Cardiopulmonary exercise testing combined with stress echocardiography for the evaluation of myocardial dysfunction in children at risk

doi:10.21203/rs.3.rs-5289482/v1

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Cardiopulmonary exercise testing combined with stress echocardiography for the evaluation of myocardial dysfunction in children at risk

https://doi.org/10.21203/rs.3.rs-5289482/v1

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Aims

In paediatric cardiology stress echocardiography is rarely used, even though it is an established tool for investigating myocardial insufficiency which represents a threat in children after arterial switch operation (ASO) or Kawasaki disease (KD). This study combines stress echocardiography with cardiopulmonary exercise testing (CPET) for evaluating these children.

Methods:

We recruited former patients from our database after ASO or KD. All undertook a CPET either on a tilt-recline ergometer or on a treadmill with intermittent echocardiography with strain measurements. In addition to the standard cardiopulmonary exercise parameters the behaviour of the O₂pulse before and after the end of exercise was evaluated.

Results:

43 children, adolescents and adults (21 ASO mean age 14.7, 10 KD aged 15.0, and 13 controls aged 15.3 years) participated in this study. The patients after ASO showed a significantly lower peak cardiopulmonary function (\(\:\dot{V}{O}_{2}peak\): 39.6 vs 45.9 ml/kg/min) as well as a lower first ventilatory threshold (VT1) in percent of \(\:\dot{V}{O}_{2}peak\) (45.7 vs. 54%). The only other significant difference was a slower decline of the O₂pulse following the end of exercise. The strain values were normal. The patients undertook significantly less sport.

Conclusion:

The lower \(\:\dot{V}{O}_{2}peak\) in combination with the lower VT1 observed in the ASO group point to a lower cardiopulmonary function with poor endurance. In combination with the slower recovery of the O2pulse after exercise this could point to an impairment in cardiac output. Interestingly this was not true for the KD patients even when giant aneurysms were present.

myocardial ischemia

strain

speckle tracking

coronary artery disease

Kawasaki disease

transposition of the great arteries

arterial switch operation

The arterial switch operation represents the first-line therapy for patients with transposition of the great arteries. After ASO, there can be residual lesions and/or sequelae from interventions that require life-long surveillance. The most concerning ones are neopulmonary stenosis, neoartic regurgitation, neoaortic root dilation, and coronary artery disease [1]. Exceptionally challenging is the rarity of symptoms attributable to potential complications, especially coronary obstruction [1] and the unknown effects of acquired coronary artery disease superimposing on manipulated coronary arteries [1]. Another group of pediatric patients who faces long-term consequences to their coronary arteries are patients after Kawasaki disease who developed coronary artery aneurysms (CAA). There is some concern regarding development of premature atherosclerosis [2].KD patients with giant aneurysms face progression to stenosis or occlusion of their coronary arteries, and the risk of ischemia-related ventricular dysfunction, myocardial infarction, and even sudden cardiac death [3]. So far, selective coronary angiography has been considered the gold standard for anatomic evaluation of the coronary lumen [4], even intravascular ultrasound has been proposed for evaluating intimal thickening [5]. Meanwhile ECG-gated CT-angiography has advanced to the study of choice for morphologic assessment in young adults after ASO [1]. However, these studies are either invasive or involve radiation exposure. Still, detection of subclinical myocardial ischemia after ASO remains a challenge, as clinical evaluation, ECG, and echocardiography possess low sensitivity for detecting coronary insufficiency [1]. In conventional transthoracic echocardiography (TTE) an experienced sonographer will be able to imagine the first 1.5 -2.0 cm of the proximal epicardial coronary arteries in the most cases. But distal coronary artery lesions cannot be visualized by standard TTE and myocardial performance might also be normal at rest.

