lesions and/or pulmonary

dysfunction. However due to low number of participants, it was not possible to perform a

stepwise logistic regression analysis to identify risk factors for a lower exercise capacity.

Patient characteristics

Although patient characteristics such as age, height, weight, BMI and BSA did not show

significant differences among the groups, they showed a significant correlation with exercise

performance in the patient groups. In the TOF group height, weight, BMI and BSA were

correlated to VO2 peak and workload (Table 6, Figure 7, 9). Additionally age was also

associated with workload. In the Fontan group all parameters were correlated to VO2 peak and

workload (Table 6, Figure 8, 9). In both patient groups there was an association between

gender and ∆VO2/∆WL in favour of the female patients (TOF -0.598, p = 0.001 resp. Fontan -

0.426, p = 0.005).

Figure 6: Relation between peak VO2

and HR recovery in the first two minutes

in Fontan patients

Figure 7: Relation between work

efficiency and HR recovery in the first

two minutes in Fontan patients

Legend: the median values are shown. Significant

correlation based on Spearmann’s correlation test.

Correlation coefficient: 0.312, p = 0.047




17

Table 6: Overview of correlation coefficients of patients characteristics to exercise

performance parameters

Control TOF Fontan

WL VO2a ∆VO2

∆WL WL VO2a ∆VO2

∆WL WL VO2a ∆VO2

∆WL

Age 0.745* 0.700* -0.009 0.655* 0.328 -0.340 0.582* 0.437* -0.058

Gender 0.173 0.000 -0.404 -0.022 -0.324 0.077 -0.315* -0.461* -0.426*

Height 0.427 0.200 -0.277 0.804* 0.582* -0.598* 0.756* 0.594* -0.027

Weight 0.573 0.436 -0.300 0.804* 0.651* -0.158 0.770* 0.667* 0.030

BMI 0.282 0.327 -0.073 0.670* 0.591* -0.056 0.685* 0.681* 0.168

BSA 0.547 0.383 -0.260 0.808* 0.644* -0.087 0.767* 0.682* 0.064 Legend: Correlations based on Spearmann’s test p = 0.05. * = significant correlation. WL = workload, a = VO2 peak not

corrected for body weight, ∆VO2/∆WL = reflects oxygen flow in exercising tissues.

Figure 8: Relation between peak

VO2 and BMI in the patient groups

Figure 9: Relation between peak

workload and BMI in the patient groups



TOF: 0.670, p < 0.001, Fontan: 0.685, p < 0.001



TOF: 0.591, p = 0.001, Fontan: 0.681 p < 0.001

18

Heart rate dynamics during exercise

There were differences between resting HR and HR max. TOF had a higher HR at rest, but

the HR max in TOF and Fontan was reduced compared to the control group (Table 7, Figure

10). The chronotropic response to exercise was also reduced both patient groups. Therefore

the patient groups also had a higher heart rate reserve (Table 7). The assessment of heart rate

dynamics in the Fontan group included Fontan patients with a beta-blockade or pacemaker. In

a separated analysis, there are not differences between these groups (Table 8). Although there

were significant differences in HR max, there was no correlation between a lower VO2 peak

and a lower HR max. In the Fontan group chronotropic response to exercise correlated with

VO2 peak (0.405, p = 0.009) and workload was associated with maximal heart rate,

chronotropic response to exercise and heart rate reserve (0.434, p = 0.005 resp. 0.548 p <

0.001 and -0.330 p = 0.035) (Figure 11,12). There was no correlation between heart rate

dynamics and exercise performance in the TOF.

Table 7: Heart rate dynamics among the groups


Heart rate at resta

78 (68-97) 86 (82-96) 74 (63-89)† 0.013

Maximum heart rate 193 (187-196) 176 (166-190)* 166 (152-179)*† < 0.001

Chronotropic responsea

112 (106-127) 90 (84-100)* 98 (73-111)* 0.016

Heart rate reserve (%) - 5.9 (-2.7-0.5) 4.9 (0.0-11.2)* 12.4 (7.0-21.1) *† < 0.001

Legend: Values are displayed as median ( IQR) and analysed by a Kruskal Wallis with post-hoc Mann Whitney p = 0.05.

