Sports practice predicts better functional capacity in children and adults with Fontan circulation

Journal Pre-proof Sports practice predicts better functional capacity in children and adults with Fontan circulation

João Rato, Ana Sousa, Susana Cordeiro, Miguel Mendes, Rui Anjos PII:

S0167-5273(19)33138-9

DOI:

https://doi.org/10.1016/j.ijcard.2019.11.116

Reference:

IJCA 28149

To appear in:

International Journal of Cardiology

Received date:

18 June 2019

Revised date:

14 October 2019

Accepted date:

15 November 2019

Please cite this article as: J. Rato, A. Sousa, S. Cordeiro, et al., Sports practice predicts better functional capacity in children and adults with Fontan circulation, International Journal of Cardiology(2019), https://doi.org/10.1016/j.ijcard.2019.11.116

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© 2019 Published by Elsevier.

Journal Pre-proof Sports practice predicts better functional capacity in children and adults with Fontan circulation Authors: 1 – João Rato, MD – Department of Pediatric Cardiology, Hospital de Santa Cruz – Centro Hospitalar Lisboa Ocidental, Lisboa, Portugal. This author takes responsibility for all aspects of the reliability and freedom from bias of the

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data presented and their discussed interpretation.

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Hospitalar Lisboa Ocidental, Lisboa, Portugal

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2 – Ana Sousa, MD – Department of Pediatric Cardiology, Hospital de Santa Cruz – Centro

This author takes responsibility for all aspects of the reliability and freedom from bias of the

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data presented and their discussed interpretation.

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3 – Susana Cordeiro, Sonographer – Department of Pediatric Cardiology, Hospital de Santa

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Cruz – Centro Hospitalar Lisboa Ocidental, Lisboa, Portugal

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This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 4 – Miguel Mendes, MD – Department of Cardiology, Hospital de Santa Cruz – Centro Hospitalar Lisboa Ocidental, Lisboa, Portugal This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 5 – Rui Anjos, MD – Head of Department of Pediatric Cardiology, Hospital de Santa Cruz – Centro Hospitalar Lisboa Ocidental, Lisboa, Portugal

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Journal Pre-proof This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. Corresponding Author: João Rato, MD. Adress: Department of Pediatric Cardiology, Hospital de Santa Cruz – Centro Hospitalar Lisboa Ocidental, Av. Prof. Dr. Reinaldo dos Santos 2790134, Carnaxide, Portugal. Mail: [email protected]. Funding: This research did not receive any specific grant from funding agencies in the public,

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commercial, or not-for-profit sectors. Conflict of interests: The authors report no relationships that could be construed as a conflict

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of interest.

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Journal Pre-proof Abstract Background Peak oxygen uptake (peak VO2) and its decline predict death or serious cardiovascular adverse events in patients with Fontan circulation. Our aim was to study VO2 in a population of Fontan patients with variable age and contemporary surgical correction, and find predictors of functional status which could lead to management changes.

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Methods

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Prospective cardiopulmonary exercise test was performed on a treadmill. Blood tests and transthoracic echocardiogram were performed on the same day. Dependent variables were

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defined as: VO2 at ventilatory threshold (VT) as a percentage of the predicted peak VO2 and

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peak VO2 as a percentage of its predicted value. Statistical analysis was performed on SPSS

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version 23 and significance was defined as a p-value <0.05.

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Results

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Forty-eight patients were included for analysis. All had a lateral or extracardiac conduit. Mean age was 18.2 years (SD 6.2). Mean age at Fontan completion of 6.5 years (SD 2.3) showed no association with functional capacity. Mean percent VO2 at VT was 37.6% (SD 9.4) and percent peak VO2 was 67.8% (SD 16.7). VO2 both at ventilatory threshold and peak was associated with age, weekly sports practice, significant atrioventricular regurgitation and having a pacemaker or being on antiarrhythmic drugs. On multivariate analysis, weekly sports practice was the best predictor for VO2 values. Conclusions Sports practice is a modifiable factor that significantly impacts functional capacity in Fontan patients despite their age. Clinicians should actively prescribe and promote physical activity in 3

Journal Pre-proof this population, either with regular sports practice or engagement in cardiac rehabilitation programs. Keywords: congenital heart disease, Fontan procedure, cardiopulmonary exercise test,

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echocardiography, exercise, sports practice

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Journal Pre-proof 1. Introduction The Fontan procedure is a surgical technique designed for long term palliation of patients with complex congenital heart disease and a functionally single ventricle [1]. This surgery creates a unique physiology: in the Fontan circuit the systemic venous return bypass’s the heart and drains directly into the pulmonary arteries without the interposition of a ventricle [2]. While eliminating arterial desaturation and avoiding a chronic volume overload to the heart, this

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circulation has been described as a ‘’critical bottleneck’’ which leads to upstream venous

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congestion and downstream decreased output [3]. This physiology leads to a series of

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complications, one of which is limited exercise capability due to an inability to adequately increase stroke volume during periods of increased demand [4]. Since its creation, the Fontan

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procedure has undergone several changes, the most recent being the lateral or extracardiac

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conduit [2].