Cardiopulmonary exercise testing (CPET) represents the main tool for estimating cardiorespiratory function in children and adults [6]. However, it still lacks behind the popularity of an electrocardiogram (ECG) stress test for diagnosing coronary artery disease (CAD) even though it provides a vast amount of additional data with respect to the haemodynamic response to exercise. By combining the parameters of oxygen consumption (\(\:\dot{V}{O}_{2}\)), carbon dioxide production (\(\:\dot{V}C{O}_{2}\)), heart rate (HR) and oxygen pulse (O₂pulse, a combination of \(\:\dot{V}{O}_{2}\) and HR), CPET provides an objective estimate of the functional reserve of the heart [7]. This functional reserve is usually reduced in patients with CAD as a consequence of the myocardium not being able to increase the stroke volume during exercise [8].

This in turn suggests that the O₂pulse is likely to decrease during exercise as the cardiac output cannot fulfil the increased demand [9]. However, even though several studies have investigated the correlation between myocardial ischemia and the behaviour of the O₂pulse during exercise the results have not been conclusive [9–13].

Another aspect, that has not been studied so far, is behaviour of the O₂pulse after the end of peak exercise. According to Sietsema et al. [14] the O₂pulse falls rapidly at the end of exercise. But when the stroke volume cannot meet the demand from the exercise the sudden decrease in afterload at the end of exercise leads to an improved cardiac function and in consequence in stroke volume. This in turn could imply a plateau or even an increase in O₂pulse in patients with coronary insufficiency.

Another advantage of using CPET for the detection of myocardial insufficiency is its non-invasiveness and the fact that it can be combined with stress echocardiography. Stress echocardiography is mainly used in diagnosing acquired coronary artery disease (CAD) in adults [15], since the myocardial wall motion abnormalities caused by subclinical metabolic abnormalities are detectable during exertion prior to the appearance of either resting electrocardiographic abnormalities or angina [16]. In adults, this method has a high sensitivity and specificity compared to other diagnostic instruments such as single-photon emission computed tomography (SPECT) in identifying coronary insufficiency due to CAD [17]. So far, the literature using stress echocardiography in children at risk for CAD like patients after Kawasaki disease (KD) [18–20], after Arterial switch operation (ASO) due to transposition of the great arteries (TGA) [21–23] or with anomalous aortic origin of the coronary arteries [24], remains scarce.

Considering the vast diagnostic possibilities of stress echocardiography in combination with its non-invasiveness, it is surprising that it has only been discussed in literature as a viable mainstream stress imaging modality in the last two decades within the paediatric population [15, 25, 26].

A limitation of echocardiography during stress testing is, that the investigated parameters, like fractional shortening or ejection fraction, cannot measure myocardial performance [27]. They show a significant cardiac load dependency, which is augmented by the before and after load changes during exercise [27]. Speckle tracking echocardiography (STE) is an echocardiographic methodology for determining myocardial performance parameters, namely strain and strain rate [28]. These parameters have been shown to be more sensitive to mild functional impairment than traditional echocardiographic function parameters as they can also assess regional myocardial function [29]. Recently, the combination of speckle tracking imaging and stress echocardiography in children has proven to unmask potential cardiac dysfunction that might remain occult at rest [27, 28, 30].

Children, and young adults with coronary aneurysms after Kawasaki disease (KD) and patients after arterial switch operation due to transposition of the great arteries (TGA) have been routinely monitored in the past using angiography for detecting early signs of CAD. We wanted to evaluate a less invasive and less radiation demanding diagnostic tool for examining these patients.

The study was approved by the Ethics Committee of the University of Erlangen-Nuremberg, FRG (21-349-B, 21-177-B). All study participants as well as their legal guardians gave written informed consent according to the standards set by the Declaration of Helsinki.

Participants

We recruited the patients out of our database according to the following inclusion criteria:

Minimum age of 6 years
Patients born with dTGA after ASO
Patients after Kawasaki disease with proven coronary aneurysms

The control group consisted of healthy age-matched volunteers.

Inclusion criteria for all participants were the ability to complete an exercise test, free of mental, physical, or neurological disabilities and no diagnosed respiratory disease.

