Physical activity is associated with better vascular function in children and adolescents with congenital heart disease

Journal Pre-proof Physical activity is associated with better vascular function in children and adolescents with congenital heart disease Jimmy Lopez, BHK, Christine Voss, PhD, Mimi Kuan, BSc, Nicole Hemphill, BSc, George Sandor, MB ChB, Kevin C. Harris, MD MHSc PII:

S0828-282X(19)31545-4

DOI:

https://doi.org/10.1016/j.cjca.2019.12.019

Reference:

CJCA 3567

To appear in:

Canadian Journal of Cardiology

Received Date: 18 August 2019 Revised Date:

13 December 2019

Accepted Date: 22 December 2019

Please cite this article as: Lopez J, Voss C, Kuan M, Hemphill N, Sandor G, Harris KC, Physical activity is associated with better vascular function in children and adolescents with congenital heart disease, Canadian Journal of Cardiology (2020), doi: https://doi.org/10.1016/j.cjca.2019.12.019. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the Canadian Cardiovascular Society.

TITLE PAGE

Physical activity is associated with better vascular function in children and adolescents with congenital heart disease

Jimmy Lopez*, BHK; Christine Voss*, PhD; Mimi Kuan, BSc; Nicole Hemphill, BSc; George Sandor, MB ChB; Kevin C Harris, MD MHSc *authors contributed equally

Affiliations (all authors): Division of Cardiology, Department of Paediatrics, British Columbia Children’s Hospital, 4480 Oak Street, Vancouver, BC, Canada V6H 3V4

Correspondence:

Kevin Harris, MD MHSc Children’s Heart Centre, BC Children’s Hospital 1F3 - 4480 Oak Street, Vancouver, BC, Canada V6H 3V4 T | +1 604 875 2345 E | [email protected] Total word count:

6,040

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BRIEF SUMMARY In this cross-sectional cohort study, we demonstrate a statistically significant inverse association between aortic stiffness and physical activity levels in children and adolescents with moderateto-severe congential heart disease (Tetralogy of Fallot, Coarctation of the Aorta, Transposition of the Great Arteries and Fontan circulation). These findings suggest that promoting physical activity should be a high priority in the care of children and adolescents with congenital heart disease.

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ABSTRACT Background: Aortic stiffness is an important marker of cardiovascular risk and is elevated in children and adolescents with congenital heart disease (CHD) compared to healthy children; however, in children with CHD, little is known about the interaction between aortic stiffness and physical activity - a key determinant of aortic stiffness. Methods: For this cross-sectional cohort study, we recruited children and adolescents aged 9-16 years with moderate-to-complex CHD from BC Children’s Hospital and travelling partnership clinics across the province of British Columbia and the Yukon territory. Mean daily minutes of moderate-to-vigorous physical activity was objectively assessed using an ActiGraph accelerometer worn over the right hip during waking hours for 7 days. Aortic pulse wave velocity (cm/s) was measured using standard 2-dimensional echocardiography and Doppler ultrasound. Results: Participants (n=104, 61% male; 85% consent rate) had a mean (SD) age of 12.4 (2.4) years. Daily moderate-to-vigorous physical activity was 46.7 (20.0) minutes/day, with 25% meeting guidelines of ≥60 minutes of moderate-to-vigorous physical activity per day. Mean (SD) aortic pulse wave velocity was 490.5 (161.9) cm/s, which was not significantly different between cardiac diagnoses. Higher levels of moderate-to-vigorous physical activity were associated with lower aortic pulse wave velocity (r=-0.226, p=0.021). Conclusion: In children and adolescents with CHD, higher levels of physical activity are associated with better vascular function. Given this association, promoting physical activity should be a high priority in the care of children and adolescents with CHD.

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INTRODUCTION Congenital heart disease (CHD) occurs in approximately 1% of all live births.1 Advances in medical interventions and surgical techniques have resulted in reduced morbidity and mortality2 leading to a growing adolescent and adult CHD population with near normal life expectancies.3 However, children with CHD are at an increased cardiovascular risk, thus clinical care aims to prevent the onset of secondary cardiovascular complications often seen in adulthood.2 Aortic stiffness, measured via pulse-wave velocity (PWV), is a useful indicator of vascular function4 and is a strong predictor of cardiovascular morbidity and mortality, as well as all-cause mortality.5 Although aortic PWV gradually increases in children starting at a young age,6 our group has previously shown that children and adolescents with certain types of CHD already have elevated PWV compared to healthy children.7,8 Since cardiovascular risk factors, including vascular dysfunction, track from childhood to adulthood,9,10 it is particularly important to optimize modifiable risk factors early in life. Physical activity, defined as any bodily movement that results in energy expenditure,11 is important for optimal health and can contribute to improving cardiovascular and metabolic profiles in childhood.12 Current evidence-based guidelines emphasize moderate-to-vigorous physical activity (≥3 metabolic equivalent) of at least 60 minutes per day for typical children, primarily in the form of aerobic activities.12-14 However, inadequate physical activity levels in children and adolescents has become a global concern,15 and similarly, children with CHD do not typically meet physical activity guidelines.16 There are no large studies that have evaluated the association between physical activity and aortic stiffness in children and adolescents with CHD. Thus, the aim of this study was to determine whether there is an association between aortic stiffness and objectively measured physical activity levels in children and adolescents with moderate to complex CHD. 4