Several papers have described the behavior of Fontan patients submitted to cardiopulmonary

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exercise test (CPET) [5-9]. The conclusions are unanimous and indicate a markedly impaired

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exercise performance when compared to the normal population. Both peak oxygen uptake

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(peak VO2) and its decline have been shown to predict death or serious cardiovascular adverse events [10-12]. Therefore, it is essential to identify modifiable predictors of VO2 that can lead to a better management of these patients. Exercise has been gaining interest as such a predictor. Historically, these individuals were advised against strenuous physical exercise, but this seems counter-intuitive: pulmonary blood flow is highly dependent on the peripheral muscle pump in the Fontan circulation [13]. As Cordina et al demonstrated, high-intensity whole body resistance training can increase exercise performance by 10% by augmenting skeletal muscle mass [14]. Cardiac rehabilitation programs show that exercise is safe for these patients, and results in improved exercise tolerance, muscle strength, activity levels and quality of life [15]. With this paper we show that 6

Journal Pre-proof sports practice increases the functional capacity in Fontan patients despite their age. The message is clear: Fontan patients should be allowed and encouraged to exercise. 2. Methods 2.1. Study Design The primary aim of the present study was to perform a functional evaluation of a population of Fontan patients with lateral or extracardiac conduit using CPET on a treadmill, and to find

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predictors of functional status. Patients eight years or older with active follow up at an outpatient clinic at a tertiary hospital were contacted. Those unable to perform a treadmill

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CPET due to motor or developmental disabilities were excluded. Consent was obtained for all

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subjects according to local guidelines.

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2.2. Patient selection

Medical records of 70 patients who had undergone a Fontan procedure were screened. Of

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those, 52 (74%) were fully eligible for this study on the basis of their ability to perform the

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necessary testing at our Hospital and agreed to participate. For final analysis, four patients

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were further excluded as they were submitted to an atriopulmonary connection. Each patient’s medical records were analyzed. 2.3 Sports practice recording

Patient’s sports activity was defined as the practice of leisure, competitive sports or exercise training, according to published international recommendations [16]. As these categories were not mutually exclusive, and often patients engaged in competition also practiced leisure sports or exercise training, we defined the variable weekly sports hours as a method to represent overall practice. Leisure sports were defined as recreational physical activities without pressure to play, continue to play, or play at a higher intensity than desired. Competitive sports as organized, competitive and skillful physical activities. Exercise training as specialized, 7

Journal Pre-proof planned programs of physical activity used to increase a subject’s physical activity capacity. Of note, no patient had ever been enrolled in a medical cardiac rehabilitation program. Sedentary lifestyle was defined as no or marginal regular physical activity or exercise and recorded as no sports activity. 2.4. Blood tests and transthoracic echocardiogram Blood samples were collected on the same day, a few hours before CPET. Levels of

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hemoglobin, hematocrit, ferritin, and transferrin saturation were specifically recorded for this study.

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Transthoracic echocardiography (TTE) was performed with standard techniques on the same

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day before CPET. TTE was evaluated especially for atrioventricular valve (AV) regurgitation or

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stenosis, outflow tract and aortic or neo-aortic valve regurgitation or stenosis, aortic arch flow, pericardial effusion and thrombus. Valve regurgitation was classified by two experienced

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operators in 2 groups: absence of significant regurgitation (none or mild) or significant

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regurgitation (moderate or severe). Function of the dominant ventricle was qualitatively evaluated, but not used as a variable as there are no current quantitative methods validated

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for this echocardiographic assessment in univentricular hearts. 2.5. Exercise Protocol

Prospective exercise testing was performed on a treadmill using the Bruce protocol. Equipment was calibrated by the manufacturers’ specifications at the beginning of the session and before each test. The test was interrupted due to fatigue at patient’s request or when respiratory exchange ratio (RER) reached 1.1. There were no severe hemodynamic changes or arterial oxygen desaturation that warranted test interruption. 2.6. Resting Pulmonary Function Test Measurements

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Journal Pre-proof After familiarization with the equipment, inspiratory and expiratory flow volume loops were assessed. Testing was repeated 3 times for reproducibility. Forced vital capacity (FVC) and forced expiratory volume at the first second (FEV1) were recorded. Maximal voluntary ventilation (MVV) was calculated as MVV = FEV1 x 40. Nine patients were unable to properly cooperate with this assessment. 2.7. CPET Measurements

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Resting 12-lead electrocardiograms were performed for all patients. Heart rate (HR) and electrocardiogram were monitored continuously. The achieved peak HR was presented as a

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adults as recommended by Wasserman et al [17].