* = post-hoc significant difference compared to the control group, † = significant difference between the patient groups, a =

1 missing value in the TOF group.

Figure 10: the course of the heart rate during the CPET

displayed as median

Legend: differences based on a Kruskal Wallis test with post-hoc Mann-Whitney

U p = 0.05. * significant difference. The time points represent the measuring

points during the CPET ( 1 = rest, 2 = warming-up, 3 = highest achieved heart rate,

4 = HR 1 min, 5 = HR 2 min, 6 = HR 3 min and 7 = HR 4 min)

19

Betablocker and pacemaker in Fontan patients

There were four patients on betablocker

medication during the CPET. Three patients had

implanted a pacemaker. No major differences

were found among these groups (table 8), but the

patients without betablocker medication and

patients independent of pacemaker had a higher

∆VO2/∆WL.

Table 8: Differences between the Fontan patients with and without beta-blockade/pacemaker

Betablockade

or pacemaker

Without Betablockade or

pacemaker P-value

Number 7 34

Workload/kg 2.1 (2.0-2.9) 2.6 (2.3-2.9) 0.224


predicted (%) 69 (68-89) 72 (62-84) 0.959

VO2 peak 26.3 (21.2-38.5) 32.8 (28.8-39.5) 0.125

VO2 as percentage pred (%) 65 (59-96) 70 (62-78) 0.552

∆VO2/∆WL 6.3 (4.9-7.0) 7.1 (6.0-9.0) 0.049

Heart rate at rest 80 (60-93) 74 (64-85) 0.906

Highest heart rate 153 (118-179) 169 (155-179) 0.244

Chronotropic response 89 (51-96) 104 (75-113) 0.080

Heart rate reserve (%) 17.3 (7.5-38.4) 11.9 (6.1-19.3) 0.175 Legend: Values are displayed as median (IQR) and analysed by a Mann-Whitney U test p = 0.005.

Figure 11: The relation between

VO2 peak and chronotropic

response in Fontan patients


workload and maximal heart rate

in Fontan patients



Correlation coefficient: 0.435 p = 0.005




20

Ventricular function

Systemic ventricular function was impaired in 6 (15%) Fontan patients and right ventricular

function in 4 (15%) TOF patients. Within the Fontan group 28 (68%) patients had a left

ventricular morphology, 3 of those had an impaired ventricular function.

Dividing both patient groups based on ventricular function on the echo, no differences

were found between the groups. There was no correlation with exercise parameters. Resting

volumes obtained from MRI assessment did neither have an association with exercise

performance (Table 9).

Table 9: Cardiac rest volumes obtained from MRI

TOF left ventricle TOF right ventricle Fontan

Number 17 17 37

End diastolic volume (mL) 112 (96-147) 173 (121-197) 84 (130-158)

End systolic volume (mL) 51 (40-64) 80 (60-120) 62 (36-82)

Stroke volume (mL) 58 (48-72) 61 (50-77) 62 (43-71)

Ejection fraction (%) 52 (48-58) 40 (31-46) 50 (44-59)

Regrugitation fraction

truncus pulmonalis (%) 21 (4-41)

Legend: MRI volumes at rest obtained from the patients reports, analysed by an expert radiologist (dr. Willemse).

Values displayed as median (IOR). No statistically relevant differences in exercise performance among the groups were

found.

Figure 13: relationship between right ventricle

end diastolic volume and VO2 peak in TOF

Legend: median values are displayed, correlation based on

Spearmann’s test: correlation coefficient -0.102 p = 0.697.

Figure 14: course of the oxygen pulse

during the CPET

Legend: differences based on a Kruskal Wallis test with

post-hoc Mann-Whitney U p = 0.05. * significant

difference among TOF and the control group. The time

points represent the measuring points during the recovery

( 1 = start of the CPET, 2 = warming-up, 3 = VO2 peak).