METHODS Sample and Protocol Patients were recruited between April 2017 and January 2019 from British Columbia (BC) Children’s Hospital and travelling partnership clinics across the province of BC and the Yukon territory during routine clinical visits. We serve as the only pediatric cardiac referral center for this large geographic region of ~540,780 mi2, and catchment population of ~4.7 million. Ethics approval was obtained from the University of British Columbia Children and Women’s Health Centre’s Clinical Research Ethics Board and signed parental consent and participant assent were obtained. Children and adolescents aged 9-16 years were invited to participate in the study if they had one of the following diagnoses: Tetralogy of Fallot (TET), Coarctation of the Aorta (COA) Transposition of the Great Arteries (TGA) or Fontan circulation (FON). Participants were excluded if they had health conditions that would prevent them from completing the study measures or participating in physical activity. Participant Characteristics Participant sex, age and cardiac diagnosis were obtained from medical records. Trained clinical staff measured height (0.1cm), body weight (0.1kg), and resting blood pressure (mmHg). Body mass index (BMI; kg/m2) was calculated and expressed as age- and sex-specific percentiles based on World Health Organization international growth charts.17 BMI was categorized into ‘thinness’, ‘normal weight’, ‘overweight’ and ‘obese’ based on International Obesity Task Force cut-offs.18 Systolic and diastolic blood pressure was expressed as age-, sex- and height-specific percentiles based on the American Academy of Pediatrics Clinical Practice Guideline.19 Any formal documented physical activity restrictions were noted in the chart review process. 5

Participants’ primary residence were geocoded and spatially linked to area-level characteristics such as median household income, population density and type of population center (ArcGIS, v. 10.6, Esri Inc., CA); area-level data were from the Canadian Census 2016 at the ‘Dissemination Area’ level (Census geography with the smallest geographic area and ~400-700 people). Aortic stiffness: aortic pulse wave velocity Aortic PWV was obtained using standard 2-dimensional echocardiography and Doppler ultrasound. Ascending and descending aortic Doppler tracings were obtained with the sample volume taken in the proximal and distal aortic arch within 10 seconds of each other, and the aortic arch length was measured between these two points.7,8,20 We used EchoPAC software v201 (GE Healthcare, Horten, Norway) to calculate transit time from the onset of the Doppler envelope in the ascending aorta to the onset of the Doppler envelope in the descending aorta. PWV was calculated by dividing the length of the arch by the transit time and was averaged over a minimum of 6 cardiac cycles. Our group has previously demonstrated acceptable inter-observer reliability in children with congenital and non-congenital heart disease (with interobserver differences of 4%8 and 10%21, respectively). Physical activity: accelerometry Participants were fitted with ActiGraph accelerometers (GT3X+ or GT9X; ActiGraph LLC, Pensacola, FL) to objectively measure habitual physical activity levels. Devices were worn on the right hip for seven consecutive days, except during water-based activity (including showering) and sleep. We used ActiLife v.6.13.2 (ActiGraph LLC, Pensacola, FL) to initialize (sampling set at 30Hz), download and analyze files. Raw files were reintegrated to 15 second epoch .agd files from raw .gt3x files for analyses. As per widely used data processing criteria in 6

population-based studies (e.g. Canadian Health Measures Survey22; National Health and Nutrition Examination Survey23), data were valid if the device was worn for ≥4 days with ≥600 minutes/day, allowing up to 60 minutes of ≤2 minutes of ‘zero’ acceleration which would indicate reasonable sedentary periods and not non-wear of the device. Mean daily minutes spent in moderate-to-vigorous physical activity was calculated using Evenson cut points (≥2296 axis 1 counts per minute).24 Participants were categorized as meeting physical activity guidelines if they achieved ≥60 minutes of moderate-to-vigorous physical activity per day, on average. Physical activity: questionnaire Participants completed the Physical Activity Questionnaire for Children (PAQ-C; 9-12 yrs) or Adolescents (PAQ-A; 13-16 yrs).25 This 7-day self-reported recall questionnaire assesses general levels of physical activity and frequency of participation in different types of sports and activities throughout the week; it is scored between 1 (low physical activity) and 5 (high physical activity) based on 8 (PAQ-A) or 9 (PAQ-C) questionnaire items. We previously demonstrated the validity of this questionnaire for use in children and adolescents with CHD.26 To gain additional insight into physical activity behaviors and how they may relate to aortic stiffness in our cohort, we identified the most common sports/activities from the PAQ and grouped responses into whether or not participants had participated ≥1 times in the past 7 days. Statistical analysis Descriptive summary statistics were calculated as frequencies (%), mean (standard deviation, SD) or median (interquartile range, IQR) for the overall cohort and stratified by CHD diagnoses. Distributions of continuous variables were assessed by visual inspection of histograms and scatter plots. Between-group differences were assessed via independent tests or 7

