The impact of sleep disordered breathing on cardiovascular health in overweight children

Accepted Manuscript The impact of sleep disordered breathing on cardiovascular health in overweight children Rosemary SC. Horne, PhD, Genevieve Shandler, MBBS (Hons), Knarik Tamanyan, BSc (Hons), Aidan Weichard, BSc (Hons), Alexsandria Odoi, BNS (Hons), Sarah N. Biggs, PhD, Margot J. Davey, MBBS, Gillian M. Nixon, MD, Lisa M. Walter, PhD PII:

S1389-9457(17)30369-6

DOI:

10.1016/j.sleep.2017.09.012

Reference:

SLEEP 3515

To appear in:

Sleep Medicine

Received Date: 7 May 2017 Revised Date:

25 September 2017

Accepted Date: 27 September 2017

Please cite this article as: Horne RS, Shandler G, Tamanyan K, Weichard A, Odoi A, Biggs SN, Davey MJ, Nixon GM, Walter LM, The impact of sleep disordered breathing on cardiovascular health in overweight children, Sleep Medicine (2017), doi: 10.1016/j.sleep.2017.09.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 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.

ACCEPTED MANUSCRIPT

The impact of sleep disordered breathing on cardiovascular health in overweight

Abbreviated title: pediatric obstructive sleep apnea and obesity

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children.

Rosemary SC Horne PhD1, Genevieve Shandler MBBS (Hons)1, Knarik Tamanyan BSc

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(Hons)1, Aidan Weichard BSc (Hons) 1, Alexsandria Odoi BNS (Hons)1, Sarah N Biggs PhD1,

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Margot J Davey MBBS1,2, Gillian M Nixon MD1,2, Lisa M Walter PhD1

The Ritchie Centre, Department of Paediatrics, Monash University and Hudson Institute of

Medical Research, Melbourne, Australia.

Melbourne Children’s Sleep Centre, Monash Children’s Hospital, Melbourne, Australia.

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Address correspondence to:

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Professor Rosemary SC Horne, [email protected], The Ritchie Centre, Department of Paediatrics, Level 5 Monash Children’s Hospital, 246 Clayton Road, Victoria, Australia 3168; Telephone: +61 3 85722827, Fax: +61 3 9594 6811.

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ACCEPTED MANUSCRIPT Abstract Background: Up to 50% of overweight/obese children have obstructive sleep apnea (OSA) compared to up to 6% of normal weight children. We compared cardiovascular variables between normal weight and overweight/obese children with and without OSA, and controls.

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Methods: Seventy-four referred children and 24 normal weight non-snoring controls (8-18 years) were recruited. Referred children were grouped according to their obstructive apnea hypopnea index (OAHI): OSA (>1 event /h) or primary snoring (PS ≤1 event/h) and whether

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they were normal weight (BMI z-score <1.04) or overweight/obese (BMI z-score ≥ 1.04). Wake blood pressure and heart rate and pulse transit time (PTT, an inverse continuous

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surrogate measure of blood pressure) during sleep were recorded.

Results: Wake blood pressure was higher in the overweight/obese OSA group compared to the control, normal weight PS and overweight/obese PS groups (P<0.05 for all). During sleep, blood pressure and heart rate were elevated in the overweight/obese OSA group

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compared to non-snoring controls (p<0.05). More children who were overweight/obese had reduced blood pressure and heart rate dipping from wake to sleep compared to normal weight children. BMI z-score predicted heart rate and PTT when asleep and both age and BMI z-

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score predicted blood pressure when awake.

Conclusion: This study showed that BMI has both combined and independent effects on

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blood pressure and heart rate in children with OSA. We have previously shown that treatment of OSA reduces blood pressure and suggest that treatment of OSA in the growing number of overweight/obese children may improve cardiovascular outcomes.

Keywords: pediatric, sleep, blood pressure, heart rate, nocturnal dipping, heart rate variability, obstructive sleep apnea, primary snoring

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ACCEPTED MANUSCRIPT Introduction Childhood obesity has been described as “one of the most serious public health challenges of the 21st century” by the World Health Organization. The prevalence of childhood obesity has doubled in the last 30 years 1. In children aged 6-11 years the prevalence of obesity has

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increased from 7% to 18% and in adolescents 12-19 years from 5% to 18% between 1980 and 2010 2. Obesity in childhood is associated with both short- and long-term adverse health outcomes 3, one of these being obstructive sleep apnea (OSA). The prevalence of OSA in

and obesity

4-6

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obese children has been reported to be up to nearly 80% depending on the definition of OSA , compared to 5.7% in the general pediatric population 7. It has been reported

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that in children, every 1kg/m2 increase in BMI above the mean for age and sex increases the risk of developing OSA by 12% 8. Furthermore, the severity of OSA is increased in obese children compared to normal weight controls

9-11

. There are a number of factors which

interact to significantly increase the risk of OSA in obese children. Similar to findings in

children

12

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normal weight children, adenotonsillar hypertrophy is also a common cause of OSA in obese and OSA is more severe in obese children than in normal weight children who

have the same degree of adenotonsillar hypertrophy

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. Other factors such as altered

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neuromuscular tone resulting in greater collapsibility of the upper airway during sleep

14

,

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central adiposity, and an excess mechanical load on the chest wall interact to reduce functional residual capacity and tidal volumes resulting in increased work of breathing also play a role

15

. In fact, the visceral distribution of adipose tissue in children is predictive of

OSA severity, regardless of BMI 16. A number of studies in children, which included overweight and/or obese children but did not specifically control for BMI, have identified significant effects of OSA on the cardiovascular system, including elevated blood pressure and heart rate and impaired autonomic cardiovascular control (for review see 17). However, there have been few studies which have

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ACCEPTED MANUSCRIPT separated the cardiovascular effects of OSA and BMI. Studies which have co-varied for BMI and OSA severity have consistently shown that both BMI and OSA are associated with elevated blood pressure 18-23. A study by Leung et al., 24 found that obese children with more severe OSA had higher blood pressure than obese children with less severe OSA, suggesting

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that the effect of OSA on blood pressure may have a dose response effect in obese children. Recently, a study in obese children showed that those with and without metabolic syndrome showed a similar prevalence of sleep disordered breathing but that sleep disordered breathing

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severity increased some markers of the syndrome 25.