21


∆VO2/∆WL and oxygen pulse per

kg in TOF and Fontan


VO2 peak and oxygen pulse per kg

in controls

In both patient groups the oxygen pulse raised less quickly than in the control group (Figure

14). Fontan patients reached a significant lower oxygen pulse at peak exercise than the control

group (Table 10). The difference between controls and the TOF group was not significant (p =

0.078). Oxygen pulse in the control group was correlated to both VO2 peak and workload per

kg. In the patient groups oxygen pulse correlated with ∆VO2/∆WL and not with VO2 peak and

workload per kg (Figure 15, 16, Table 10).

Table 10: Overview of the oxygen pulse response to exercise and correlation coefficients with

exercise performance parameters


Oxygen pulse at resta

5.1 (3.1-5.4) 3.7 (3.5-4.2) 4.1 (3.2-4.9) 0.604

Oxygen pulse at peak 11.2 (9.6-13.5) 9.4 (8.0-10.8)

7.8 (6.7-10.7)* 0.002

O2-pulse correlation

coefficient to VO2 peak 0.680

# -0.049 0.234


coefficient to WL/kg 0.761

# -0.075 0.076


coefficient to ∆VO2/∆WL 0.521 0.433

# 0.543

#

Legend: Values are displayed as median (IQR) and analysed by a Kruskal Wallis with post-hoc Mann Whitney p = 0.05.

* = post-hoc significant difference compared to the control group, † = significant difference between the patient groups, # =

significant correlation, a = values at rest have a smaller number because of missing data: controls 8, TOF 25, Fontan 21.

Legend: the median values are shown.

Significant correlation based on Spearmann’s

correlation test. Correlation coefficient:

0.680, p = 0.021

Legend: the median values are shown.

Significant correlation based on Spearmann’s

correlation test. Correlation coefficient: TOF:

0.433 p = 0.021, Fontan: 0.543 p < 0.001

22

Blood pressure response to exercise and transcutanous oxygen saturation

In general no major differences were found among the groups in the course of the blood

pressure during the CPET (Figure 17). But at peak exercise the TOF group had a lower

diastolic pressure (p = 0.042) and after four minutes of cessation the Fontan group had a

lower diastolic pressure (p = 0.015). Diastolic recovery pressures correlated with workload

per kg, VO2 peak and ∆VO2/∆WL in Fontan patients. In TOF patients no correlation was

found between diastolic pressure in the recovery phase and the exercise parameters.

Transcutanous oxygen saturation was the lowest in the Fontan group during the hole course of

the CPET (Table 11). Unexpectanly this did not correlated to any of the exercise parameters

in any of the groups (Figure 18).

Figure 17: Course of the blood pressure during CPET

Table 11: Transcutanous oxygen saturation during the CPETa


N N N

SpO2 at rest 7 99 (98-100) 16 98 (98-99) 30 95 (92-97)* † < 0.001

SpO2 at peak 6 97 (96-98) 17 98 (96-99) 26 91 (85-94)* † < 0.001

SpO2 1st minute of recovery 6 97 (95-98) 15 97 (96-99) 25 94 (87-96) † 0.004

SpO2 4th

minute of recovery 6 98 (97-98) 14 98 (95-99) 27 94 (89-96) † 0.004 Legend: Values are displayed as median (IQR) and analysed by a Kruskal Wallis with post-hoc Mann Whitney p = 0.05.

* = post-hoc significant difference compared to the control group, † = significant difference between the patient groups, a =

missing data because of the use of finger pulse oximetry.

Legend: Upper line reflects the median systolic pressure, lower line represents the median

diastolic pressure. Differences based on a Kruskal Wallis test with post-hoc Mann-Whitney U

p = 0.05. The time points represent the measuring points during the CPET ( 1 = rest, 2 =

warming-up, 3 = VO2 peak, 4 = HR 1 min, 5 = HR 2 min, 6 = HR 3 min and 7 = HR 4 min).