one-way ANOVA (post hoc Bonferroni correction) for continuous variables or via chi-square tests for categorical variables. Associations between PWV and potential explanatory variables were assessed using Pearson correlations and multiple linear regression. Statistical analyses were performed using Stata/IC version 14.0 (StataCorp LP, College Station, TX) and significance set at p<0.05. RESULTS Cohort characteristics One hundred and forty-nine individuals were recruited to the study (85% consent rate) and we included 104 participants (mean (SD) 12.4 (2.4) yrs, 61% males) with complete and valid echocardiography and accelerometry data in the current analysis. Exclusions were primarily due to incomplete echocardiographic data with PWV (minimum 6 cycles; n=39) or children not meeting accelerometry wear time inclusion criteria (≥3 days with ≥600 minutes wear time; n=6). There were no significant differences between included and excluded participants in terms of sex, diagnosis and daily minutes of moderate-to-vigorous physical activity (where such data were available). Study participants resided across nearly all Census Divisions in BC and the Yukon and at a rate that is broadly in accordance with the distribution of similarly aged individuals across BC and the Yukon (Figure 1). Participant characteristics are shown in Table 1. Characteristics were similar between diagnoses (Table 1), and did not differ significantly by sex (not shown). Using International Obesity Task Force Criteria to define weight status, prevalence of thinness was greater when compared with Canadian data (20 vs. 1.6%), and fewer were overweight (13 vs. 16.4%) or obese (4 vs. 8.4%).27 Median area-level household income was C$82,140 (23,293), which was higher than the median income for the province of BC overall 8

(C$69,995) but lower than that of BC households comprised of a couple with children (C$109,553).28 The majority of participants identified as Caucasian/European Origin (64 vs. 65% in BC); compared with BC, fewer participants identified as Asian (South-, East- or Southeast: 16 vs. ~23%), but more identified to be at least in part of aboriginal origin (14 vs. 6%).29 Physical activity levels Participants wore the accelerometer on average for 13.3±1.6 hours per day for 6±1 days, which is comparable to wear time parameters typically reported for this age group, including participants in the nationally representative Canadian Health Measures Survey.22 Mean (SD) moderate-to-vigorous physical activity was 46.7 (20) minutes per day, with 25% meeting physical activity guidelines of achieving 60 minutes of moderate-to-vigorous physical activity per day on average. This was only slightly lower than Canadian national data, where 6-17 yearolds achieve on average 55 minutes of moderate-to-vigorous physical activity per day and 33% meet guidelines.22 There was a significant main effect for diagnosis, with individuals with TGA and COA being more active than other groups (see Table 1). Overall boys were significantly more active than girls (mean (SD) 50.2 (9.6) vs. 41.3 (20.1) minutes per day, p=0.027). Meeting guidelines was significantly more common among individuals with COA and TGA (see Table 1). Physical activity questionnaire scores were not significantly different between diagnoses, but tended to follow similar patterns to accelerometry-derived values. Overall, only 6% (n=6) of participants had documented physical activity restriction to avoid intense isometric activity (i.e. weight lifting); almost all of these participants had COA (n=5), and one FON. These specific physical activity restrictions did not significantly impact overall physical activity levels (accelerometry- or questionnaire-based). Among our cohort, the most commonly self-reported 9

activities (at least once per week) were: running (87%), walking (83%), soccer (43%) and basketball (43%). Participation was no different according to cardiac diagnosis, and while more boys tended to participate than girls, this difference was significant only for soccer (56 vs 21%, p=0.001). Accelerometry-derived daily minutes of MPVA were higher only in runners vs. nonrunners (mean (SD) 50 (19) vs 33 (24) min/d, p=0.007); otherwise, no significant differences were observed in objectively measured physical activity according to participation in these common activities. Aortic stiffness and associations with physical activity Overall mean (SD) values for aortic PWV was 490.5 (161.9) cm/s. There was a significant main effect for diagnosis (Table 1); individuals with FON tended to have the highest values, but this was not statistically significant after Bonferroni-correction for multiple comparisons. Both systolic and diastolic blood pressure percentiles were positively associated with aortic PWV (r=0.232, p=0.023; and r=0.257, p=0.012; respectively). Aortic PWV was not significantly different by sex or documented activity restrictions, and was not related to age or BMI percentile. Aortic PWV was also no different according to whether participants reported to engage in commonly reported activities (running, walking, soccer and basketball). Accelerometry-derived minutes of moderate-to-vigorous physical activity, however, was significantly and inversely associated with aortic PWV (r= -0.226, p=0.021; Figure 2). Regression analyses identified that moderate-to-vigorous physical activity explained approximately 5% of the variance in aortic PWV, and for every additional minute of moderateto-vigorous physical per day, aortic PWV was lower by 1.8 cm/s. (β=-1.81, 95% confidence interval -3.34 – -0.28; Table 2, Model 1). This association was unchanged if the regression model was adjusted for sex, age and BMI percentile (Table 2, Model 2). 10