Height and weight were measured using a stadiometer and electronic scale (Seca 704 S, Hamburg, Germany). All participants underwent a full structural and functional resting echocardiogram for exclusion of other cardiac disease than described according to paediatric guidelines [31, 32]. We used a non-standardized questionnaire to determine school or work transport habits (walking, cycling, bus), and subjective exercise tolerance described previously [33]. After clinical examination for ruling out infection, the participants underwent cardiopulmonary exercise testing. When they were too small for supine bicycle testing (< 140 cm) they were tested on a treadmill with intermittent echocardiographic assessment.

Cardiopulmonary exercise test

A 12-lead ECG was recorded continuously throughout the test and recovery period (MAC 2000, GE Healthcare, Chicago US). All subjects were encouraged verbally to exercise until exertion.

For children less than 140 cm in height an incremental step test on the treadmill (COSMED T 170, COSMED, Italy) according to the adapted Bruce protocol was performed by all participants [34]. The starting speed was set at 2 km/h with no gradient and was then increased every minute by 0.5 km/h with an additional increase in gradient by 3% every step starting at the third step (at 3 km/h). After the fourth step, around VT₁ (3.5 km/h and 6% gradient) the treadmill was stopped, the participant asked to bend forward and an echocardiographic evaluation undertaken for 30 seconds. After this break the protocol was continued with the speed and gradient of the next step (4 km/h and 9% gradient). The same echocardiographic examination was repeated after the 8th step, around VT₂ (5.5 km/h and 18% gradient). At peak exertion, the echocardiogram at peak exercise was performed. The participant then remained standing for the remainder of the recovery period (5 minutes) with echocardiograms undertaken after 2 and 3 minutes.

For adolescents and adults ≥ 140 cm an incremental step test on a tilt-reclining ergometer (COSMED E1200, COSMED, Italy) was performed with a starting load of 25 Watts in women and 50 Watts in men. The ergometer was tilted as to achieve optimal imaging. Every two minutes the load was increased by 25 Watts. Echocardiographic examinations were undertaken 30 seconds into each step for a maximum duration of one minute. After peak exercise had been achieved the participant was asked to stop pedalling and echocardiograms were recorded at 2 and 3 minutes into the recovery period (5 minutes).

Measurement of gas exchange

A small, low-dead-space respiratory valve (88 ml) with a size-matched mouthpiece and headgear was fitted for each participant (Metalyzer 3B, Cortex, Leipzig, Germany). Gas-exchange was measured continuously during each test using a breath-by-breath method and averaged over 15 second intervals. The criteria for maximal exertion were: a respiratory exchange ratio (RER) of > 1.1, peak heart rate (peak HR) within 5% of the age-predicted maximum, and volitional fatigue. Ventilatory thresholds VT₁ and VT₂ were determined using the V-slope method [35].

O₂pulse slope behaviour

The O₂pulse was investigated using software provided by the manufacturer of the CPET equipment (Metasoft, Cortex, Leipzig, Germany). When an O₂pulse plateau was observed before the end of exercise, its duration as well as its slope were measured. The duration of a plateau was also measured after the termination of exercise, if one was observed. The slope of the O₂pulse after the termination of exercise was measured over the first 30 seconds and over the first 2 minutes after the end of exercise. For the explanation of the duration and slope of the O₂pulse after termination of exercise s. Figure 1.

Echocardiography

Echocardiographic studies were performed with an iE33 and a 1–5 MHz sector probe S5-1 (Philips, Amsterdam, Netherlands). Images were obtained in 2-D and optimized for off-line 2-D speckle tracking assessment. All strain analyses were performed using manufacturer-specific software TOMTEC-ARENA-Software (TOMTEC Imaging Systems GmbH, Unterschleissheim, Germany) and obtained in apical four-, two-, and three-chamber views. One out of four acquired cardiac cycles was manually selected and then analysed. The endocardial borders were manually contoured at end systole with the range of interest adjusted to include the whole myocardium. Peak systolic global longitudinal (SI) and circumferential (Sc) strain was defined as the maximal deformation of a segment in systole and is represented as a percentage (%) of the original size. Peak systolic global strain rate (SRc) was defined as the rate of maximal deformation of a segment in systole over time and is expressed in 1/s [36]. Standard nomenclature was used to describe LV 2-D strain [36]. Circumferential peak systolic strain was measured at the base of the LV. If good tracking was obtained in at least four segments, mean and global values for circumferential and longitudinal strain were calculated for each level. All image acquisition and off-line analysis was performed by the same two experienced paediatric cardiologists.