23

Figure 18: relationship between

transcutaneous oxygen saturation and

VO2 peak.

Residual lesions in Fontan patients – ventricular morphology and presence of the right-left-

shunt

The Fontan group consisted of 28 (68%) patients with a left ventricular morphology and 13

(32%) with a right ventricular morphology. At the time of the CPET 4 (10%) patients had a

fenestration allowing right-to-left shunt. Patients with a right ventricular morphology

achieved a higher workload and a higher VO2 peak than patients with a left ventricular

morphology (table 12). Ventricular morphology correlated with workload per kg (0.324, p =

0.039), but not with VO2 peak (Figure 19). The right-to-left shunt did not seem to have an

association with imapired exercise performance (WL: -0.031, p = 0.846, VO2: 0.056, p =

0.730)

Table 12: Residual lesions Fontan – differences between left and right dominance

Ventricular morphology

Left Right P-value

Number 28 13

Workload/kg 2.5 (2.1-2.9) 2.7 (2.6-3.1) 0.041


predicted (%) 68 (57-79) 82 (68-88) 0.038

VO2 peak 27.7 (23.2-33.3) 32.9 (28.4-36.9) 0.085

VO2 as percentage pred (%) 67 (58-73) 75 (69-92) 0.041 Legend: Values are displayed as median (IQR) and analysed by a Mann Whitney U test p = 0.05.

Figure 19: boxplot of workload per kg and

dominance of the Fontan circulation.

Legend: Boxplot of the workload per kg in Fontan groups.

Significant differences based on Mann Whitney U p = 0.041.

Correlation based on Spearmann’s test: correlation

coefficient: 0.324, p = 0.039 Legend: the median values are shown. Significant


Correlation coefficient: control 0.677, p = 0.14,

TOF 0.085, p = 0.746, Fontan 0.163, p = 0.426

24

Residual lesions in the TOF

46% of the TOF patients had severe pulmonary insufficiency and 30% had a mildly

insufficient pulmonary valve. Mildly pulmonary stenosis was present in 42% of the TOF

patients, 17% presented with a moderate stenosis. The group with a severe insufficient

pulmonary valve mainly consisted of patients with a TAP (10 out of 11). However in the

group with moderately pulmonary stenosis 25% had a TAP.

No differences were present between the groups with various degrees of pulmonary

insufficiency or pulmonary stenosis (Figure 20,21). As well as there were no differences

between the groups with or without pulmonary insufficiency or pulmonary stenosis. No

relationship was found between pulmonary insufficiency/pulmonary stenosis and exercise

parameters (workload per kg and VO2 peak)

Legend: Boxplot of the VO2 peak in two degrees of

pulmonary insufficiency groups in TOF patients

(Left: non/mild N = 11, Right: moderate/severe N =

15). Significant differences based on Mann Whitney

U p = 0.330. Correaltion based on Spearmann’s test.

Correlation coefficient 0.202, p = 0.321.

Figure 21: Residual lesions in TOF

patients – pulmonary stenosis.

Legend: Boxplot of the VO2 peak in two degrees of

pulmonary stenosis groups in TOF patients (Left:

non/mild Right: N = 20, moderate/severe N = 6).

Significant differences based on Mann Whitney U p =

0.790. Correlation based on Spearmann’s test.

Correlation coefficient 0.061, p = 0.768.

Figure 20: Residual lesions in TOF

patients – pulmonary insufficiency.

25

Pulmonary function

Both patient groups showed a remarkably lower ventilation at peak exercise (Figure 22).

Although the patient groups started with a higher breathing rate at rest, the breathing rate at

peak exercise is resembling (Table 13). Ventilation efficiency (Ve/VCO2) is significantly

lower in the Fontan group than in both other groups (Figure 23). However these differences in

ventilation parameters, VO2 peak and workload per kg did not correlate with ventilation or

ventilation efficiency in the TOF group. But ventilation in the Fontan group correlated with

∆VO2/∆WL (Figure 24).