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percentage of the predicted value by the formula peak HR = 220 – age both for children and

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Expired gases were measured for 3 minutes at rest and throughout the exercise protocol. Oxygen uptake (VO2), carbon dioxide production (VCO2 ) and minute ventilation (VE) were

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measured using breath-by-breath gas analysis and reported on a 20 seconds averaging. RER

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was calculated as the ratio between VO2 and VCO2 at peak exercise. Adequate performance of the CPET was defined as an RER ≥ 1, a threshold deemed acceptable for maximum effort by

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children and adolescents on a treadmill [18-21]. For those who did not achieve this value, the only studied variable was VO2 at ventilatory threshold (VT). This threshold is defined by the lowest point of O2 equivalent, coming backwards from the end of the exercise period to its beginning, and marks the moment when pulmonary ventilation increases disproportionally to VO2. VO2 at VT was indexed to body weight and calculated as a percentage of the predicted peak VO2 [17]. Peak oxygen uptake was calculated as the highest VO2 measurement attained during exercise indexed to body weight. Values for peak VO2 were expressed as percentage of predicted values for healthy matched subjects as reported by Cooper et al for subjects ≤ 18 years old [17] and Wasserman et al for subjects > 18 years old [17]. Oxygen pulse (O2 pulse) was recorded at peak VO2. Other variables recorded were: VE/VCO2 slope for the whole test 9

Journal Pre-proof and breathing reserve defined by the formula BR = 1 – (VE/MVV) x 100. Arterial O2 saturation was measured continuously by ear oximeter. Arterial pressure was measured at rest, every 3 minutes during exercise and at 1 minute and 3 minutes after exercise. 2.8. Statistical analysis Statistical inference was performed using SPSS version 23. Two exercise performance measures were selected as the dependent variables for statistical analysis: VO2 at VT defined

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as a percentage of the predicted peak VO2; and peak VO2 defined as a percentage of its predicted value. The independent variables used for statistical correlation are defined on table

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1.

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Student’s t-test was used for binomial and continuous variable correlation. Linear regression

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was used for continuous variable correlation. Linear multivariate models were constructed based on a step down approach using significant univariate associations. Statistical significance

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was defined as p-value < 0.05.

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Additional analysis included A - correlation of peak VO2 data only in patients who achieved

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peak heart rate >85% of the predicted value for age, another threshold to ensure adequate effort [21], and B - detailed characterization of patients with normal functional capacity (peak VO2 > 80%). 3. Results 3.1 Baseline patient’s characteristics Patients had a mean age of 18.2 years (SD 6.2, min. 9.0 – max. 35.0), 54% (N=26) had ≤ 18 years, 60% (n=29) were female. Body mass index (BMI) was 20.1 kg/m2 (SD 4.4, min. 14.6 – max. 38.9). One adolescent girl was overweight (BMI percentile 85th to 95th) and other was obese (BMI percentile >95th), while one male adult was overweight (BMI 28.7kg/m2) and other

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Journal Pre-proof obese (BMI 38.9kg/m2) [22]. Age at Fontan completion was 6.5 years (SD 2.3, min. 3.0 – max. 12.0) and time since Fontan surgery was 11.7 years (SD 6.2, min. 1.0 – max. 31.0). On this cohort, all patients had Fontan surgery with a lateral or an extracardiac conduit and 96% (n=46) had a previous superior cavopulmonary connection. Only one patient was operated before 1990, and has since had a Fontan redo with an extracardiac conduit. Baseline diagnoses are described in table 2. Heterotaxy syndrome was present in 15% (n=7) of patients. The cohort had a prevalence of significant comorbidities of 46% (n=22). Among these, current or

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previous arrhythmia was diagnosed in 19% (n=9); these were complete heart block (n=2), sinus node disease (n=5), paroxysmal supraventricular tachycardia (n=1) and atrial fibrillation (n=1).

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In total, 22% (n=11) of patients had a pacemaker or were on antiarrhythmic drugs including

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beta-blockers. Other significant comorbidities included, but were not limited to, sequels from

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previous stroke (n=7), sequels from diaphragmatic palsy (n=6), protein-losing enteropathy (n=4), and diabetes (n=2). Other current medications were: angiotensin-converting-enzyme

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inhibitors or angiotensin II receptor blockers in 65% (n=31), loop diuretics in 21% (n=10),

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3.2 Sports practice

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warfarin in 63% (n=30) and aspirin in 29% (n=14).

According to definitions, 54% (n=26) of the study’s population engaged in exercise training, whether at school classes or fitness centers. Moreover, 31% (n=15) also practiced leisure sports, and 23% (n=11) competitive sports. Competitive sports included football, basketball, running and swimming. No patient reported adverse events during or following exercise in the past. Mean weekly sports practice frequency was 1.7 hours (SD 1.7, min. 0 – max. 5.0). Individuals with a sedentary lifestyle (46%, n=22) were significantly older than those who practiced sports (mean age 21.6 years (SD 6.3) vs. 15.2 years (SD 4.5), p-value < 0.001) and had a significantly higher BMI (mean BMI 21.8kg/m2 (SD 5.2) vs. 18.7kg/m2 (SD 3.1), p-value = 0.012), but had no other differences. 11

Journal Pre-proof 3.3 Blood tests Mean values of the recorded parameters were: hemoglobin 14.9 g/dl (SD 2.0, min. 7.7 – max. 18.7), hematocrit 44.9% (SD 5.8, min. 25.8 – max. 56.3), ferritin 97.0 ng/ml (SD 86.0, min. 3.5 – max. 414.0), transferrin saturation 22.0% (SD 10.9, min. 3.0 – 51.0). None of these values had a significant relation with the dependent variables. 3.4 Transthoracic echocardiogram

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Moderate or severe AV valve regurgitation was present in 40% of patients (n=19). None had AV valve stenosis. Regarding the ventricular outflow tract and aortic or neo-aortic valve, 13%

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had some degree of stenosis (n=6) and 11% (n=5) had moderate regurgitation. None of the

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patients with an aortic arch anastomosis had restenosis. None had pericardial effusion or

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thrombus.