The mechanism linking OSA and impaired cardiovascular function is believed to be

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autonomic dysfunction (for review see 26). To date, there has been only one study in children which has examined this in obese children with and without OSA, and this study found increased sympathetic heart activity in the obese children with OSA 27. The independent cardiovascular consequences of OSA and obesity in children have been well

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studied, however to date there have been limited studies which have examined the separate and combined effects of these conditions. We therefore aimed to examine in children the relative contributions of OSA and being overweight or obese on blood pressure, heart rate

with

or

without

OSA,

and

overweight/obese

children

without

OSA,

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children

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and autonomic cardiovascular control. We hypothesized that compared to normal weight

overweight/obese children with OSA would have increased cardiovascular impairment including elevated blood pressure and heart rate and increased sympathetic activity.

Methods Ethical approval for this study was granted by the Monash Health and Monash University Human Research Ethics Committees. Written informed consent was obtained from parents and verbal assent from children.

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Subjects

Participants were children (aged 8-18 years) attending the Melbourne Children’s Sleep Centre for assessment of suspected OSA (n=74) and age-matched non-snoring children

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recruited from the community (n=24). All children were born at term and children with conditions such as neuromuscular diseases, craniofacial syndromes, genetic syndromes, Attention Deficit Hyperactivity Disorder or Autism Spectrum Disorder, or taking medications

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known to affect sleep, breathing, or blood pressure were not recruited. Children were otherwise healthy and not undergoing treatment with either nasal steroids or antibiotics on the

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day of the study or for the preceding two weeks. Protocol

All children underwent overnight polysomnography (PSG) using standard pediatric criteria 28

. Prior to the PSG study, height and weight were measured and converted to a body mass 29

. Obesity was defined as ≥ 95th percentile

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index (BMI) z-score to adjust for sex and age

(BMI z-scores ≥ 1.65) and overweight as ≥ 85th percentile (BMI z-scores ≥ 1.04) as computed by using Centers for Disease Control and Prevention 2000 growth standards

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http://www.cdc.gov/growthcharts and software (Epi Info [Centers for Disease Control and Prevention, Atlanta, GA]). Office BP was measured in triplicate during quiet wakefulness,

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sitting upright, using an electronic BP monitor (Dinamap V100, CARESCAPETM, Freiburg, Germany) with an appropriately sized cuff. Polysomnographic (PSG) study Electrophysiological signals were recorded using a commercially available PSG system (E-Series, Compumedics, Melbourne, Australia) using standard pediatric techniques-, full details have been previously published 30. In summary, electroencephalogram (EEG), left and right electrooculogram (EOG), submental electromyogram (EMG), left and right anterior

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ACCEPTED MANUSCRIPT tibialis muscle EMG and electrocardiogram (ECG), thoracic and abdominal breathing movements, transcutaneous carbon dioxide (TcCO2), nasal pressure, oronasal airflow, oxygen saturation (SpO2) were recorded. An additional photoplethysmographic probe (PPG; Adult Flex Sensor 3M, Nonin Medical Inc., Plymouth, MN, USA) recorded the pulse waveform

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necessary to calculate pulse transit time (PTT) as an inverse, surrogate measure of blood pressure change. We have previously validated the use of PTT against continuous measurements of blood pressure using photoplethysmography 31. Both the ECG and the PPG

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were sampled at 512 Hz. Pediatric sleep technologists sleep-staged and scored the PSG studies manually in 30 s epochs according to clinical practice 28,32. A minimum of 4 h of sleep

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was required for children to be included in the study in order to diagnose OSA severity. Sleep parameters recorded and calculated included: time in bed (TIB; the time from lights out until the end of the study), sleep period time (the amount of time from sleep onset until morning awakening), total sleep time (TST; the sleep period excluding any periods of

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wake), sleep latency (the period from lights out until sleep onset), REM latency (the period from sleep onset to the onset of the first REM period), sleep efficiency (the ratio of TST to TIB), %WASO (wake after sleep onset as a percentage of sleep period time), percentage of

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TST in %N1, %N2, %N3 and REM sleep.