Table 13: Breathing and ventilation changes during CPET


N N N

Breathing rate at rest 8 17.0 (13.0-18.8) 25 21.0 (18.0-24.8)* 21 19.0 (17.0-21.0) 0.017

Ventilation at rest 8 9.8 (8.8-11.1) 25 9.7 (8.5-12.9) 21 9.5 (8.3-14.0) 0.877

Breathing rate

at VO2 peak 11 42.0 (41.0-49.0) 28 47.0 (37.5 -53.5) 41 41.0 (33.0-47.5) 0.296

Ventilation

at VO2 peak 11 77.0 (59.0-83.5) 28 53.8 (43.3-65.0)* 41 51.0 (38.5-60.5)* 0.001

Ve/VCO2 11 26.3 (20.9-29.0) 28 29.9 (24.6-32.1) 40 32.2 (28.3-36.0)* † 0.001 Legend: Values are displayed as median + IQR and analysed by a Kruskal Wallis with post-hoc Mann Whitney p = 0.05.

* = post-hoc significant difference compared to the control group, † = significant difference between the patient groups.

Figure 22: course of the ventilation during the CPET,

displayed as median + IQR

Legend: differences based on a Kruskal Wallis test with post-hoc Mann-Whitney U p =

0.05. * significant difference between all groups. The time points represent the

measuring points during the CPET ( 1 = rest, 2 = warming-up, 3 = VO2 peak, 4 = HR 1

min, 5 = HR 2 min, 6 = HR 4 min)

*

26

Figure 23: Ventilation efficiency among the groups

Figure 24: relationship ventilation (L/min)

and work efficiency in Fontan

Legend: differences based on a Kruskal Wallis test with post-hoc Mann-

Whitney U p = 0.05. * significant difference.

Legend: the median values are shown. Significant correlation

based on Spearmann’s correlation test. Correlation

coefficient: controls 0.251, p = 0.457, TOF 0.291 p = 0.133,

Fontan 0.491 p = 0.001

27

– Discussion –

Our study showed that Fontan children at the age of 14 are impaired in their exercise capacity.

These children had a reduced chronotropic response to exercise, which may add to the

reduction in exercise. The TOF children appeared to have a lower performance than their

healthy peers. Similar to the Fontan children, they had a reduced chronotropic response to

exercise, albeit not correlated to exercise performance. In contrast to our expectations,

residual lesions were not related to exercise capacity and ventilation at peak exercise was

reduced in both patient groups.

Exercise performance in Fontan

Studies on exercise capacity in children are scarce, although there are many studies involving

adult. There are two large studies that report a lower exercise capacity than we do. One is an

European multicentre study (32) and the other is a cross-sectional American study (33). In the

European study, adolescents from four large European adult CHD centres were included (n

=171). Therefore the patients in this study are relatively older (17±7). Diller et al. reported

lower exercise capacity compared to our patients (VO2 peak: 23.7±7.5)(32). Reasons for the

lower VO2 peak might be that there was no distinction based on maximal or submaximal

exercise (no RER criterion was used), therefore also patients with a submaximal CPET and

lower VO2 peaks were included. The use of different protocols in CPET among the centres

may cause a variation in actual data measured. And all patients in the study were at tertiary

adult CHD centres, therefore it is possible that there is a selection bias within the centres.

Furthermore it is possible that the older age in this population causes the lower VO2 peak

compared to ours.

The second study from Paridon et al. performed a cross-sectional study including 411

patients (33). In this study the mean age of the population is similar to ours (13.9±2.9). But a

remarkable fact is that only 40% of the children are capable of performing a maximal exercise

test (RER criterion over 1.1). This study population had a lower VO2 peak (27.2±6.3) and a

lower workload (98±37) compared to our population. This could be due to a selection bias,

because only 40% of the population is included in the analysis or it might suggest that there is

a role for culture or country of residence differences. Dutch children learn to ride the bicycle

at a young age and develop more biking skills, resulting in a possible better VO2 peak.