DISCUSSION We demonstrate a meaningful inverse association between physical activity and aortic stiffness in a large cohort of children and adolescents with moderate-to-complex CHD. This is an important clinical finding as physical activity is potentially modifiable and its promotion may optimize vascular health in this population. Aortic stiffness is particularly important because of ventricular vascular coupling and the fact that it is an established surrogate marker for cardiovascular events later in life.30 To date, the important role of physical activity for vascular health in individuals with CHD has been scarcely studied. Our findings build on a small pilot study of 17 children with CHD, which found a negative association between arterial stiffness and physical activity.31 Importantly, our findings align with what has been reported for healthy32 and obese children,33 lending further credence to the notion that physical activity is a potentially modifiable behavior that is associated with vascular health. Longitudinal and interventional studies are needed to confirm whether modifying physical activity can improve vascular function and characterize the dose-response relationship between physical activity and vascular function in children with CHD. This may better inform physical activity guidelines for children and adolescents with CHD to optimize long-term health in this special population. Physical activity behaviors in children and adolescents with CHD There are conflicting reports as to whether children with CHD achieve similar levels of moderate-to-vigorous physical activity compared with their healthy peers.16,34-38 Our current cohort had slightly lower levels of moderate-to-vigorous physical activity compared with the general Canadian population22 (47 vs. 55 minutes per day), which are both below the 11

recommended guidelines of 60 minutes per day. While there were no dramatic differences in activity levels between representative national data and our cohort overall, we observed that both FON and TET groups achieved significantly lower levels of activity compared to COA and TGA. This finding is not particularly surprising given the underlying physiology of children with single ventricle physiology or tetralogy repair with residual pulmonary insufficiency. Previous research has shown that children with Fontan physiology and children that have undergone Tetralogy repair have reduced exercise capacity compared to healthy children,39,40 and while this may not limit them from many forms of physical activity, these children may be socially isolated from participating in group activities or sports which can be an important contributor to moderate-to-vigorous physical activity.41These data are important when considering how best to promote physical activity in these particular CHD groups. The new Canadian 24-hour movement guidelines focus on a lifestyle approach that promotes light physical activity, reduced sedentary behaviors including limited screen time, and adequate sleep time, in addition to achieving the recommended minimum of 60 minutes of moderate-to-vigorous physical activity per day.13 The emphasis on the day as a whole in these new guidelines aims to support the establishment of healthy behaviors at a young age, which is important as physical activity levels track from childhood to adulthood.42 In our study, data from the physical activity questionnaires identified that walking, running, soccer and basketball were the most common activities in our cohort. Such activities do not necessitate organized structure and are achievable through recreational free-play, including during school break. In the minority of children in whom there are exercise restrictions due to their heart condition, it is most common that they are instructed to avoid isometric exercise by their cardiologist (eg. left ventricular outflow tract obstruction, hypertrophic cardiomyopathy, aortopathy).43 Even in 12

patients in whom isometric activities may be restricted, dynamic activities of low-to-moderate intensity can have important health benefits. Other markers of vascular function The endothelium is a key modulator of vascular function44 and it serves as a predictor of future cardiovascular events.45 Impaired endothelial function is known to precede the development of atherosclerosis46 and can coincide with aortic stiffness. It is most commonly evaluated non-invasively using flow mediated dilatation (FMD).47,48 Case-control studies have shown reduced FMD in children with CHD,49 specifically among the Tetralogy of Fallot50 and Fontan51 populations, when compared to healthy controls. Given that CHD clearly confers longterm cardiovascular risk, it is important to identify modifiable risk factors that can be optimized early in life. In children and young adults, well established risk factors associated with atherosclerosis are elevated body mass index, blood pressure and cholesterol.52 It is important to address modifiable risk factors in this high risk population. Physical activity has been associated with better vascular function in those with a Fontan circulation.53 Physical activity or exercise interventions may positively affect cardiovascular risk profile in adolescents with CHD. Interventions have been successful in improving the cardiovascular risk profile in healthy children54 and children with type one diabetes.55 Similar results have also been observed in a meta-analysis among obese children, after participating in an exercise program for a minimum of six weeks.56 However, there is a paucity of data on physical activity or exercise interventions and vascular function in the CHD population. The optimal specific vascular outcome measures have not been defined for children with CHD. In adults, both endothelial function and PWV are similarly associated with coronary events.57 We continue to favour PWV 13

given that it can easily be obtained using echocardiography at the time of routine clinic assessments. Clinical significance The negative association between physical activity and aortic stiffness indicates this is a potential key modifiable risk factor in a population that is known to be at increased cardiovascular risk. Obtaining a physical activity history and promoting physical activity should be a central component of every patient encounter for pediatric cardiologists. It is important to consider the entire family when evaluating physical activity, as patterns of activity may be influenced by parents or siblings.58 While historically the emphasis on activity restrictions evolved from the time of the initial Bethesda guidelines,59 this focus on competitive athletics and the associated fear of risk has contributed to a broad culture of physical activity concern and avoidance in CHD that was unintended. Changing the paradigm in pediatric cardiology to one of physical activity promotion, in a safe and inclusive manner, is the challenge we face in the current era. A recent statement from the AHA identified physical activity counselling as a priority for such at risk patients.60 It is incumbent upon pediatric cardiologists to avail themselves of current physical activity guidelines and initiate discussions around physical activity with all patients. With so few children meeting current guidelines it is imperative that we incorporate physical activity histories and plans into routine patient encounters as opposed to only considering it in those patients who have contraindications to certain activities due to their cardiac condition.