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The obstructive apnea hypopnea index (OAHI) was defined as the total number of obstructive apneas, mixed apneas, obstructive hypopneas and respiratory event-related arousals per hour of TST

32

. Primary snoring (PS) was defined as an OAHI ≤1 event/h with

parental report of snoring, OSA was defined as an OAHI>1 events/h

33,34

. Non-snoring

controls all had an OAHI≤1 event/h, no history of snoring, and snoring was not detected on the night of the PSG. The central apnea hypopnea index (CnAHI) was defined as the total number of central apneas and hypopneas per hour of TST. Pulse transit time (PTT) analysis

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ACCEPTED MANUSCRIPT Following the PSG study all data were exported via electronic data format to specialised analysis software (LabChart, ADInstruments, Sydney Australia). PTT was calculated beat-beat in

LabChart, using peak detection of the ECG R-wave 30. The point of 50% of pulse wave height on the corresponding PPG signal was similarly determined, as this point is most resistant to

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artifact and PTT was calculated beat-beat as the time delay between these two points. An average PTT was then calculated for each 30s epoch for the whole study. Individual differences are inherent to PTT measurement, precluding comparison of raw PTT values

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between subjects. Thus, the PTT value for each epoch was normalized to that child’s mean PTT during restful wake before sleep onset by dividing the epoch PTT by the mean wake

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PTT. Nocturnal dipping analysis

Nocturnal dipping of heart rate and blood pressure were calculated as the percent change between values averaged for wake before sleep onset and for the first period of N1,

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N2, N3 and REM to occur during the night for each child. The first period of each sleep cycle was defined as the first cluster of 3 or more continuous epochs of that sleep stage after sleep onset. Given that percentage change in PTT is not directly equivalent to percentage change in

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blood pressure, it was impossible to divide subjects into ‘dippers’ and ‘non-dippers’ in the traditional manner based on a nocturnal fall in blood pressure of greater or less than 10% 35

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compared to wake levels

. Instead the study population was arbitrarily divided into two

groups; the quartile exhibiting the least percentage change in heart rate or PTT from wake to total sleep (≤25th percentile), who were therefore most likely to be ‘non-dippers’, and the remainder of the cohort (≥25th percentile) 36. Heart rate variability (HRV) analysis. Heart rate variability analysis was performed to assess autonomic control. All available 2-min bins were selected based on the following criteria: the four 30s epochs had to

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ACCEPTED MANUSCRIPT be of the same sleep stage and be preceded by an epoch of the same sleep stage. Bins could not contain ECG artifact or be preceded by an epoch with ECG artifact. There had to be an epoch separating consecutive 2-minute bins

37

. Power spectral density was determined for

total power (the total power in the spectrum for the analysis region ≤ 0.4 Hz), low frequency 38

. The LF/HF was

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(LF, 0.04-0.15 Hz) and high frequency (HF, 0.15-0.4 Hz) bands

calculated as a measure of sympathovagal balance. A 12-hour urine sample was collected on the night of the PSG, (7:00 PM–7:00 AM) as previously described

39

. Dopamine,

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noradrenaline, and adrenaline were measured using high performance liquid chromatography, with adjustment for renal function using creatinine concentration, as a global measure of

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sympathetic activity 39-42.

Statistical Analysis

We calculated our group size based on our primary outcome measure of blood pressure which

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we considered a 10 mmHg difference for systolic blood pressure to be of clinical significance. With a power of 0.8 and an α of 0.05 we required 21 children in each group. Statistical analysis was performed in SigmaPlot (Version 13, Systat Software Inc, California, USA).

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Data were first tested for normality and equal variance. Parametric data were analyzed with

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one-way analysis of variance (ANOVA) with Student Newman-Keuls post hoc testing and data are presented as mean ± sem. Non parametric data were tested with Kruskal-Wallis ANOVA and Dunn’s post hoc testing and data are expressed as median with interquartile range. Frequencies were tested with Chi-square analysis. Linear regressions were performed to determine significant predictors of wake and sleep heart rate and blood pressure. Heart rate and blood pressure were entered as the dependant variables and age, BMI z-score and OAHI as the independent variables. Significance was taken at the p<0.05 level.

Results 8

ACCEPTED MANUSCRIPT The children were divided 5 groups into: a normal weight non-snoring control group (n=24), a normal weight PS group (n=19), a normal weight OSA group (n=16), an overweight/obese PS group (n=18; 12 obese), and an overweight/obese OSA group (n=21; 16 obese). All participants were born at term. The demographic characteristics of these groups

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are shown in Table 1. There were more males than females in all groups other than the control group; this is reflective of children referred to the Melbourne Children’s Sleep Centre. Participant age was similar between groups, although the normal weight PS group was There was no

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significantly younger than the overweight/obese PS group (P<0.05).

significant difference in socio-economic status or height between groups. By design, BMI z-

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score, waist circumference, hip circumference and neck circumference were significantly higher in the overweight/obese groups than in the control and normal weight groups (p<0.001 for all). Sleep and respiratory characteristics

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Sleep characteristics are presented in Table 2. There were no significant differences any of the sleep parameters between groups with the exception of % time spent in N1, where both the normal weight OSA and overweight/obese OSA groups had a higher %N1 compared

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to the non-snoring control group, the normal weight PS group and the overweight/obese PS

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groups (p<0.05 for all). There was an overall difference between the groups in %N3 (p<0.05), however posthoc testing could not identify where the differences lay. Respiratory characteristics are presented in Table 3. By design, the OAHI, respiratory

disturbance index, and percentage of respiratory arousals were significantly higher in the normal weight OSA group and the overweight/obese OSA group compared to the control group, the normal weight PS group and the overweight/obese PS group (P<0.001). There were no differences in OAHI between the two OSA groups. There was no difference in CnAHI between groups. The normal weight OSA group (P<0.05) and the overweight/obese

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ACCEPTED MANUSCRIPT OSA group (P<0.001) had significantly lower SpO2 nadir than the normal weight PS group. The overweight/obese OSA group had a significantly higher rate of SpO2 dips below 90% than the control group (P<0.05) and the normal weight PS group (P<0.05). The overweight/obese OSA group had a significantly higher rate of dips in SpO2 of > 4% than the

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control group (P<0.05), the normal weight PS group (P<0.001) and the overweight/obese PS group (P<0.001). The AI was significantly higher in both the normal weight and overweight/obese groups with OSA compared to the other 3 groups (p<0.001). There were no

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significant differences in average SpO2 dip with respiratory events or average TcCO2. Awake blood pressure and heart rate

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Comparison of awake systolic, mean, and diastolic blood pressure and heart rate measurements are presented in Figure 1. Systolic blood pressure was significantly higher in the overweight/obese OSA group compared to the control, normal weight PS and overweight/obese PS groups (P<0.05 for all), but was not different from the normal weight

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OSA group. There were no significant differences between groups for mean or diastolic blood pressure or heart rate.