Recently a Dutch cohort of Fontan patients (n = 101) was analysed (34). These patients were

similar to ours in age (12.2±2.5) and in performance (VO2 peak: 33.5±6.8).

Exercise in TOF children is also rarely described in the literature. Friedberg et al.

described a younger population (11.9± 3.3) with a plain lower VO2 peak (30.6±6.8),

unfortunately they did not make a comparison to healthy peers (35). But the lower VO2 peak

might be due to the relatively late repair of the TOF (16.9±17.6 months). Another study in

Rotterdam showed an older population (16.6±5.6), but with similar results to ours (36). Both

studies were more focussed on ventricular function and ventricular volume assessments. And

especially the Dutch study has relatively small numbers (n = 19). This means that further

assessment of the exercise capacity and origin of the reduced exercise performance in TOF

children is required.

The pattern in scarce studies is that the Dutch population has a better exercise capacity

than the populations in the USA or other countries. And that age and age of repair may

influence outcome. Further studies are necessary to evaluate these findings.

28

Recovery

Heart rate recovery in exercise assessments is an upcoming topic in the literature. Heart rate

dynamics after exercise are important because they have been associated with mortality in

men with coronary artery disease (14). We do not know if the same holds true for children

with CHD, because the children in our study did not reach endpoints (mortality or

transplantation). But we observed differences in heart rate recovery, especially in Fontan

patients and these differences correlated with VO2 peak.

There are two Japanese studies in heart rate recovery in CHD patients (37, 38). Both

studies found a delayed heart rate recovery in Fontan patients. In these studies heart rate

recovery is used to estimate cardiac vagal control of the heart rate in Fontan patients.

There are some suggestions about the heart rate recovery in children with CHD, but

further research is required to examine possible predictive values.

Parameters of the cardiovascular system

Ventricular function and heart rate dynamics during exercise play a key role in the assessment

of the influence of cardiovascular system on exercise (38). Unfortunately, ventricular function

during exercise is difficult to assess. As a surrogate, function at rest is used but in our study

this did not correlate with outcome. In other studies in older patients with TOF, right

ventricular dilation as a result of pulmonary insufficiency correlated with exercise capacity,

but not in our cohort. This is not due to less residual lesions as our patients show more dilated

right ventricles than in other studies(35,36). The good results in our population might be

explained by the relatively young age at surgery and young age at study. Findings in adult

studies demonstrated that right ventricular contractile reserve is preserved in young operated

children. This suggest that right ventricular myocardial performance might be maintained in

our TOF patients, despite an enlarged right ventricle (39).

Oxygen pulse serves as a surrogate for cardiac output during exercise. A reduced

oxygen pulse may indicate reduced oxygen extraction at the cellular level or simply lower

stroke volume (12). Our Fontan patients had a remarkably lower oxygen pulse at peak

exercise, this may indicate that cardiac output during exercise is reduced in Fontan patients.

But oxygen pulse is not related to peak exercise performance. Another way to assess oxygen

flow is to use ∆VO2/∆WL. ∆VO2/∆WL- slope is a valid measurement of oxygen flow or

utilization in the exercising tissues (30). We found a reduced value in our Fontan patients and

the value in the TOF group appeared to be reduced. Further research is necessary to examine

the role of this relatively new parameter.

Heart rate dynamics during exercise, such as chronotropic response to exercise and

maximum heart rate were reduced in both patient groups. This is conform the other studies in

Fontan and TOF patients (32-36). The reduced heart rate dynamics are independent on beta-

blocker or pacemaker use, although studies in the literature are divided on this matter (34, 40).