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3.5 CPET variables

CPET variables are described at length on table 3. Mean RER was 1.06 (SD 0.07, min. 0.84 –

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max. 1.26). Only three patients did not reach the endpoint RER ≥ 1, and for these percent VO2

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at VT was the only dependent variable for statistical analysis. 3.6 Correlation analysis

Correlation data is detailed on table 4. On univariate analysis, higher values of dependent variables were related to younger age, different categories of exercise, weekly sports practice, absence of pacemaker or antiarrhythmic agents, and absence of significant AV valve regurgitation. Peak VO2 was also related to higher peak HR and higher baseline O2 saturation. Multivariate analysis identified higher weekly sports practice as being the best predictor of both VO2 at VT (p-value <0.001) and peak VO2 (p-value <0.001). Having a pacemaker or being on antiarrhythmic drugs also reduced the VO2 at VT (p-value=0.021).

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Journal Pre-proof These results were consistent in the additional analysis with a threshold of peak heart rate >85% of the predicted value for age (n=23), however multivariate analysis identified the practice of exercise training as the only and best predictor of peak VO2 in this group (pvalue=0.007). When comparing with the rest of the cohort, patients with normal peak VO2 (n=10) spent more hours practicing sports (1.5 hours (SD 1.6) vs. 2.7 (SD 1.8) respectively, p-value = 0.038). This

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was the only significant difference between both groups. Discussion

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This Fontan cohort comprised young subjects (mean age 18.2 years), with an adequate BMI

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(mean 20.1 kg/m2). The mean age at Fontan surgery was 6.5 years. This may be a little later

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than currently recommended [19]. However, unlike previous studies, we found no association between age at Fontan and functional capacity [6,23-25]. In most published papers there are

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patients with different surgical modalities for Fontan, but our group was exclusively comprised

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of patients with a lateral or extracardiac conduit. Bolin EH et al found that later Fontan completion (i.e. ≥ 4 years of age) might be associated with improved exercise capacity in

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patients with a superior cavopulmonary connection at ≤1 year of age, followed by Fontan completion with lateral or extracardiac conduit [26]. These findings stress the need for more longitudinal data before making definitive recommendations about the ideal age for Fontan completion. Functional capacity in our Fontan patients is compromised (table 3). VO2 at VT as a percentage of predicted VO2 should normally reach between 40% and 60%, unless severe deconditioning or pathology is present [20]. The mean value of this cohort was 37.6% (SD 9.4, min. 21.0 – max. 75.0). Peak VO2 was also diminished, at 67.8% (SD 16.7, min. 42.0 – max. 119.0) of the predicted value for a healthy population of the same age. Oxygen uptake during exercise depends on cardiac output, which is the product of stroke volume and heart rate, and arterial13

Journal Pre-proof venous O2 difference. On this study there was a univariate correlation between peak VO2 and peak HR and baseline O2 saturation, which did not hold on multivariate analysis. However, being on antiarrhythmic drugs, including beta-blockers, and having a pacemaker significantly reduced VO2 at VT. The negative impact of these medications and devices in VO2 values due to their association with chronotropic incompetence is well-described [21,27], but in this cohort it seemed to be especially relevant to exercise capacity only on a submaximal level.

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Pulmonary function also impacts the Fontan circulation [28-29]. Both FVC and FEV1 were

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mildly decreased and the VE/VCO2 slope was elevated. However, Dimopoulos et al have

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demonstrated that VE/VCO2 slope is a predictor of mortality in noncyanotic patients with adult congenital heart disease, but not in cyanotic patients [30]. In fact, cyanosis was the strongest

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predictor of abnormal VE/VCO2 slope in their study [30]. As most of our patients show mild to

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moderate decrease in O2 saturation during exercise, this slope does not have prognostic usefulness. Mean breathing reserve was 34.9%. Eight patients showed values below the

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expected, 20% to 40% of the MVV [20], possibly indicating a ventilatory limitation to exercise

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capacity. None of these variables seemed to influence VO2 values. However, given the strong

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relation between respiration and ventricular filling even in exercise [29], pulmonary function after the Fontan procedure deserves further research. Regarding echocardiographic parameters, AV valve function is known to significantly affect outcomes in patients with a Fontan circuit [31-32]. Cardiac output during exercise is mainly dependent on transpulmonary flow in the Fontan circuit [33], which depends on transpulmonary gradient. Therefore, the elevation of atrial pressure caused by significant AV valve regurgitation is likely to compromise cardiac output at rest and its increase during exercise. The burden of AV valve failure in the Fontan circuit raises important challenges. The Mayo Clinic experience is that one-half of the patients who had been submitted to atrioventricular valve surgery after Fontan operation died within a decade of these operations