Stepwise linear regression results are presented in Table 5 and show that BMI z-score

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predicted wake HR (p<0.007) and both age and BMI z-score predicted wake systolic, mean

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and diastolic blood pressure (p<0.001 for all). OAHI did not predict either HR or blood pressure.

Sleep blood pressure and heart rate There was no significant difference in normalized PTT between any of the groups in

N1, REM or in sleep overall (Figure 2). N2 normalized PTT was different between groups (p=0.04), however post-hoc testing was unable to determine where the differences lay. During N3, the overweight/obese PS group had a significantly lower normalized PTT, indicating higher blood pressure, than the normal weight PS group (p=0.01).

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ACCEPTED MANUSCRIPT There was no significant difference in heart rate between any of the groups in N1, N2 or REM (Figure 3). The overweight/obese OSA group had a significantly higher heart rate than the control group in both N3 (p=0.02) and sleep overall (p<0.05). Stepwise linear regression revealed that BMI z-score predicted N1 (p<0.05), N2 (p<0.05),

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REM (p<0.01) and total sleep HR (p<0.05) and N1, N2, N3, REM and total sleep PTT (p<0.001 for all). Heart rate variability

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Results of comparison between groups for HRV parameters are presented in Table 4. There were no differences between groups in any HRV parameters in either Wake or N1. In

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N2 LF power was significantly higher in the normal weight OSA group compared to the overweight/obese PS group (p<0.05) and there was an overall difference between groups for total power (p<0.05). In N3 there was an overall difference between groups for LF power (p<0.05), HF power was significantly higher and total power significantly lower in the

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overweight/obese OSA group compared to the normal weight PS group (p<0.05 for both). There were no significant differences between groups for 12 hour urinary catecholamine analyses (adrenaline, nor-adrenaline or dopamine) (data not shown).

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Nocturnal dipping

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Nocturnal dipping of heart rate calculated as the % change from awake to each sleep stage N1, N2, N3, REM and total sleep for each group was not different between sleep stages (data not shown). The fall in heart rate was significantly less in the overweight/obese OSA group compared to the control group in both N2 and N3 (p<0.05 for both) and was also significantly less between the overweight/obese group and the normal weight PS group in N3 (p<0.05). There were no differences between groups for the % change in PTT. The proportion of “dippers” and “non-dippers” in each group is presented in in Figure 4. There was no difference in the proportion of “non-dippers” between groups for heart rate, however

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ACCEPTED MANUSCRIPT the proportion of blood pressure “non-dippers” was significantly higher in the overweight/obese PS and overweight/obese OSA groups compared to the control group (p<0.05 for both).

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Discussion

This study showed that being overweight/obese has both independent and additive effects on blood pressure and heart rate in children with OSA. We found that when awake

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systolic blood pressure was significantly higher in the overweight/obese OSA group compared to the control, normal weight PS and overweight/obese PS groups, and although

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not reaching significance, was also higher compared to the normal weight OSA group, suggesting the effects on blood pressure when awake are additive. During sleep, blood pressure and heart rate were elevated in the overweight/obese OSA group only when compared to non-snoring controls, also suggesting an additive effect. In contrast, reduced

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nocturnal dipping of heart rate was also only observed in the overweight/obese OSA group compared to the control and normal weight PS groups. More overweight/obese children were “non-dippers” for blood pressure when asleep compared to normal weight children,

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suggesting independent effects of BMI and OSA. BMI z-score predicted heart rate and PTT

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when asleep and both age and BMI z-score predicted blood pressure when awake, while OAHI did not predict any of the cardiovascular variables. Previous studies have not compared obese/overweight children with both OSA and PS to normal weight children with OSA and PS and also to normal weight non-snoring control children. The majority of studies have included both normal weight and overweight/obese children in the same groups and have co-varied for the effect of BMI in their analyses or have not considered BMI. The majority of previous studies have used ambulatory blood pressure monitoring which measures blood pressure intermittently across 24 hours. Using this method

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ACCEPTED MANUSCRIPT Leung et al.,

24

found that Chinese children aged 6-15 years with an apnea hypopnea index

(AHI) >5 event/h had higher 24 hour systolic and sleep diastolic blood pressure compared to those with an AHI <5 events/h and that BMI z-score was a significant predictor of wake systolic, sleep systolic and sleep diastolic blood pressure. In a similar study, also using

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ambulatory blood pressure monitoring Amin et al., 23 showed that after adjusting for physical activity and controlling for confounding factors, children aged 7-13 years with OSA exhibited a significantly higher 24-hour blood pressure and faster heart rate than age- and

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gender-matched healthy controls. The study separated the participants into lean children with and without OSA and obese children with and without OSA in a subgroup analysis and found

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that the lean OSA group had significantly higher wake systolic, wake diastolic, wake mean arterial pressure, wake heart rate, sleep diastolic blood pressure and sleep mean arterial blood pressure than the lean control group. The obese children with OSA had a higher wake systolic blood pressure and sleep systolic blood pressure than the lean children with OSA, however