In Fontan patients cardiac parameters such as heart rate response to exercise play an important

role in the reduced exercise capacity. On the other hand peak exercise performances has no

correlation with heart rate dynamics in the TOF group. This suggest that other factors play a

role in the reduced exercise performance of TOF patients and further research is necessary to

map these factors.

29

Influence of pulmonary function

An unexpected finding in our population is the reduced ventilation capacity at peak exercise

in both patient groups. There is a lack of ventilation assessment during CPET in children. In

adults it has been described that lung function and volumes at rest are reduced (41). A

previous thoracotomy has been reported as a strong predictor of moderately to severely

impaired lung function in rest. Temporal interruption or reduction of the pulmonary blood

flow during cardiopulmonary surgery may a trigger inflammatory processes in the pulmonary

vasculature, leading to abnormal gas-exchange. Besides, that cardiac surgery in childhood

may cause inadequate thoracic cavity growth, leading to a reduced ventilation capacity.

Another explanation for a reduced ventilation capacity may be given by respiratory muscle

weakness (42) Assessment of ventilation capacity is important in monitoring morbidity in

CHD patients, especially in Fontan patients. Fontan patients are dependent on the ventilatory

pump, which provides an increase in venous return during inspiration (43). Expanding

ventilation capacity and enlarging the thoracic cavity creates a possibility to increase the

pulmonary blood flow. Therefore it is necessary to map this feature in further studies.

Influence of muscular factors

Although not directly assessed in this research, muscles play an important role in exercise

performance. Our results show a plain correlation between BMI and exercise performance in

the patient groups. Patients with a higher BMI are more likely to have a higher VO2 peak and

achieve a higher workload. The opposite is shown in adults, these participants performed

better when they had a lower BMI (44). This contrast might be explained by the difference in

body fat and muscle mass. Our population mainly consists of non-obese children, the study

group of the other study population consisted of a divers scale of older healthy volunteers(44).

Furthermore a few studies on muscle strength in CHD patients show that there is a

reduced muscle strength in patients with several CHDs, including Fontan and TOF patients

(45-48). For that reason we suspect that muscle strength may be of influence on exercise

performance.

Influence of residual lesions on exercise performance

In this study we also displayed several parameters that did not reach statistically relevance.

One of these is the influence of residual lesions. Nowadays decisions to treat are amongst

others based upon CPET results and the question is of that is still valid if there is no relation

between residual lesions and exercise performance. An argument against this is that our group

does not have severe residual lesions, hence mild residual lesions may be well tolerated.

Further studies with higher numbers and preferably different kinds of residual lesions must

validate our findings.

Implications for further studies

Fontan children are impaired in their exercise capacity compared to healthy peers, however

this might not be a realistic goal for them to aim for. Further research in larger studies may set

a more realistic baseline for the Fontan patients.

TOF children appeared to have a reduced exercise capacity in our study, yet not

significant lower than controls. Studies in adults show a significant lower peak exercise

performances, question may be asked when this decrement develops and what is trigger this

feature. Assessment of factors influencing CPET in children with CHD has hardly been done

before. Examination of these factors may result in explaining why CHD patients are impaired

in their exercise capacity.

30

Limitations of the study

This retrospective analysis comes with limitations which hamper the interpretation of the data.

First of all, the numbers are relatively small and no serial follow-up is available at the

moment. Yet this cohort will be serially assessed every two years allowing prospective

analysis of risk factors for outcome. Also, we have missing data in several sets. In contrast to

our American colleagues we are able to test more children (in which only 40% of the patients

were able to perform a maximum exercise test), but we still have limitations in obtaining all

data like saturation measurements. A remark to this thesis is the big amount of data that is

analysed, which results in a complex thesis. We chose to display non-significant data,

because of its possible relevance for further studies and treatment goals.

Conclusions

Fontan children are early impaired in their exercise performance, possibly due to reduced

cardiac response to exercise. TOF children have a mildly reduced exercise capacity, although

not yet explainable. Further studies are necessary to explain the role of heart rate recovery,

ventilation capacity and muscle strength factors.

31

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