Statistics

Statistical analysis was performed using Microsoft Excel 2000® for data collection and SPSS 12.0® (SPSS Inc., Chicago, IL). All measured values are reported as means and standard deviations. The Kologomorov-Smirnov test was used to check for normal distribution. Homogeneity of variance was investigated using Levine’s F-test. For normally distributed variables differences in strain and strain rate measures were assessed with paired t-tests and one-way analysis of variance ANOVA. Statistical significance was set at p < 0.05.

The Pearson correlation coefficient was used to investigate univariate correlation between independent variables and \(\:\dot{V}{O}_{2}peak\).

For comparison of ordinal and nominal variables we used the Fisher’s exact-Test.

43 children, adolescents and adults (21 with ASO after dTGA, 10 after Kawasaki disease with persistent coronary aneurysms of which 2 were giant, and 13 were healthy).

Anthropometric parameters and physical activity

The participant’s mean anthropometric data are presented in Table 1 along with their sex distribution. The three groups were comparable with regards to height, weight, BMI, sex, and type of test form (ergometer vs. treadmill) as expected due to the matching with the control group.

Table 1

Mean anthropometric values with standard deviations for the three groups investigated in this study, as well as the amount of sport undertaken during childhood, adolescence and recently along with the p-values of the comparison betwenn patients and control group.
	Patients after ASO	Patients after Kawasaki disease	Control group	p-value
Males (n)	12	7	8	0.943
Females (n)	8	3	5	0.943
Tilt recline ergometer (n)	13	8	8	0.341
Treadmill (n)	7	2	5	0.341
Age (y)	14.7 ± 4.6	15.0 ± 4.6	15.7 ± 5.7	0.590
Height (cm)	159 ± 16	158 ± 20	161 ± 16	0.738
Weight (kg)	49.8 ± 19.5	54.0 ± 19.4	53.8 ± 19.1	0.677
BMI (kg/m²)	19.1 ± 4.2	20.6 ± 4.0	20.1 ± 3.	0.688
Sport during childhood (h)	3.2 ± 2.7	6 ± 3.3	7.8 ± 3.4	0.007
Sport during adolescence (h)	3.6 ± 2.6	5.2 ± 2.8	8.8 ± 3.7	< 0.001

The physical activity questionnaire [33] revealed that the patients after ASO and those with coronary aneurysms due to Kawasaki disease undertook significantly less sport than their control group (s. Table 1). This was also true when comparing the subgroups on their own (KD and TGA) with the control group (KD as a child p = 0.025 and as an adolescent p = 0.014, TGA as a child p = 0.017 and as an adolescent p = 0.008). However, the two groups showed comparable amount of physical activity when compared with each-other (as a child p = 0.646 and as an adolescent p = 0.182).

Cardiopulmonary exercise test

The data from the cardiopulmonary exercise test (mean ± standard deviation) are presented in Table 2. The p-values always represent the significance between patients and control group.