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Strengths and limitations We note several important strengths of the current study. Our overall recruitment success rate of 85% suggests that participation or selection bias - whereby active children would be overrepresented in the study group - unlikely to be a serious threat to the validity of the current study. It is of note that our recruitment success rate is much higher than for example the ~40% reported for the nationally representative Canadian Health Measures Survey.22 Our cohort was recruited through the only pediatric cardiac referral center for BC and the Yukon, and combined with our excellent recruitment success rate (85%), our cohort is representative of children and adolescents with moderate-to-complex CHD from this large geographic region (~540,380 mi2 with a population of ~4.7 million). Our technique to localize PWV measures within the central aorta eliminates variability observed in alternative methodologies30 and potentially establishes vascular changes in the aortic arch alone as a fundamental marker of cardiovascular risk. The sample size of our population did not permit additional subgroup analyses based on specific anatomic variants of each condition or of the various surgical approaches that have been used. Aortic PWV is an important measure and is relatively simple to integrate during clinic visits with minimal disruption to patient care. Physical activity was measured objectively and according to conventional data collection and data processing protocols, thus allowing for comparisons of our physical activity data with other studies and normative data. However, we take heed of some limitations. When using acceleromters to measure physical activity, it is of note that certain physical activities are either not at all captured (e.g. swimming, devices not worn) or inadequately captured (e.g. cycling and other gliding motions); however, given the relatively small contribution of these specific activities to an individual’s overall physical activity levels acrued during an entire day’s waking hours, this is an acceptable limitation. Importantly, the 15

cross-sectional study design precludes us from describing the association between physical activity and aortic stiffness as causal. Longitudinal or interventional studies are needed to identify if, how, and at what dose physical activity causes improvements in vascular health in children and adolescents with CHD. CONCLUSION Children with CHD who engage in greater levels of moderate-to-vigorous physical activity have lower aortic stiffness. Our study further supports the importance of physical activity engagement in early childhood to optimize cardiovascular health and may act as a modifiable risk factor in future interventional studies.

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ACKNOWLEDGEMENTS We are appreciative of all the participants and their families who volunteered their time to participate in this research study. We thank the ultrasound technicians, nurses and administrative staff at the Children’s Heart Centre and travelling partnership clinics for their continued support. The authors declare no conflict of interest. FUNDING SOURCES We received funding from the Heart and Stroke Foundation of Canada. DISCLOSURES None.

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REFERENCES 1. van der Linde D, Konings EE, Slager MA, et al. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol. 2011; 58:2241-7. 2. Bouma BJ, Mulder BJ. Changing Landscape of Congenital Heart Disease. Circ Res. 2017; 120:908-22. 3. Marelli AJ, Mackie AS, Ionescu-Ittu R, Rahme E, Pilote L. Congenital heart disease in the general population: changing prevalence and age distribution. Circulation. 2007; 115:16372. 4. Laurent S, Cockcroft J, Van Bortel L, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J. 2006; 27:2588-605. 5. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and allcause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol. 2010; 55:1318-27. 6. Voges I, Jerosch-Herold M, Hedderich J, et al. Normal values of aortic dimensions, distensibility, and pulse wave velocity in children and young adults: a cross-sectional study. J Cardiovasc Magn Reson. 2012; 14:77. 7. Mivelaz Y, Leung MT, Zadorsky MT, et al. Noninvasive Assessment of Vascular Function in Postoperative Cardiovascular Disease (Coarctation of the Aorta, Tetralogy of Fallot, and Transposition of the Great Arteries). Am J Cardiol. 2016; 118:597-602. 8. Myers KA, Leung MT, Terri Potts M, Potts JE, Sandor GG. Noninvasive assessment of vascular function and hydraulic power and efficiency in pediatric Fontan patients. J Am Soc Echocardiogr. 2013; 26:1221-7. 9. Li S, Chen W, Srinivasan SR, et al. Childhood cardiovascular risk factors and carotid vascular changes in adulthood: the Bogalusa Heart Study. JAMA. 2003; 290:2271-6. 10. Raitakari OT, Juonala M, Kahonen M, et al. Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study. JAMA. 2003; 290:2277-83. 11. Caspersen CJ, Powell KE, Christenson GM. Physical activity, exercise, and physical fitness: definitions and distinctions for health-related research. Public Health Rep. 1985; 100:12631. 12. Janssen I, Leblanc AG. Systematic review of the health benefits of physical activity and fitness in school-aged children and youth. Int J Behav Nutr Phys Act. 2010; 7:40. 13. Canadian Society for Exercise Physiology. 24-Hour Movement Guidelines for Children and Youth. Available at: 18