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Journal Pre-proof [34]. Moreover, this surgery had a 13% 30-day mortality [34]. Although our study found an association between AV valve regurgitation and functional capacity only in univariate analysis, we believe this should not be dismissed. AV valve regurgitation warrants close surveillance and a multidisciplinary approach. Our most significant finding was the strong association between sports practice and functional capacity. Fontan patients were initially advised against vigorous exercise because of concerns

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about arrhythmic events and adverse remodeling. However, experience has shown that acute

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arrhythmias are rare and usually not associated with physical activity [35]. Furthermore, more

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than 200 Fontan patients who have attended exercise training programs without any related adverse events have been described in the literature [15]. Our cohort never reported an

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adverse advent related to sports practice. McCrindle et al showed that the majority of children

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and adolescents with Fontan circulation fail to achieve recommended levels of physical activity [36]. Restrictions imposed by parents and doctors are one of the causes - a study by Rhodes et

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al showed that 50% of children with congenital heart disease perceived that their parents and

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[37].

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doctors limited their physical activities, on account of concerns about their heart problems

Currently, there has been a higher focus on the role of physical activity in the Fontan circulation. Moderate-to-vigorous exercise and resistance training has been described as the most effective therapy for improving exercise capacity in this group due to mechanisms that are unique to the Fontan physiology, such as improving venous return through an augmented peripheral muscle pump [13]. Cordina et al demonstrated that after 20 weeks of high-intensity resistance training peak oxygen consumption increased by 183 ml/min associated with a 43% and 1.9kg increase in muscle strength and total muscle mass respectively [14]. In the same group, magnetic resonance analysis showed an improvement in stroke volume both at rest and during exercise after the program [14]. Other exercise-related mechanisms seem to be

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Journal Pre-proof beneficial for Fontan patients, including better ventilatory efficiency [38], and perhaps even an increase in pulsatile pulmonary flow during exercise which may be advantageous for pulmonary endothelial function [39]. Studies also reported the enhancement of quality of life by improving physical self-perception, satisfaction with life, physical activity levels and general health after an exercise-training period [40]. Therefore, it is easy to understand how sports practice could predict better functional capacity

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in our population. Patients who exercise more often are the ones who tend to participate in

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leisure or competitive sports, activities which demand more vigorous exercise. Even just

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regular exercise training, which in children often consists in schools’ exercise classes, seems to be beneficial, as demonstrated with a more restrictive analysis. Kodama et al also showed that

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middle and high school students who attended sports club had significantly higher peak VO2

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[41]. The Australian and New Zealand Fontan registry ‘’Super-Fontans’’, Fontans who had normal our supranormal exercise capacity, were all individuals who participated frequently in

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vigorous sporting activities [42]. Of note, this last cohort had neither an accelerated rate of

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decline, nor an increased incidence of cirrhosis, concerns raised because of higher systemic

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venous pressure during periods of vigorous activity which could eventually predispose to endorgan injury [43]. It is unclear if this transient increase in systemic venous pressure for short periods has any long-term significance, especially if, as Ohuchi et al showed, positive exercise capacity trajectory during childhood predicts better adult Fontan pathophysiology, including lower resting venous pressure [44]. On the basis of this data, some groups have started to consider moderate-to-vigorous exercise as standard-of-care for Fontan patients, recommending and prescribing it actively and implementing rehabilitation programs as soon as possible to increase the likelihood of long-term sustenance [13]. Based on our own data, Fontan patients with normal VO2 exercise for a mean of 3 hours per week. This may point to an acceptable threshold for regular sports practice and help to guide patient management.

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Journal Pre-proof 4.1. Study limitations This study was limited to subjects who could be contacted and that could perform an exercise test, which does not reflect the entire Fontan population and inevitably results in a selection bias. As a cross sectional study rather than a longitudinal study, this study also does not account for variations of the studied variables across time, nor does it account for possible outcomes.

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We used RER ≥ 1 to define adequate performance of the CPET. This may be considered a somewhat low threshold by some investigators. However, as mentioned before, many find it

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acceptable to define maximum effort by children and adolescents on a treadmill [18-20]. We

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rate >85% of the predicted value for age.

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minimized it by performing a subsequent analysis only in patients who achieved peak heart

It is also worth mentioning that correlation does not equal causation. Patients may practice

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more sports because they have a better functional capacity, and not the other way around.

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However, we believe that both the physiologic rationale and the literature’s strong cumulative

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evidence, which we cited, point towards causation. 4. Conclusion

The results of the present study suggest that clinicians should actively prescribe, promote and maintain physical activity in Fontan patients, either with regular sports practice or engagement in cardiac rehabilitation programs. Other factors affecting the patient’s ability to increase stroke volume during exercise, such as significant AV regurgitation, define a higher risk group that should be carefully monitored, and appropriate intervention should be addressed. 5. References 1 - Fontan F, Baudet E. Surgical repair of tricuspid atresia. Thorax, 1971 May: 26(3):240-8.