Table 2

Mean cardiopulmonary exercise variables with standard deviations fort he three groups investigated in this study along with the p-values of the comparison betwenn patients and control group.
	Patients after ASO	Patients after Kawasaki disease	Control group	p-value
RER peak	1.15 ± 0.1	1.31 ± 0.1	1.11 ± 0.1	0.012
\(\:\dot{V}{O}_{2}peak\) (ml/kg/min)	39.6 ± 7.1	39.6 ± 12.8	45.9 ± 10.7	0.054
\(\:\dot{V}{O}_{2}\) at VT₁ (ml/kg/min)	18.1 ± 4.1	18.6 ± 7.0	25.2 ± 9.7	0.004
\(\:\dot{V}{O}_{2}\) at VT₁ (% of \(\:\dot{V}{O}_{2}peak\))	45.7 ± 6.7	46.8 ± 8.8	54.0 ± 10.8	0.007
Peak HR (bpm)	182 ± 17	184 ± 13	186 ± 10	0.475
Peak \(\:\dot{V}E\) (ml/min)	75.8 ± 24.9	84.4 ± 19.8	87.8 ± 31.8	0.300
Peak O₂pulse (ml)	10.9 ± 4.4	11.0 ± 3.4	12.8 ± 4.9	0.197
OUES	2.1 ± 0.7	2.1 ± 0.5	2.5 ± 0.8	0.046
\(\:\dot{V}E/\dot{V}C{O}_{2}\)-slope	30.6 ± 4.1	31.4 ± 5.5	30.6 ± 6.6	0.899
HRR (bpm)	-20.3 ± 7.7	-24.8 ± 5.7	-23.5 ± 13.5	0.339
Slope of O₂pulse before end	0.00 ± 0.9	0.4 ± 0.46	0.5 ± 0.7	0.191
Duration of O₂pulse-plateau before end (msec.)	117.4 ± 142.3	109.2 ± 91.2	116.0 ± 64.5	0.980
Slope of O₂pulse after end (over 30sec.)	-2.4 ± 2.2	-3.5 ± 1.8	-4.9 ± 2.5	0.006
Duration of O₂pulse-plateau after end (sec.)	18.7 ± 6.3	17.0 ± 8.9	16.7 ± 6.5	0.733

All participants achieved maximal exertion, defined as an RER > 1.1 (s. Table 2) and a peak HR within 5% of the age-predicted maximum. The control group achieved a significantly lower peak RER than the patients. This difference was caused by a mainly significantly higher peak RER in the KD group (KD and control p < 0.001, KD and TGA p < 0.001). The peak HR was comparable in all three groups.

The peak oxygen uptake was (\(\:\dot{V}{O}_{2}peak\)) was higher in the control group than in the patients with coronary affection. However, this difference did not reach significance except when investigating the subgroups. The ASO group was significantly lower than the control group (p-value 0.048), but the KD group was not. This effect was also reflected in the significantly lower oxygen uptake efficiency slope (OUES). Oxygen uptake at the first ventilatory threshold \(\:(\dot{V}{O}_{2}\)at VT₁) between patients and controls was also significantly lower in the ASO group (p-value 0.007) compared to their controls both in absolute values (p = 0.004) as well as in percent of achieved \(\:\dot{V}{O}_{2}peak\) (p = 0.007).

All the other cardiopulmonary exercise parameters showed comparable results with slightly higher values for the control group in comparison with the KD and ASO groups.

When investigating the slopes which have shown a potential for determining a difference in coronary perfusion, namely the occurrence of an O₂pulse plateau before or after the termination of exercise, there were no differences with respect to the behaviour of the O₂pulse before the end of exercise. But the steepness of the slope in the first 30 seconds after the termination of exercise proved to be significantly steeper in the control group in comparison with the ASO group (p = 0.005, s. Figure 2). This was not true for the KD group (p = 0.098).

Stress echocardiography

There were no significant differences between the groups with respect to any of the strain values recorded during the stress test (s. Figure 3). The values remained within normal values throughout the whole test and showed a slight decrease according to the increase in load. All strain-values recorded during each step showed a strong interstep correlation. Because it was difficult to achieve all three views in the short pauses in the treadmill test and echocardiography on the tilt-recline ergometer was difficult at higher exercise intensity we also report the strain of the four-chamber view which we achieved in all steps in 65% of all examinations but only in 31% GLS could be established at peak exercise.

