Exercise and Vascular Function in ChildObesity: A Meta-AnalysisKatrin A. Dias, BExSSa, Daniel J. Green, PhDb,d, Charlotte B. Ingul, PhDc, Toby G. Pavey, PhDa, Jeff S. Coombes, PhDa
abstract CONTEXT: Conduit artery flow-mediated dilation (FMD) is a noninvasive index of preclinicalatherosclerosis in humans. Exercise interventions can improve FMD in both healthy andclinical populations.
OBJECTIVE: This systematic review and meta-analysis aimed to summarize the effect of exercisetraining on FMD in overweight and obese children and adolescents as well as investigate therole of cardiorespiratory fitness (peak oxygen consumption [VO2peak]) on effects observed.
DATA SOURCES: PubMed, Medline, Embase, and Cinahl databases were searched from the earliestavailable date to February 2015.
STUDY SELECTION: Studies of children and/or adolescents who were overweight or obese wereincluded.
DATA EXTRACTION: Standardized data extraction forms were used for patient and interventioncharacteristics, control/comparator groups, and key outcomes. Procedural quality of thestudies was assessed using a modified version of the Physiotherapy Evidence Base Databasescale.
RESULTS: A meta-analysis involving 219 participants compared the mean difference of pre-versus postintervention vascular function (FMD) and VO2peak between an exercise trainingintervention and a control condition. There was a significantly greater improvement in FMD(mean difference 1.54%, P , .05) and VO2peak (mean difference 3.64 mL/kg/min, P , .05)after exercise training compared with controls.
LIMITATIONS: Given the diversity of exercise prescriptions, participant characteristics, and FMDmeasurement protocols, varying FMD effect size was noted between trials.
CONCLUSIONS: Exercise training improves vascular function in overweight and obese children, asindicated by enhanced FMD. Further research is required to establish the optimum exerciseprogram for maintenance of healthy vascular function in this at-risk pediatric population.
aSchool of Human Movement and Nutrition Sciences, The University of Queensland, St Lucia, Brisbane, Queensland, Australia; bSchool of Sport Science, Exercise and Health, The University ofWestern Australia, Crawley, Western Australia, Australia; cDepartment of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway; and dResearchInstitute for Sport and Exercise Sciences, Liverpool John Moores University, Merseyside, United Kingdom
Miss Dias and Drs Green and Coombes conceived and designed the research; Miss Dias and Dr Green acquired the data and performed statistical analysis; Drs Greenand Coombes handled funding and supervision; Miss Dias and Drs Green, Ingul, and Pavey drafted the manuscript; and all authors made critical revisions of themanuscript for key intellectual content, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.
www.pediatrics.org/cgi/doi/10.1542/peds.2015-0616
DOI: 10.1542/peds.2015-0616
Accepted for publication Jun 25, 2015
Address correspondence to Professor Jeff Coombes, School of Human Movement and Nutrition Sciences, The University of Queensland, St Lucia, QLD, Australia 4072.E-mail: [email protected]
Obesity has placed a large burden onthe pediatric population over the last30 years, with steady increases notedin several countries.1–3 Pediatricobesity is often carried intoadulthood4,5 and is associated withrisk factors for chronic diseases suchas cardiovascular disease and type 2diabetes.6,7 Impaired vascularfunction may contribute to increasedcardiovascular disease risk, asatherosclerosis begins in childhoodand endothelial dysfunction has beenidentified as an early eventcontributing to the development ofatherosclerosis.8 There is strongevidence that obese children andadolescents have lower arterialcompliance and distensibility thantheir healthy matched controls, aswell as depressed (2%) endothelium-dependent and -independent conduitartery vasodilator function.9–12
Endothelial dysfunction isprognostically significant, as it canpredict future cardiovascular events,even after established risk factors foratherosclerosis are accountedfor.13–15 A meta-analysis found thata 1% decrease in flow-mediateddilation (FMD) was associated witha 13% increase in risk of futurecardiovascular events.13 Retardingatherosclerosis with early preventivemeasures that enhance vascularfunction may reduce the likelihood offuture cardiovascular disease througha reduction of global cardiovascularrisk.16
Previous reviews in adults found thatimpaired vasodilator function isimproved with exercise training;however, findings are not asconsistent in healthy populationswith normal vascular function as theyare in those with risk factors andcardiovascular disease,17,18 in partowing to countervailing changes invascular function and structure.19,20
The aim of this systematic review wasto meta-analyze and examine theeffects of exercise training onvascular function in obese childrenand adolescents. Changes in body
composition and cardiorespiratoryfitness were also evaluated toexamine the general efficacy of theexercise intervention and therelationship betweencardiorespiratory fitness, bodycomposition, and vascular functionimprovements.
METHODS
We conducted and reported thissystematic review in accordance withthe Preferred Reporting Items forSystematic Reviews and Meta-Analyses (PRISMA) statement.21
Literature Search
PubMed, Medline, Embase, and Cinahldatabases were searched from theearliest available date to February2015, limited to studies in humansand the English language. TheMedical Subject Heading (MeSH)database was used to retrieve allarticles related to exercise trainingand FMD in overweight or obesechildren and adolescents. MeSH termsused were “obesity” OR “overweight”OR “child” OR “adolescent” OR“atherosclerosis” and their relatedterms. Text words used inconjunction with the MeSH termswere (“exercise training” OR “physicaltraining” OR “exercise” OR “exerciseintervention”) AND (“arterialfunction” OR “vascular function” OR“vascular dysfunction” OR “flow-mediated dilation” OR “endothelium-dependent dilation”). Reference listsof retrieved articles were alsosearched for other relevant studies.