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Journal Pre-proof 2 - Gewillig M. The Fontan circulation. Heart, 2005 Jun: 91(6):839-46. 3 - Gewillig M, Brown SC. The Fontan circulation after 45 years: update in physiology. Heart, 2016 Jul: 102(14):1081-6. 4 – Rychik J. The Relentless Effects of the Fontan Paradox. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu, 2016: 19(1):37-43. 5 - Takken T, Tacken MH, Blank AC, Hulzebos EH, Strengers JL, Helders PJ. Exercise limitation in

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patients with Fontan circulation: a review. J Cardiovasc Med (Hagerstown), 2007 Oct:

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8(10):775-81.

6 - Ovroutski S, Ewert P, Miera O. Long-term cardiopulmonary exercise capacity after modified

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Fontan operation. Eur J Cardiothorac Surg, 2010 Jan: 37(1):204-9.

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7 - Paridon SM, Mitchell PD, Colan SD et al. A cross-sectional study of exercise performance

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during the first 2 decades of life after the Fontan operation. J Am Coll Cardiol, 2008 Jul:

8 - Wolff D, van Melle JP, Bartelds B. Fontan Circulation over Time. Am J Cardiol, 2017 Aug:

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120(3):461-466.

9 - Hock J, Reiner B, Neidenbach RC. Functional outcome in contemporary children with total cavopulmonary connection - Health-related physical fitness, exercise capacity and healthrelated quality of life. Int J Cardiol, 2018 Mar: 255:50-54. 10 - Ohuchi H, Negishi J, Noritake K. Prognostic value of exercise variables in 335 patients after the Fontan operation: a 23-year single-center experience of cardiopulmonary exercise testing. Congenit Heart Dis, 2015 Mar-Apr: 10(2):105-16. 11 - Egbe AC, Driscoll DJ, Khan AR. Cardiopulmonary exercise test in adults with prior Fontan operation: The prognostic value of serial testing. Int J Cardiol, 2017 May: 235:6-10. 18

Journal Pre-proof 12 - Udholm S, Aldweib N, Hjortdal VE, Veldtman GR. Prognostic power of cardiopulmonary exercise testing in Fontan patients: a systematic review. Open Heart, 2018 Jul: 5(1):e000812. 13 - Cordina R, d'Udekem Y. Long-lasting benefits of exercise for those living with a Fontan circulation. Curr Opin Cardiol. 2019 Jan;34(1):79-86. 14 - Cordina RL, O'Meagher S, Karmali A et al. Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology. Int J Cardiol,

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2013 Sep: 168(2):780-8. 15 - Sutherland N, Jones B, d'Udekem Y. Should We Recommend Exercise after the Fontan

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Procedure? Heart Lung Circ. 2015 Aug;24(8):753-68.

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16 - Takken T, Giardini A, Reybrouck T, et al. Recommendations for physical activity, recreation

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sport, and exercise training in paediatric patients with congenital heart disease: a report from the Exercise, Basic & Translational Research Section of the European Association of

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Cardiovascular Prevention and Rehabilitation, the European Congenital Heart and Lung

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2012 Oct;19(5):1034-65.

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Exercise Group, and the Association for European Paediatric Cardiology. Eur J Prev Cardiol.

17 - Wasserman K, Hansen JE, Sue DY et al. Principles of Exercise Testing and Interpretation: Including Pathophysiology and Clinical Applications. Philadelphia, USA: Lippincott Williams & Wilkins, 1987. 18 - Takken T, Blank AC, Hulzebos EH, van Brussel M, Groen WG, Helders PJ. Cardiopulmonary exercise testing in congenital heart disease: (contra)indications and interpretation. Neth Heart J. 2009 Oct;17(10):385-92.

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Journal Pre-proof 19 – Rowland TW, American College of Sports Medicine, North American Society for Pediatric Exercise Medicine. Cardiopulmonary Exercise Testing in Children and Adolescents. Champaign, USA: Human Kinetics, 2018. 20 - Van Brussel M, Bongers BC, Hulzebos EHJ, Burghard M, Takken T. A Systematic Approach to Interpreting the Cardiopulmonary Exercise Test in Pediatrics. Pediatr Exerc Sci, 2019 Jan: 28:1-10.

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21 - Malhotra R, Bakken K, D'Elia E, Lewis GD. Cardiopulmonary Exercise Testing in Heart Failure. JACC Heart Fail. 2016 Aug;4(8):607-16.

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22 – Centers for Disease Control and Prevention’s Body Mass Index calculators for children,

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teenagers and adults. https://www.cdc.gov/healthyweight/assessing/index.html. Last assessed

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on September of 2019.

23 - Daley M, d'Udekem Y. In patients undergoing Fontan completion, does a younger age at

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operation result in better long-term exercise capacity and prognosis?. Interact Cardiovasc

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Thorac Surg, 2019 Feb: 28(2):301-305.