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no differences between the obese children with and without OSA were identified, likely because of the small number of obese children (n=5) without OSA. In contrast to our study, which found that OSA severity was not associated with blood pressure, in their mixed model

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analyses with Log AHI as a continuous variable they showed that AHI was a significant

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predictor for systolic, diastolic, and mean arterial BP surge as well as diurnal and nocturnal systolic, diastolic and mean arterial BP. In a study by Marcus et al

18

which also used

intermittent measurements of blood pressure during overnight polysomnography, children with OSA had no difference in systolic blood pressure but a significantly higher diastolic blood pressure compared with those with PS during both sleep and wake. The differences in blood pressure between PS and OSA were similar when children were divided into obese and non-obese. Multiple linear regression showed that blood pressure could be predicted by apnea index, BMI, and age. The differences between other studies which have found an association

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ACCEPTED MANUSCRIPT between OSA severity and blood pressure and our study which did not find this association may have been due to the methods of blood pressure measurement. Our use of PTT as a surrogate inverse measure of blood pressure change provides a continuous rather than intermittent measure of blood pressure using a photoplethysmographic finger cuff

31

.

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Intermittent blood pressure measurement has the potential to either under or over sample different sleep states as highlighted by some studies finding no differences in blood pressure between sleep states 18 or not accounting for sleep state 23,24. In previous studies by our group

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using continuous measurements of blood pressure across the night we have identified elevated blood pressure during both sleep and awake, together with sleep state differences in

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blood pressure in elementary school aged children with all severities of sleep disordered breathing, including primary snoring 43. In the current study we did not identify differences in blood pressure or heart rate between non snoring control children and normal weight children with OSA. The differences between the current study and our previous study was likely

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because in the former study we did not separate the effects of BMI and included overweight and obese children in all groups.

The use of continuous measures of heart rate and blood pressure also allowed us to assess the

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effects of OSA and BMI on nocturnal dipping. We found that the % change in PTT from

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wake to sleep was significantly less in both the overweight/obese PS and OSA groups compared to the control group, suggesting being overweight/obese has an independent effect on nocturnal dipping. We and others have previously shown that nocturnal dipping is preserved in school aged children with OSA

18,24,44,45

. The identification that

overweight/obese children with all severities of sleep disordered breathing show reduced nocturnal dipping compared to non-snoring control children is important as the absence of a nocturnal fall in blood pressure has been associated with hypertension in adults 46,47.

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ACCEPTED MANUSCRIPT We also examined autonomic control of heart rate and found few differences between groups, with HF power being significantly higher and total power significantly lower in the overweight/obese OSA group compared to the normal weight PS group in N3 sleep. The only other study which has examined the effects of obesity on HRV found that although HRV was 27

. Similar to our study, elevated

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affected by OSA this was independent of obesity and age

heart rate was also identified in the children with OSA. Previous studies which have not accounted for BMI have identified that OSA is associated with reduced HRV

48-50

. As a

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measure of overall sympathetic activity we also measured overnight urinary catecholamines, but found no differences between groups. Similar to our study, Snow et al.,

41

also found no

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association between urinary catecholamines and BMI in obese and non-obese children with and without OSA. However, when the children were grouped into those with and without OSA they did find a correlation between both noradrenaline and adrenaline and OAHI. We and others have also shown this association in studies which did not account for BMI 39,40,51,52.

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The mechanisms which lead to increased blood pressure and impaired autonomic control are thought to be similar to those identified in adults – repetitive hypoxia and arousal at event termination, which potentially lead to oxidative stress, inflammation, endothelial dysfunction

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and sympathetic activation, despite the different etiology of the disorder53. Obesity also

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independently affects similar biological pathways as OSA and both OSA and obesity are independent risk factors for insulin resistance and both result in increased levels of inflammation and oxidative stress 54. In this study we did not identify major differences in sleep architecture between the groups, with the exception of amounts of N1, and these findings are consistent with the current literature. Various studies have compared the polysomnographic sleep characteristics of obese children with OSA to either obese children without OSA or normal weight children

15

ACCEPTED MANUSCRIPT with OSA and have consistently found no difference in total sleep time, sleep latency, sleep efficiency or the percentage of total sleep time spent in each sleep stage 11,41,55-60. Limitations We must acknowledge the limitations of this study. Dividing the sample into five groups

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limited the sample size of each group, which we had calculated to be 21, and some of the analyses may have been underpowered to achieve statistical significance. The small sample size also precluded analysis for the effects of gender. In this study we used PTT as a

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surrogate measure of blood pressure change rather than direct continuous measurement with photoplethysmography as we had used in a previous studies43,61. We used this method as it is

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less disruptive to children’s sleep and, we have previously validated its use with photoplethysmography31. We also did not obtain a measure of puberty and this may have been associated with the changes we observed. Clinical implications

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Our finding that BMI has both combined and independent effects on the cardiovascular consequences of OSA in children is particularly important as childhood obesity tracks into adulthood with 75% of obese children becoming obese adults

62

. The cardiovascular effects

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of OSA or being overweight or obese in childhood can lead to serious long-term health consequences. Elevated blood pressure during childhood is a predictor of elevated blood

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pressure and hypertension in adulthood 63. Although weight loss has been shown to improve the severity of OSA in overweight/obese children 64,65