http://www.csep.ca/CMFiles/Guidelines/24hrGlines/Canadian24HourMovementGuidelines2 016.pdf. Accessed on July 12, 2019. 14. World Health Organization. Global Recommendations of Physical Activity for Health - 5-17 years old. Available at: http://www.who.int/dietphysicalactivity/physical-activityrecommendations-5-17years.pdf?ua=1. Accessed on July 12, 2019. 15. Aubert S, Barnes JD, Abdeta C, et al. Global Matrix 3.0 Physical Activity Report Card Grades for Children and Youth: Results and Analysis From 49 Countries. J Phys Act Health. 2018; 15:S251-S73. 16. Voss C, Duncombe SL, Dean PH, de Souza AM, Harris KC. Physical Activity and Sedentary Behavior in Children With Congenital Heart Disease. J Am Heart Assoc. 2017; 6:e004665. 17. de Onis M, Onyango AW, Borghi E, et al. Development of a WHO growth reference for school-aged children and adolescents. Bull World Health Organ. 2007; 85:660-7. 18. Cole TJ, Bellizzi MC, Flegal KM, Dietz WH. Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ. 2000; 320:1240-3. 19. Flynn JT, Kaelber DC, Baker-Smith CM, et al. Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents. Pediatrics. 2017; 140 20. Sandor GG, Hishitani T, Petty RE, et al. A novel Doppler echocardiographic method of measuring the biophysical properties of the aorta in pediatric patients. J Am Soc Echocardiogr. 2003; 16:745-50. 21. Bradley TJ, Potts JE, Potts MT, DeSouza AM, Sandor GG. Echocardiographic Doppler assessment of the biophysical properties of the aorta in pediatric patients with the Marfan syndrome. Am J Cardiol. 2005; 96:1317-21. 22. Colley RC, Carson V, Garriguet D, et al. Physical activity of Canadian children and youth, 2007 to 2015. Health Rep. 2017; 28:8-16. 23. Troiano RP, Berrigan D, Dodd KW, et al. Physical activity in the United States measured by accelerometer. Med Sci Sports Exerc. 2008; 40:181-8. 24. Evenson KR, Catellier DJ, Gill K, Ondrak KS, McMurray RG. Calibration of two objective measures of physical activity for children. J Sports Sci. 2008; 26:1557-65. 25. Kowalski KC, Crocker RE, Donen RM. The Physical Activity Questionnaire for Older Children (PAC-C) and Adolescents (PAQ-A) Manual. Saskatoon, Canada: University of Saskatchewan; 2004. 26. Voss C, Dean PH, Gardner RF, Duncombe SL, Harris KC. Validity and reliability of the Physical Activity Questionnaire for Children (PAQ-C) and Adolescents (PAQ-A) in individuals with congenital heart disease. PLoS One. 2017; 12:e0175806. 19

27. Roberts KC, Shields M, de Groh M, Aziz A, Gilbert JA. Overweight and obesity in children and adolescents: results from the 2009 to 2011 Canadian Health Measures Survey. Health Rep. 2012; 23:37-41. 28. Statistics Canada. Income Highlight Tables, 2016 Census. Available at: https://www12.statcan.gc.ca/census-recensement/2016/dp-pd/hlt-fst/increv/Table.cfm?Lang=Eng&S=99&O=A&RPP=25. Accessed on July 19, 2019. 29. Statistics Canada. 2016 Census of Population, Immigration and ethnocultural diversity. Available at: https://www12.statcan.gc.ca/census-recensement/2016/dp-pd/dt-td/Rpeng.cfm?TABID=2&LANG=E&APATH=3&DETAIL=0&DIM=0&FL=A&FREE=0&GC =0&GK=0&GRP=1&PID=110528&PRID=10&PTYPE=109445&S=0&SHOWALL=0&S UB=0&Temporal=2017&THEME=120&VID=0&VNAMEE=&VNAMEF=. Accessed on July 19, 2019. 30. Cavalcante JL, Lima JA, Redheuil A, Al-Mallah MH. Aortic stiffness: current understanding and future directions. J Am Coll Cardiol. 2011; 57:1511-22. 31. Boyes NG, Stickland MK, Fusnik S, et al. Physical activity modulates arterial stiffness in children with congenital heart disease: A CHAMPS cohort study. Congenit Heart Dis. 2018; 13:578-83. 32. Proudfoot NA, King-Dowling S, Cairney J, et al. Physical Activity and Trajectories of Cardiovascular Health Indicators During Early Childhood. Pediatrics. 2019; 144 33. Farpour-Lambert NJ, Aggoun Y, Marchand LM, et al. Physical activity reduces systemic blood pressure and improves early markers of atherosclerosis in pre-pubertal obese children. J Am Coll Cardiol. 2009; 54:2396-406. 34. Ewalt LA, Danduran MJ, Strath SJ, Moerchen V, Swartz AM. Objectively assessed physical activity and sedentary behaviour does not differ between children and adolescents with and without a congenital heart defect: a pilot examination. Cardiol Young. 2012; 22:34-41. 35. Massin MM, Hovels-Gurich HH, Gerard P, Seghaye MC. Physical activity patterns of children after neonatal arterial switch operation. Ann Thorac Surg. 2006; 81:665-70. 36. Kao CC, Chang PC, Chiu CW, Wu LP, Tsai JC. Physical activity levels of school-age children with congenital heart disease in Taiwan. Appl Nurs Res. 2009; 22:191-7. 37. Stone N, Obeid J, Dillenburg R, et al. Objectively measured physical activity levels of young children with congenital heart disease. Cardiol Young. 2015; 25:520-5. 38. 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; 92:509-14. 39. Kotby AA, Elnabawy HM, El-Guindy WM, Abd Elaziz RF. Assessment of exercise testing after repair of tetralogy of fallot. ISRN Pediatr. 2012; 2012:324306. 20