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24 - Shiraishi S, Yagihara T, Kagisaki K et al. Impact of age at Fontan completion on postoperative hemodynamics and long-term aerobic exercise capacity in patients with dominant left ventricle. Ann Thorac Surg, 2009 Feb: 87(2):555-60. 25 - Madan P, Stout KK, Fitzpatrick AL. Age at Fontan procedure impacts exercise performance in adolescents: results from the Pediatric Heart Network Multicenter study. Am Heart J, 2013 Aug: 166(2):365-372.e1. 26 - Bolin EH, Maskatia SA, Tate AL, Petit CJ. Older Age at Completion of Fontan Procedure Is Associated with Improved Percentage of Predicted Maximum Oxygen Uptake. Tex Heart Inst J., 2015 Aug: 42(4):333-40.

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Journal Pre-proof 27 - Gavotto A, Abassi H, Rola M et al. Factors associated with exercise capacity in patients with a systemic right ventricle. Int J Cardiol. 2019 Oct 1;292:230-235. 28 - Hjortdal VE, Emmertsen K, Stenbøg E et al. Effects of exercise and respiration on blood flow in total cavopulmonary connection: a real-time magnetic resonance flow study. Circulation, 2003 Sep: 108(10):1227-31. 29 - Van De Bruaene A, Claessen G, La Gerche A et al. Effect of respiration on cardiac filling at

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rest and during exercise in Fontan patients: A clinical and computational modeling study. Int J Cardiol Heart Vasc, 2015 Dec: 9:100–108.

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30 - Dimopoulos K, Okonko DO, Diller GP et al. Abnormal ventilatory response to exercise in

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adults with congenital heart disease relates to cyanosis and predicts survival. Circulation, 2006

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Jun: 113(24):2796-802.

31 - Pundi KN, Johnson JN, Dearani JA et al. 40-Year Follow-Up After the Fontan Operation:

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Long-Term Outcomes of 1,052 Patients. J Am Coll Cardiol, 2015 Oct: 66(15):1700-10.

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32 - King G, Ayer J, Celermajer D et al. Atrioventricular Valve Failure in Fontan Palliation. J Am

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Coll Cardiol, 2019 Feb: 73(7):810-822.

33 - Van De Bruaene A, Kutty S. The peculiar challenges of breathing and exercising with a Fontan circulation. Am J Physiol Heart Circ Physiol, 2019 Feb: 316(2):H311-H313. 34 - Menon SC, Dearani JA, Cetta F. Long-term outcome after atrioventricular valve surgery following modified Fontan operation. Cardiol Young, 2011 Feb: 21(1):83-8. 35 - Koyak Z, Harris L, de Groot JR, et al. Sudden cardiac death in adult congenital heart disease. Circulation. 2012 Oct 16;126(16):1944-54.

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Journal Pre-proof 36 - McCrindle BW, Williams RV, Mital S, et al. Physical activity levels in children and adolescents are reduced after the Fontan procedure, independent of exercise capacity, and are associated with lower perceived general health. Arch Dis Child. 2007 Jun;92(6):509-14. 37 - Rhodes J, Curran TJ, Camil L, et al. Sustained effects of cardiac rehabilitation in children with serious congenital heart disease. Pediatrics. 2006 Sep;118(3):e586-93. 38 - Wittekind S, Mays W, Gerdes Y, et al. A Novel Mechanism for Improved Exercise

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Performance in Pediatric Fontan Patients After Cardiac Rehabilitation. Pediatr Cardiol. 2018 Jun;39(5):1023-1030.

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39 - Cordina R, Celermajer DS, d'Udekem Y. Lower limb exercise generates pulsatile flow into

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the pulmonary vascular bed in the setting of the Fontan circulation. Cardiol Young. 2018

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May;28(5):732-733.

40 - Dua JS, Cooper AR, Fox KR, Graham Stuart A. Exercise training in adults with congenital

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heart disease: feasibility and benefits. Int J Cardiol. 2010 Jan 21;138(2):196-205.

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41 - Kodama Y, Koga K, Kuraoka A. Efficacy of Sports Club Activities on Exercise Tolerance

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Among Japanese Middle and High School Children and Adolescents After Fontan Procedure. Pediatr Cardiol, 2018 Oct: 39(7):1339-1345. 42 - Cordina R, du Plessis K, Tran D, d'Udekem Y. Super-Fontan: Is it possible? J Thorac Cardiovasc Surg. 2018 Mar;155(3):1192-1194. 43 - Navaratnam D, Fitzsimmons S, Grocott M, et al. Exercise-Induced Systemic Venous Hypertension in the Fontan Circulation. Am J Cardiol. 2016 May 15;117(10):1667-1671. 44 - Ohuchi H, Negishi J, Miike H, et al. Positive pediatric exercise capacity trajectory predicts better adult Fontan physiology rationale for early establishment of exercise habits. Int J Cardiol. 2019 Jan 1;274:80-87. 22

Journal Pre-proof Table 1 – Independent variables used for statistical analysis Clinical Variables Age (years) Sex (0=male,1=female) BMI (kg/m2) Age at Fontan procedure (years)

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Time since Fontan procedure (years)

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Serious comorbidities (0=no,1=yes)

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Pacemaker or antiarrhythmic agent (0=no,1=yes)

Leisure sports practice (0=no,1=yes)

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Exercise training practice (0=no,1=yes)

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Angiotensin-converting-enzyme inhibitors or angiotensin II receptor blockers (0=no,1=yes)