A positive correlation between the O₂pulse slope in the first 30 seconds after termination of exercise and the strain in the 4-chamber view could be observed at VT₁ and VT₂

Case reports

When considering the slope of O₂pulse curve in the first 30 seconds after termination of exercise, three patients out of the ASO group showed positive values consistent with a plateau. We evaluated each of these patients in turn. The first, with a slope of 3.99 was a 20-year old male with originally simple dTGA and ASO. He had strain values of up to -16 during the stress echocardiography which got worse with increasing load. He had undergone pulmonary valve repair 5 months prior to the stress test. His peak oxygen uptake was reduced (27 ml/kg/min)

The second was an 11-year old girl with dTGA, subpulmonary VSD, ASD, and a coronary anomaly (ramus circumflexus originating from the right coronary artery) who had undergone ASO and VSD closure as an infant. Neither her ECG at rest, nor her stress ECG showed any repolarisation abnormalities. The behaviour of her O₂pulse is depicted in Fig. 1. After the stress echocardiography she received stress MRI and coronary angiography, revealing a filiforme stenosis of the ramus circumflexus with retrograde perfusion through collaterals originating from the left coronary artery. Her global longitudinal strain values during the stress echocardiography were − 13 at VT₁, -15.6 at VT₂ and − 16.3 at peak exercise. Stress MRI revealed dyskinesis of the posterior wall of the left ventricle. She was started on anticongestive medication. In contrast to the first patient her \(\:\dot{V}{O}_{2}peak\) was well within normal limits (46 ml/kg/min) and she had no subjective exercise limitations.

The third patient was a fourteen-year old boy after simple dTGA after ASO. We performed coronary angiography which revealed a slight aortic insufficiency and a slightly dilated aortic bulbus. He did not complain of exercise limitation and the strain values during the stress test were well within normal limits (-18.8 to -21).

In the group of Kawasaki patients all post-exercise O₂-slopes showed normal behaviour and there were no pathologic strain values, even though all patients had coronary aneurysms.

In this study, the participants after ASO or KD were significantly less active than their control group. This is consistent with other studies reporting the physical activity levels of children with congenital heart disease [37], even though current guidelines don’t exclude any form of physical activity for ASO patients with no systolic dysfunction, normal pulmonary artery pressure, no aortic dilatation, no arrhythmias and no central cyanosis [38]. The same is true for patients after KD if no giant aneurysms have been observed [39]. This finding underlines the importance of educating children with congenital or acquired heart disease and their families about a more active lifestyle.

All three groups reached peak exertion according to international standards. However, it was surprising that the KD patients achieved significantly higher RER values than the control patients. This could have been caused by the fact that 80% of the Kawasaki-patients undertook the test on the tilt-recline ergometer in comparison to 62% in the control and 65% in the ASO group. RER values were significantly higher on the tilt-recline ergometer than on the treadmill probably due to a higher lactate buildup on the bicycle.

In our study, peak oxygen uptake was comparable between the patients and the control group with a tendency towards higher values in the control group. This is in accordance with previous studies with patients after KD [40, 41]. However, after ASO \(\:\dot{V}{O}_{2}peak\) has been observed to be reduced in comparison with age-matched controls [42, 43]. When comparing the subgroups with their respective controls it became obvious that whereas the Kawasaki patients did not reach a significantly lower \(\:\dot{V}{O}_{2}peak\), the ASO patients did. It has been hypothesized that this finding is due to chronotropic incompetence in consequences of changes on sympathetic innervation of the myocardium due to arterial transection and coronary reimplantation during surgery [42]. However, this finding could not be objectified in another study, in which the lower \(\:\dot{V}{O}_{2}peak\) could be correlated to the contractile reserve of these patients using cardiac magnetic resonance (CMR) imaging during exercise [43]. Interestingly, they also noted that the function of the RV at rest could be an early marker of impaired exercise capacity [43]. The authors hypothesize that the persistent pressure load of the RV and the persistent volume load on the LV might play a role [43]. A reduced RV longitudinal function (TAPSE) at rest was also observed in another CMR study in which no LV dysfunction could be observed at rest [44].