7,11

, it is difficult to achieve and maintain

and is less successful in adolescents than younger children 66,67. Studies have shown that

the majority of children who are overweight or obese who have OSA are adolescents 68,69. On the other hand OSA is effectively treated with adenotonsillectomy or continuous positive airway pressure (CPAP). Studies have shown that in obese children the success rate of complete resolution of OSA with adenotonsillectomy is significantly less than in normal

16

ACCEPTED MANUSCRIPT weight children; 51% had a postoperative AHI ≥ 5 events/h

70

. This is important as studies

have shown that any reduction in OSA severity is associated with a lowering of blood pressure

26

and improvement in autonomic cardiovascular control

71,72

. A recent systematic

review and meta-analysis has shown that in adolescents OSA is associated with higher levels

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of triglycerides, insulin and lower levels of high-density lipoprotein cholesterol together with elevated blood pressure. All these variables are markers of the metabolic syndrome 73. Since obesity in adolescence is a risk factor for early development of type 2 diabetes and

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atherosclerosis and metabolic syndrome increases this risk, obese adolescents with OSA may be at increased risk of developing these chronic cardiovascular diseases. Currently, OSA is

all overweight/obese children for OSA. Conclusions

74

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under recognized and under diagnosed in primary care settings

so it is important to screen

This study showed that BMI has both combined and independent effects on blood pressure

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and heart rate in children with OSA. We have previously shown that treatment of OSA reduces blood pressure and suggest that treatment of OSA in the growing number of overweight/obese children may improve cardiovascular outcomes.

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Acknowledgements

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We would like to thank all the children and their parents who participated in our research study and the staff of the Melbourne Children’s Sleep Centre where the studies were carried out.

Conflict of Interest: The authors have no financial relationships relevant to this article to disclose. Disclosure Statement: Funding for this project was provided by The Heart Foundation of Australia (G12M 6564), The National Health and Medical Research Council of Australia (APP1008919 and the Victorian Government’s Operational Infrastructure Support Program.

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ACCEPTED MANUSCRIPT Figure Legends Figure 1: Awake office blood pressure and heart rate (a) systolic blood pressure; (b) mean arterial pressure; (c) diastolic blood pressure and (d) heart rate in control non-snoring, normal weight

primary

snoring

(PS),

normal

weight

obstructive

sleep

apnea

(OSA),

RI PT

overweight/obese PS and Overweight/obese OSA groups. Values are mean ± sem. *P<0.05. Figure 2: Pulse transit time (PTT) during (a) Total sleep, (b) N1, (c) N2, (d) N3, (e) REM in control non-snoring, normal weight primary snoring (PS), normal weight obstructive sleep

SC

apnea (OSA), overweight/obese PS and Overweight/obese OSA groups. Values are mean ± SEM. *P<0.05.

M AN U

Figure 3: Heart rate (HR) during (a) Total sleep, (b) N1, (c) N2, (d) N3, (e) REM in control non-snoring, normal weight primary snoring (PS), normal weight obstructive sleep apnea (OSA), overweight/obese PS and Overweight/obese OSA groups.. Values are mean ± SEM.. *P<0.05.

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Figure 4: % of children in each group with the smallest change in (A) blood pressure and (B)

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heart rate from wake before sleep onset to total sleep. Dotted line indicates 25th percentile.

23

ACCEPTED MANUSCRIPT Non

Normal

Normal

snoring

weight PS

weight OSA

Overweight Overweight / obese PS

P-value

/ obese OSA

19

16

18

21

10M/14F

12M/7F

10M/6F

12M/6F

12M/9F

ns

11.9 ± 0.5ab

9.9 ± 0.4a

12.2 ± 0.7ab

12.0 ± 0.6 b

12.2 ± 0.6ab

P<0.05

SES

1036 ± 8

999 ± 15

1011 ± 12

BMI

0.13 ± 0.12a

0.19 ± 0.13a

67.0 ± 1.9a

65.8 ± 1.3a

n Gender (M/F) Age

Waist (cm)

78.1 ± 2.2a

Hip (cm)

30.0 ± 0.5a

1.93 ± 0.10b

2.09 ± 0.10b

P<0.001

69.0 ± 12.2a

91.1 ± 3.6b

95.1 ± 3.8b

P<0.001

78.1 ± 2.3a

100.4 ± 4.6b

103.1 ± 4.0b

P<0.001

30.5 ± 0.5a

30.5 ± 0.5a

34.2 ± 0.9b

35.7 ± 1.0b

P<0.001

AC C

(cm)

ns

72.0 ± 1.8a

EP

Neck

1008 ± 11

-0.06 ± 0.20a

TE D

z-score

1004 ± 11

M AN U

(years)

RI PT

24

SC

Control

Table 1: Demographic data of normal weight and overweight/obese children with and without OSA, and non-snoring healthy weight controls. Values are mean ± SEM OSA= Obstructive Sleep Apnea, PS= Primary Snoring; M= Male, F= Female, SES= Socioeconomic Status (Postal area index of relative socio-economic disadvantage). BMI= Body Mass Index. Within each row, columns that do not have a letter in common are significantly different.