Weekly sports practice (hours)

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Blood tests

Ferritin

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Hemoglobin Hematocrit

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Competitive sports practice (0=no,1=yes)

Transferrin saturation Echocardiographic Variables AV significant regurgitation (0=no,1=yes) VA significant regurgitation (0=no,1=yes) VA stenosis (0=no,1=yes) Resting Pulmonary Function Test Measurements FVC (as percentage of predicted value)

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Journal Pre-proof FEV1 (as percentage of predicted value) CPET Cardiac Variables Peak HR (as percentage of predicted value) CPET Pulmonary Variables VE/VCO2 slope Breathing Reserve Baseline arterial O2 saturation

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Peak arterial O2 saturation

Legend: AV – atrioventricular, BMI – body mass index, FEV1 - forced expiratory volume till the

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first second, FVC – forced vital capacity, HR – heart rate, VA – ventricular-arterial, VE – minute

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ventilation.

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Journal Pre-proof Table 2 – Patient’s main diagnosis Number of patients n (%)

Tricuspid Atresia

11 (22.8%)

Unbalanced AVSD

7 (14.6%)

Double inlet left ventricle

7 (14.6%)

Double outlet right ventricle

7 (14.6%)

Pulmonary atresia + VSD

4 (8.3%)

Pulmonary atresia + intact septum

4 (8.3%)

Hypoplastic Left Heart

2 (4.2%)

Congenitally corrected transposition of the

2 (4.2%)

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great arteries

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Main diagnosis

4 (8.4%)

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Other

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Journal Pre-proof Table 3 – Cardiopulmonary exercise test (CPET) results CPET variable

Mean (SD, minimum - maximum)

Cardiac variables VO2 at VT

16.3 ml/min/kg (SD 3.4, min. 10.1 – max. 25.0) 37.6% (SD 9.4, min. 21.0 – max. 75.0)

Peak VO2

28.7 ml/min/kg (SD 6.0, min. 19.8 – max.

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47.5)

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Percent VO2 at VT

67.8% (SD 16.7, min. 42.0 – max. 119.0)

Peak O2 pulse

9.0 ml/beat (SD 3.9, min. 4.0 – max. 22.0)

Peak HR

165.6 bpm (SD 24.7, min. 113.0 – max. 210.0)

Respiratory variables

82.1% (SD 11.5, min. 55.0 – max. 104.0)

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Peak HR as a percentage of predicted

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Percent peak VO2

74.4% (SD 12.9, min. 46.0 – max. 107.0)

FEV1 as a percentage of predicted

77.7% (SD 13.4, min. 49.0 – max. 115.0)

MVV

95.9 L/min (SD 30.6, min. 54.0 – max. 177.0)

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FVC as a percentage of predicted

Baseline O2 saturation

96.0% (SD 3.4, min. 84.0 – max. 100.0)

Peak O2 saturation

87.1% (SD 7.6, min. 62.0 – max. 98.0)

VE/VCO2 slope

36.6 (SD 7.0, min. 24.3 – max. 66.0)

VE

60.4 L/min (SD 19.8, min. 32.0 – max. 101.0)

Breathing reserve

33.9% (SD 15.5, min. 0.0 – max. 66.0)

Legend: FEV1 - forced expiratory volume at the first second, FVC – forced vital capacity, HR – heart rate, MVV – maximal voluntary ventilation, VE – minute ventilation, VT – ventilatory threshold. 26

Journal Pre-proof Table 4 – Statistical analysis results for predictors of functional capacity in Fontan circulation Univariate analysis Peak VO2 (n=45)

p-value

p-value

Age

0.003

0.005

Exercise training

0.001

0.001

Leisure sports

0.050

-

Competitive sports

0.032

Weekly sports practice

<0.001

AV valve regurgitation

0.034

Pacemaker or

0.014

0.049

Peak HR

-

Baseline O2 saturation

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0.014 0.042

0.025 0.013

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Multivariate analysis

<0.001

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FVC

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antiarrhythmic agents

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VO2 at VT (n=48)

VO2 at VT (n=48, r2 = 0.37)

Peak VO2 (n=45, r2 = 0.25)

Regression

p-

Regression

p-

coefficient (95% CI)

value

coefficient (95% CI)

value

Weekly sports practice

2.87 (1.57 to 4.17)

<0.001

4.95 (2.45 to 7.46)

<0.001

Pacemaker or

-6.24 (-11.49 to -0.99)

0.021

-

-

antiarrhythmic agents

Table 4 - Statistical analysis results for predictors of functional capacity in Fontan circulation. Only the variables with statistical significance (p-value < 0.05) are shown. Other independent 27

Journal Pre-proof variables used for statistical analysis are shown on table 1. Legend: AV – atrioventricular, FVC –

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forced vital capacity, HR – heart rate.

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Journal Pre-proof Highlights 1- Sports practice significantly impacts functional capacity in Fontan patients. 2- Clinicians should actively prescribe and promote exercise in this population. 3- AV regurgitation, among other factors, also appears to impact exercise capacity.

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4- Age at Fontan had no association with functional capacity in this group.

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