We used stress echocardiography for objectifying our values from the cardiopulmonary exercise test, as the intention of the study was to establish non-invasive parameters for evaluating coronary insufficiency. Interestingly, there were no significant differences in the echocardiography between participants after KD or ASO and the control group either at rest or during exercise.

Previous studies were able to show reduced strain values at rest during the acute [45] and midterm phase [46, 47], and also during follow-up of the KD [48]. Using stress echocardiography signs of myocardial ischemia in high-risk patients could be observed [49], but an abnormal stress echocardiogram was rare in asymptomatic children [50]. In our study 4 children after KD were classified as high-risk but none showed signs of systolic dysfunction either at rest or during exercise. A possible explanation for the discrepancy of these findings with our results could be that the examination was undertaken a long time after the initial disease, and the ventricles could have recovered by the time the echocardiography was undertaken.

In patients after ASO, the left ventricle usually presents with normal GLS values during follow-up [51, 52]. However, when having variant coronary arterial anatomy, a reduced LV contractile reserve has been observed [23]. Using Adenosine or dobutamine for stress echocardiography, several studies were able to detect an impaired LV contractility in children after ASO [21, 22]. We applied exercise testing on a treadmill in smaller children with intermittent echocardiograms approximately at VT₁ and VT₂ and a tilt recline ergometer in the ones tall enough. In our study no patients showed any impaired systolic function at rest. Overall, the strain values decreased with increasing workload as observed in healthy adolescents [27]. However, one patient revealed an increase in GLS with the beginning of exercise and then decreased from there, up to a value of -16.3%. The girl after ASO had a filiforme stenosis of the ramus circumflexus with retrograde perfusion through collaterals originating from the left coronary artery. She was completely asymptomatic.

Using \(\:\dot{V}{O}_{2}peak\) for evaluating CAD has so far been limited to studies in adult patients. A study by Belardinelli et al. [9], in which 202 patients with coronary artery disease (CAD) were compared with 196 healthy controls, could not show any differences of \(\:\dot{V}{O}_{2}peak\) between CAD patients and healthy controls. In another study Munhoz et al. [12] could also not detect any differences with respect to this parameter when comparing patients with normal exercise myocardial perfusion scintigraphy and those who presented with exercise induced ischemia. However, patients with extensive transient perfusion defects during exercise achieved significantly lower values [12]. A lower \(\:\dot{V}{O}_{2}peak\) in symptomatic patients was also observed in other studies [11, 53].

Investigating further CPET variables the oxygen uptake at the first ventilatory threshold was significantly lower in our group of ASO and KD patients in comparidon with their age-matched controls. A lower \(\:\dot{V}{O}_{2}\) at VT1 suggests an earlier transition into an anaerobic metabolism. This could be explained by a reduced flow of oxygen resulting in worsened oxygen extraction at the myocardium and at the tissue level with increasing load during exercise consistent with CAD [10]. On the other hand, it could also point to a less active lifestyle with less endurance as evidenced by the less active lifestyle observed in the ASO and KD patients in our study. Thus, two possible explanations present themselves with regards to the significantly lower \(\:\dot{V}{O}_{2}\) at VT1 representing an earlier transition into an anaerobic metabolism: reduced blood flow to the myocardium or a lower cardiopulmonary fitness. However, a differentiation between these two causes is impossible.

In summary, \(\:\dot{V}{O}_{2}peak\), and \(\:\dot{V}{O}_{2}\) at VT₁ seem to be poor parameters for predicting coronary insufficiency in patients after KD or ASO but allows for an evaluation of the overall cardiopulmonary fitness at the moment of testing.