ACCEPTED MANUSCRIPT Normal Non

Normal weight

snoring

Overweight

Overweight/

/ obese PS

obese OSA

21

weight PS

Control

P-value

OSA

19

16

18

471 ± 7

501 ± 8

481 ± 7

475 ± 10

485 ± 8

ns

SPT (mins)

436 ± 8

468 ± 8

449 ± 8

434 ± 13

456 ± 9

ns

TST (mins)

391 ± 10

406 ± 14

384 ± 11

374 ± 14

399 ± 11

ns

32 ± 5

32 ± 7

28 ± 5

37 ± 7

29 ± 6

ns

154 ± 13

155 ± 15

150 ± 15

185 ± 17

167 ± 21

ns

WASO (min)

45 ± 7

61 ± 13

64 ± 10

55 ± 8

58 ± 12

ns

SE (%)

83 ± 2

81 ± 3

80 ± 2

82 ± 2

82 ± 2

ns

%N1

6 ± 1a

6 ± 1a

11 ± 2 b

7 ± 1a

10 ± 2 a

P<0.05

%N2

51 ± 1

48 ± 1

46 ± 1

47 ± 2

47 ± 2

ns

24 ± 1

30 ± 2

23 ± 1

28 ± 2

26 ± 1

P<0.05

16 ± 1

20 ± 1

18 ± 1

17 ± 1

ns

Time available

M AN U

Sleep Latency (min) REM Latency

AC C

EP

TE D

(mins)

%N3 %REM

18 ± 1

SC

for sleep (mins)

RI PT

24

n

Table 2: Sleep characteristics of normal weight and overweight/obese children with and without OSA, and non-snoring healthy weight controls. Data presented as mean±SEM. OSA= Obstructive Sleep Apnea, PS= Primary Snoring; SPT= Sleep Period Time; TST= Total Sleep Time; REM= Rapid Eye Movement; WASO= Wake After Sleep Onset; SE= Sleep Efficiency. Within rows, columns that do not have a letter in common are significantly different.

ACCEPTED MANUSCRIPT

Normal weight OSA

Overweight Overweight / obese PS /obese OSA P-Value

N=24

N=19

N=16

N=18

N=21

OAHI

0.1a

0.4a

6.1b

0.0a

7.6b

(events/h)

(0.0, 0.4)

(0.0, 0.7)

(1.9, 11.9)

(0.0, 0.7)

(2.4, 13.0)

RDI

1.1a

1.0a

7.5b

1.0a

9.6b

(events/h)

(0.8, 2.6)

(0.6, 1.4)

(3.2, 13.6)

(0.1, 2.3)

(4.2, 14.2)

CnAHI

0.9

0.4

0.8

0.4

0.7

(events/h)

(0.4, 1.9)

(0.1, 1.0)

(0.4, 1.6)

(0.1, 1.0)

(0.2, 2.1)

95.0a

92.0b

93.0ab

89.0b

(91.0, 93.8)

(90.5, 94.5)

(86.5, 93.5)

(91.0, 95.0)

(93.0, 96.0)

Average

3.5

3.0

SpO2 drop

(3.0, 4.0)

(3.0, 4.0)

SpO2<90%

0.0a

0.0a

(events/h)

(0.0, 0.0)

(0.0, 0.0)

0.5a

0.1a

(events/h) Average TcCO2 (mmHg)

(0.1, 1.1)

45.4 (42.4, 47.4)

3.0

3.5

4.0

(3.0, 3.8)

(2.8, 5.0)

(3.0, 5.0)

0.0ab

0.0ab

0.2b

(0.0, 0.0)

(0.0, 0.0)

(0.0, 0.7)

0.8ab

0.2a

2.0b

TE D

drop

(0.0, 0.5)

(0.2, 3.2)

(0.0, 0.9)

(0.6, 7.5)

43.8

44.3

45.9

42.9

(36.8, 48.4)

(41.7, 47.6)

(41.6, 50.6)

(38.4, 46.4)

EP

SpO2>4%

M AN U

(%)

SC

SpO2 Nadir 92.5ab

RI PT

Control

Normal weight PS

10.5a

11.2ab

16.8b

9.1a

14.6b

(events/h)

(7.9, 11.9)

(9.3, 13.3)

(12.9, 22.3)

(6.4, 11.0)

(11.2, 21.5)

% Resp Ar

3.5a

6.0a

34.5b

6.0a

35.0b

(2.0, 11.0)

(4.0, 9.0)

(20.0, 56.8)

(0.0, 9.8)

(20.0, 52.5)

AC C

AI

P<0.001

P<0.001

ns

P<0.001

ns

P<0.001

P<0.001

ns

P<0.001

P<0.001

Table 3: Respiratory characteristics of normal weight and overweight/obese children with and without OSA, and non-snoring healthy weight controls. Data presented as median (interquartile range). OSA= Obstructive Sleep Apnea, PS=Primary Snoring; OAHI= Obstructive Apnoea Hypopnoea Index; RDI= Respiratory Disturbance Index; CnAHI= Central Apnoea Hypopnoea Index; SpO2 = Oxygen Saturation, TcCO2= Transcutaneous Carbon Dioxide; AI=Arousal Index; Resp Ar= Respiratory Arousal. Within rows, columns that do not have a letter in common are significantly different.

ACCEPTED MANUSCRIPT

Total Sleep Wake N1 N2 N3 REM Total Sleep Wake N1 N2 N3 REM Total Sleep Wake N1 N2

1142 (598, 2218) 2103 (1779, 5642) 2096 (833, 4482) 1802 ab (739, 3292) 2189 (590, 4456) 2079 (882, 3797) 3401 (2271, 7030) 7667 (5129, 13249) 4869 (2674, 8800) 3576 ab (1577, 6157) 7012 (3238, 12145) 5960 (3170, 9229) 0.949 (0.686, 1.666) 0.770 (0.329, 1.055) 0.843

Overweight/ obese OSA

PValue

N=21 1101 (467, 1665) 1169 (283, 3887) 1170 ab (586, 2172) 649 (400, 899) 1119 (559, 3878) 1378 (697, 2607)