40. Troutman WB, Barstow TJ, Galindo AJ, Cooper DM. Abnormal dynamic cardiorespiratory responses to exercise in pediatric patients after Fontan procedure. J Am Coll Cardiol. 1998; 31:668-73. 41. Knowles RL, Tadic V, Hogan A, et al. Self-Reported Health Experiences of Children Living with Congenital Heart Defects: Including Patient-Reported Outcomes in a National Cohort Study. PLoS One. 2016; 11:e0159326. 42. Telama R. Tracking of physical activity from childhood to adulthood: a review. Obes Facts. 2009; 2:187-95. 43. Longmuir PE, Brothers JA, de Ferranti SD, et al. Promotion of physical activity for children and adults with congenital heart disease: a scientific statement from the American Heart Association. Circulation. 2013; 127:2147-59. 44. Stary HC. Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adults. Arteriosclerosis. 1989; 9:I19-32. 45. Matsuzawa Y, Kwon TG, Lennon RJ, Lerman LO, Lerman A. Prognostic Value of FlowMediated Vasodilation in Brachial Artery and Fingertip Artery for Cardiovascular Events: A Systematic Review and Meta-Analysis. J Am Heart Assoc. 2015; 4 46. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993; 362:801-9. 47. Celermajer DS, Sorensen KE, Gooch VM, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992; 340:1111-5. 48. Flammer AJ, Anderson T, Celermajer DS, et al. The assessment of endothelial function: from research into clinical practice. Circulation. 2012; 126:753-67. 49. Sabri MR, Daryoushi H, Gharipour M. Endothelial function state following repair of cyanotic congenital heart diseases. Cardiol Young. 2015; 25:222-7. 50. de Groot PC, Thijssen D, Binkhorst M, et al. Vascular function in children with repaired tetralogy of Fallot. Am J Cardiol. 2010; 106:851-5. 51. Jin SM, Noh CI, Bae EJ, Choi JY, Yun YS. Impaired vascular function in patients with Fontan circulation. Int J Cardiol. 2007; 120:221-6. 52. Berenson GS, Srinivasan SR, Bao W, et al. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med. 1998; 338:1650-6. 53. Goldstein BH, Urbina EM, Khoury PR, et al. Endothelial Function and Arterial Stiffness Relate to Functional Outcomes in Adolescent and Young Adult Fontan Survivors. J Am Heart Assoc. 2016; 5 21

54. Mueller UM, Walther C, Adam J, et al. Endothelial Function in Children and Adolescents Is Mainly Influenced by Age, Sex and Physical Activity- An Analysis of Reactive Hyperemic Peripheral Artery Tonometry. Circ J. 2017; 81:717-25. 55. Seeger JP, Thijssen DH, Noordam K, et al. Exercise training improves physical fitness and vascular function in children with type 1 diabetes. Diabetes Obes Metab. 2011; 13:382-4. 56. Dias KA, Green DJ, Ingul CB, Pavey TG, Coombes JS. Exercise and Vascular Function in Child Obesity: A Meta-Analysis. Pediatrics. 2015; 136:e648-59. 57. Maruhashi T, Soga J, Fujimura N, et al. Endothelial Dysfunction, Increased Arterial Stiffness, and Cardiovascular Risk Prediction in Patients With Coronary Artery Disease: FMD-J (Flow-Mediated Dilation Japan) Study A. J Am Heart Assoc. 2018; 7 58. Bennett E, Faulkner G, Voss C, Harris K. From ‘it makes me feel free’ to ‘they won’t let me play’: The body and physical activity-related perceptions and experiences of children with congenital heart disease. Qual Res Sport Exerc Health. 2019:[in revision Oct 2019]. 59. Mitchell JH, Maron BJ, Epstein SE. 16th Bethesda Conference: Cardiovascular abnormalities in the athlete: recommendations regarding eligibility for competition. October 3-5, 1984. J Am Coll Cardiol. 1985; 6:1186-232. 60. de Ferranti SD, Steinberger J, Ameduri R, et al. Cardiovascular Risk Reduction in High-Risk Pediatric Patients: A Scientific Statement From the American Heart Association. Circulation. 2019; 139:e603-e34.