Several other parameters have been discussed for examining coronary insufficiency using CPET. The O₂pulse, a surrogate parameter of the stroke volume, usually shows a continuous increase according to an increase in work rate. The appearance of a plateau or even decrease of the O₂pulse with increasing work rate is a sign that the stroke volume cannot adequately be increased according to the demand from the working muscle [14]. As symptoms of angina pectoris and ECG ST segment changes are more delayed than regional myocardial dysfunction due to perfusion abnormalities [54], a slower rate of increase in O2pulse in form of a plateau or even a decline before the end of exercise could indicate an early sign of myocardial ischemia [9, 12, 55]. However, its diagnostic performance has been questioned in several studies as its sensitivity and its negative predictive value were low [56, 57] or only detects severely affected patients [10–12, 53, 58, 59]. Usually the O₂pulse decreases quickly after the termination of exercise as the demand for an increased cardiac output (CO) vanishes [14]. However, in a ventricle that was unable to increase its CO according to the muscular demand, the O₂pulse remains high or even increases as afterload decreases [14], and the arteriovenous oxygen difference increases with termination of exercise [60]. A plateau of the O₂pulse after termination of exercise in asymptomatic patients could therefore be suggestive of myocardial ischemia. In this study the slope of the O₂pulse in the first thirty seconds after termination of exercise was significantly higher in patients after ASO. Furthermore, there was a positive correlation between this parameter and the strain in the 4-chamber-view at VT₁ and VT₂, which signifies a worse contractility with a more positive slope of the O₂pulse after the end of exercise. Interestingly, three patients were identified as having such a plateau of the O₂pulse, one of which already showed impairment of her myocardial function without reporting any symptoms. However, the other two patients with a conspicuous post-exercise O₂pulse did not have coronary insufficiency but had suffered from pulmonary stenosis and aortic insufficiency. The O₂pulse represents a surrogate parameter of the cardiac output, but it cannot distinguish between the right and the left ventricle. Nor does it allow the distinction of the cause of the loss in cardiac output. However, an abnormal O₂pulse plateau after the termination of exercise could alert the clinician that a more thorough investigation is warranted. Surprisingly, there were no differences between the KD patients and the control group. Two patients had giant aneurysms measuring up to 30 mm in Diameter. Still, their CPET parameters all remained within normal limits, and none showed an abnormal O₂pulse plateau before or after termination of exercise. Possibly, coronary aneurysms don’t cause coronary insufficiency in the investigated age-group.

The study has several limitations. The number of patients in the subgroups was small, especially with respect to the KD patients. This is mainly due to the fact that we limited this cohort to patients with significant coronary aneurysms.

The strain measurements during the cardiopulmonary exercise test were not complete due to poor image quality especially during the higher work rates. This was more pronounced on the tilt recline ergometer than on the treadmill.

Only three patients had an obviously abnormal O₂pulse plateau after termination of exercise. This doesn’t allow to draw conclusions on this plateau. Further studies with a larger patient cohort at risk are needed for evaluating this parameter further.

In conclusion, the combination of stress echocardiography and cardiopulmonary exercise testing is feasible even in smaller children. We were able to perform several echocardiographic examinations at approximately VT₁ and VT₂ by stopping the treadmill and performing echocardiograms with the child standing upright. This did not influence the CPET peak values.

The behaviour of the O₂pulse after the termination of exercise could be a new parameter for evaluating cardiac function in children at risk of myocardial dysfunction like patients after ASO or Kawasaki disease. However, larger studies are needed to evaluate this parameter further.

Especially the combination of the two methods, i.e. stress echocardiography and the slope of the O₂pulse could present a new non-invasive possibility for evaluating children at risk for myocardial dysfunction with the added benefit of being radiation-free.

Conflict of interest

The authors have no financial or non-financial interests that are directly or indirectly related to the work submitted for publication.

Author’s Contributions

Author’s name	Conception and design of the study	Data acquisition,	Data analysis and interpretation	Drafting of Manuscript	Critical Revision of Manuscript	Accountability for all aspects of work, ensuring integrity and accuracy
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WA	√				√	√
DS	√				√	√
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Cardiopulmonary exercise testing combined with stress echocardiography for the evaluation of myocardial dysfunction in children at risk

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