RI PT

N=16 N=18 Low Frequency power 1130 978 1125 (645, 1938) (732, 2416) (586, 2187) 2125 2173 1253 (995, 5314) (843, 6167) (569, 3877) 2507 ab 2275a 1095b (1214, 2944) (1753, 2974) (829, 1571) 1375 1096 819 (664, 2563) (758, 1862) (612, 1321) 2308 1538 1294 (1375, 4009) (948, 3896) (970, 1879) 1832 2123 1152 (1321, 3581) (1093, 3561) (876, 2174) High Frequency power 1241 1934 813 (965, 3060) 771, (2456) (302, 2137) 3655 5269 2436 (1050, 9469) (2318, 8047) (424, 6819) 3527 4272 1813 (1723, 7861) (2138, 10028) (1084, 3552) 3169 a 3243 ab 18889 ab (2119, 7765) (1771, 7127) (1116, 3560) 3146 2904 2082 (1224, 5355) (1001, 5647) (728, 3547) 3477 3682 2364 (2195, 8720) (2367, 6541) (1137, 3473) Total power 4632 5118 3350 (2734, 6345) (3664, 8550) (1938, 9712) 6625 10915 7708 (3256, 22949) (4060, 19540) (2264, 14559) 8237 7850 3986 (4771, 16849) (6309, 16295) (3366, 6794) 6229 a 5634 ab 3885ab (3708, 12448) (3730, 13119) (2317, 7704) 9668 6865 5845 (4669, 14585) (4024, 13718) (3363, 8756) 8167 8810 5482 (5492, 18704) (5209, 13315) (3370, 8214) Low Frequency High Frequency ratio 0.865 1.208 1.417 (0.511, 1.251) (0.742, 1.871) (0.792, 2.608) 0.649 0.760 0.749 (0.402, 0.949) (0.529, 1.300) (0.371, 2.166) 0.560 0.584 0.604

SC

REM

Overweight/ obese PS

M AN U

N3

800 (579, 2506) 2170 (821, 3267) 1649ab (743, 2482) 707 (371, 1801) 1693 (890, 3097) 1476 (870, 2250)

Normal weight OSA

TE D

N2

N=19

EP

N1

N=24

AC C

Wake

Control

Normal weight PS

P<0.05

1172 (344, 1978) 900 (230, 6397) 1469 (551, 8098) 1084 b (366, 2490) 1732 (536, 5674) 1446 (544, 4701) 4127 (1153, 6417) 4367 (1311, 16667) 4126 P<0.05 (2338, 13891) 2511 b (1450, 4336) 4463 (2580, 16042) 6038 (2656, 9868) 1,200 (0.897, 2.085) 1,289 (0.470, 3.795) 0.755

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

(0.568, 1.127) (0.323, 1.070) (0.410, 0.806) (0.438, 1.290) (0.428, 1.427) N3 0.495 0.453 0.397 0.595 0.485 (0.361, 0.889) (0.293, 0.613) (0.247, 0.682) (0.382, 0.841) (0.285, 1.262) REM 1.072 0.924 0.902 1.236 0.958 (0.672, 2.515) (0.610, 1.079) (0.674, 1.504) 0.617, 2.583) (0.557, 1.963) Total 0.879 0.599 0.705 0.810 0.770 Sleep (0.615, 1.511) (0.452, 0.850) (0.477, 1.039) (0.523, 1.751) (0.470, 1.622) Table 4: Heart rate variability parameters in normal weight and overweight/obese children with and without OSA, and non-snoring healthy weight controls during wake and each sleep stage. OSA= Obstructive Sleep Apnea, PS=Primary Snoring. Data presented as median (interquartile range). Within rows, columns that do not have a letter in common are significantly different. P values indicate an overall group difference, however posthoc testing could not distinguish which groups differed

ACCEPTED MANUSCRIPT

p

0.08

-0.268

0.007

0.07

-0.223

0.03

0.07

-0.223

0.03

0.09

-0.273

0.006

0.07

-0.232

0.02

0.66

0.803

<0.001

0.65

0.801

<0.001

0.65

0.799

0.65

0.799

0.66

0.801

0.26

<0.001 <0.001

<0.001 <0.001

0.487 -0.376

<0.001 <0.001

0.486 -0.381

<0.001 <0.001

EP

0.31 Age BMI z-score Office MAP

<0.001

0.442 -0.354

TE D

Age BMI z-score Office DBP

SC

STD β

M AN U

Wake HR BMI z-score N1 HR BMI z-score N2 HR BMI z-score REM HR BMI z-score Sleep HR BMI z-score N1 PTT BMI z-score N2 PTT BMI z-score N3 PTT BMI z-score REM PTT BMI z-score Sleep PTT BMI z-score Office SBP

Model R2

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Table 5: Significant determinants of heart rate (HR), pulse transit time (PTT) and Office blood pressure (BP)

0.31

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Age BMI z-score

BMI= Body Mass Index; SBP=systolic blood pressure; MAP= mean arterial pressure; DBP= Diastolic blood pressure.

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beats/min

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Figure 4

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ACCEPTED MANUSCRIPT Sleep-D-17-00346 Highlights

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SC M AN U TE D

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Up to 50% of overweight/obese children have obstructive sleep apnea (OSA). Both OSA and being overweight have significant adverse effects on the cardiovascular system. BMI and OSA had combined effects on blood pressure and heart rate. More overweight/obese children were “non-dippers” for blood pressure compared to normal weight children, suggesting independent effects of BMI and OSA. Treatment of OSA in overweight/obese children may improve cardiovascular outcomes.

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