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Table 1. Sample characteristics, physical activity levels and aortic stiffness by cardiac diagnosis p-valueՓ

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Coarctation of the Aorta 32

Transposition of the Great Arteries 20

41 (39%)

11 (46%)

13 (41%)

6 (30%)

11 (39%)

0.759

Age, mean (SD), yrs

12.2 (2.4)

12.7 (2.4)

12.9 (2.2)

11.5 (2.5)

11.3 (2.1)

0.013†

Height, mean (SD), cm

149.3 (16.0)

148.1 (17.0)

154.8 (16.4)

149.6 (16.1)

143.8 (13.0)

0.063

Weight, mean (SD), kg

43.3 (15.4)

44.6 (14.8)

48.7 (17.3)

40.1 (13.8)

37.8 (13.1)

0.041†

BMI, mean (SD), %ile¶

51.8 (34.0)

56.1 (34.7)

56.0 (33.5)

45.2 (33.0)

48.2 (35.1)

0.589

Thinness No. (%)

21 (20%)

4 (17%)

6 (19%)

4 (20%)

7 (25%)

Normal weight No. (%)

65 (63%)

13 (54%)

22 (69%)

13 (65%)

17 (61%)

Overweight No. (%)

14 (13%)

4 (17%)

3 (9%)

3 (15%)

4 (14%)

All

Tetralogy of Fallot

No.

104

Female No. (%)

Fontan

(main effect)

28

BMI Weight Category

⸸

Obese No. (%)

4 (4%)

3 (13%)

1 (3%)

0 (0%)

0 (0%)

ǂ

52.5 (22.5-81.0)

41.5 (14.0-79.0)

54.0 (17.0-82.0)

64.0 (46.0-81.0)

57.5 (22.5-80.0)

0.325

ǂ

49.5 (33.0-73.5)

60.0 (38.0-76.0)

46.0 (73.0-26.0

44.0 (26.0-74.0)

59.0 (43.0-71.0)

0.313

35.0 (13.0)

52.6 (15.5)‡

61.7 (21.1)§

39.2 (20.9)

0.000

4 (14%)

0.000

SBP, median (IQR), %ile DBP, median (IQR),%ile Physical activity

0.515

MVPA, mean (SD), min/d 46.7 (20.2) #

26 (25%)

0 (0%)

11 (35%)

◊

2.72 (0.71)

2.63 (0.75)

2.62 (0.66)

3.12 (0.68)

2.60 (0.68)

0.051

526.7 (164.4)

421.7 (130.8)

491.9 (175.0)

537.0 (163.6)

0.023†

meet guidelines No. (%) PAQ, mean (SD), Score

Pulse Wave Velocity, mean 490.5 (161.9) (SD), cm/s

‡

11 (55%)

§

BMI – Body Mass Index (kg/m2), %ile – Percentile; SBP/DBP – Systolic-/Diastolic Blood Pressure (mmHg), MVPA – Moderate-to-Vigorous Physical Activity (min/day); PAQ – Physical Activity Questionnaire. Փ p-value for main effect for diagnosis † No significant Bonferroni-adjusted post hoc comparisons present between groups (p<0.008) ¶ BMI (kg/m2) percentiles calculated based on age-sex-specific World Health Organization 2007 reference charts17 ⸸ BMI weight category based on International Obesity Task Force cut-offs18 ǂ SBP and DBP percentiles calculated based on age-sex-specific American Academy of Pediatrics 2017 reference charts19 # Meeting physical activity guidelines is defined as mean daily minutes of moderate-to-vigorous physical activity per day of ≥60 minutes § Transposition of the Great Arteries significantly higher than Fontan and Tetralogy of Fallot (post-hoc Bonferroni; p<0.008) ‡ Coarctation of the Aorta significantly higher than Tetralogy of Fallot (post-hoc Bonferroni; p<0.008) ◊ Scored on a scale from 1 (no/low activity) to 5 (very active)25

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Table 2. Multiple linear regression analyses for pulse wave velocity and physical activity Model 1 DV: Pulse Wave Velocity, cm/s MVPA, min/d

β -1.810

Model 2 (adjusted) 95% CI -3.343 – -0.277

Age, yrs Sex (ref: male) BMI, %ile r2

¶

0.051

β -1.807

95% CI -3.420 – -0.194

-5.714

-19.016 – 7.589

14.185

-52.450 – 80.821

0.309

-0.633 – 1.251 0.064

DV – Depdendent Variable; 95% CI – 95% Confidence Interval; MVPA – Moderate-to-Vigorous Physical Activity (min/day); BMI – Body Mass Index (kg/m2), %ile – Percentile ¶

BMI (kg/m2) percentiles calculated based on age-sex-specific World Health Organization 2007 reference charts17

Model 1 – association between pulse moderate-to-vigorous physical activity and aortic pulse wave velocity; Model 2 – Model 1 adjusted for age, sex, and BMI percentile

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Figure 1. Distribution and density of children and adolescents residing across British Columbia and the Yukon Territory, Canada (panel A; Census 2016) and the distribution and density of our cohort across British Columbia and the Yukon Territory, Canada (panel B). 25

Figure 2. Association between aortic stiffness and physical activity. There was a significant inverse association between aortic pulse wave velocity and daily minutes of moderate-to-vigorous physical activity (β=-1.81, 95%CI -3.42 – -0.19); adjusted for sex, age and BMI percentile). There was no significant difference by sex; male and female symbology of observations is for illustration purposes only.

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