Study Inclusion Criteria
Studies were considered eligible forinclusion if they met criteriaregarding population, intervention,comparator, outcomes, and studydesign. Participants were required tobe obese or overweight children oradolescents (according to age- andgender-specific criteria) whocompleted an exercise interventionusing aerobic exercise training of $6weeks in the form of a randomizedcontrolled trial (individual or cluster).
Studies that included exercisesadditional to aerobic exercisetraining, such as resistance trainingor agility training, were alsoconsidered. A nonexercisecomparator or control group wasrequired for study inclusion. Themeasurement of FMD was necessary.
We excluded editorials, opinions,studies not published in a peer-reviewed journal, and studiesavailable only as meeting abstracts.
Study Selection Process
All abstracts retrieved werescreened, and clearly irrelevantstudies were excluded. Full texts ofall potentially eligible studies wereexamined. Supplemental Table 3includes studies that were excludedafter full-text examination. Figure 1outlines the study selection processfrom initial search to inclusion.
Data Extraction
Data were extracted by usinga standardized data extraction form.Patient characteristics (age, gender,and overweight/obesityclassification), intervention (exercisemode, frequency, duration, intensity,and supervision), control/comparatorgroups, methodological quality, andkey outcomes were noted.Corresponding authors werecontacted for information notavailable in the journal article.
Risk of Bias Assessment
Methodological quality of all studieswas assessed by 2 independentreviewers using a modifiedPhysiotherapy Evidence BaseDatabase (PEDro) 10-point scale. Onepoint was awarded for each criterionmet (Fig 2). The average score wasrecorded when a discrepancy wasnoted.
Data Analysis and Synthesis
Data synthesis was descriptive, withdetailed tabular summariespresented (Tables 1 and 2). For theprimary outcome of FMD, data wereextracted from all 6 studies, allowing
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a quantitative summary using meta-analysis. For the secondary outcomesof weight/BMI and VO2peak, data wereextracted from 6 and 3 studies,
respectively. We compared absolutechanges and calculated a weightedmean difference (95% confidenceinterval [CI]) for each study.
Heterogeneity was investigated byreviewing study populations,methods, and interventions and byusing the x2 test for homogeneity andthe I2 statistic. A fixed-effects modelfor the meta-analysis was used unlessstatistical heterogeneity was identified(x2 test P # .05 or I2 $ 50%), forwhich a random effects model wasused. We were unable to undertakea funnel plot for assessment ofpublication bias given the smallnumber of studies meeting the criteriafor meta-analysis. Analyses wereconducted by using Review Manager5.0 (Nordic Cochrane Centre,Copenhagen, Denmark).
RESULTS
Identification and Selection ofStudies
The bibliographic search yielded 176articles (Fig 1). After examining thetitles and abstracts, 14 full-textarticles were retrieved, with 6identified as meeting the inclusioncriteria.11,12,22–25 The correspondingauthors of 4 of these 6 studies weresuccessfully contacted for furtherdata.11,22–24
Risk of Bias
A mean modified PEDro scale score of8.2/10 was recorded for the 6studies. All 6 studies satisfied thefollowing criteria: eligibility criteriawere specified, participants wererandomly allocated to groups,assessors measuring the primaryoutcome were blinded, results ofbetween-group statisticalcomparisons were reported forprimary outcomes, and both pointmeasures and measures of variabilityfor $1 key outcome were provided.PEDro defines a key outcome as theprimary measure of therapeuticeffectiveness. Only 1 study reportedhaving concealed allocation.12
Study Characteristics
Table 1 summarizes the 6 includedtrials, which involved 219participants (116 females and 103
FIGURE 1Consolidated Standards of Reporting Trials (CONSORT) diagram of articles from initial search toinclusion. The systematic review process identified 6 articles for inclusion in the meta-analysis.
FIGURE 2Methodological quality of included studies. +, criterion achieved (1 point awarded); 2, criterion notachieved; 6, contrasting views from 2 different reviewers regarding achievement of criterion (half-point awarded).
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TABLE1
Summaryof
StudiesComparing
theEffectsof
Exercise
Interventions
onVascular
Function
Reference
Country
nAge,years[m
ean
(SD)
orrange]
Males,%
Overweight/Obesity
Definition
Intervention
Intervention
Supervision
Controlor
Comparison
Intervention
Duration,wks
Farpour-Lambert
etal
200912
Switzerland
44Intervention9.1(1.4);
control8.8(1.6)
36BM
I.97th
age-and
gender-specificpercentile29
CT:3
1-hsessions/wk;30
min
AEX
(walking,running,b
allgames,
swimming)
at55%–65%
V O2m
ax;
20-min
RT,10-min
stretching,
cool-dow
n
Physical
education
teachers
Notreatm
ent;instructed
tomaintaincurrentlevelsof
physical
activity
Kelly
etal
200422
UnitedStates
20Intervention11.0
(0.20);control
11.0(0.22)
45BM
I.85th
age-and
gender-specificpercentile
AEX:4sessions/wk;30-min
cycle
ergometer
at50%–60%
V O2peak
including5-min
warm-upand
cool-dow
n;intensity/duration
increase
each
weekto
reach
70%–80%
V O2peakfor50
min
inweeks
7–8
Researchers
Notreatm
ent;instructed
tomaintaincurrentlevelsof
physical
activity
12
Murphy
etal
200925
UnitedStates
35Intervention7–12;
controlnot
reported
51BM
I.85th
age-and
gender-specificpercentile
(Must1991)
DDR5d/wk;instructed
ontim
eand
approximatenumberof
songs
required
toachievetim
e;recorded
daily
DDRuseand
stepstook
whileplaying
None
Notreatm
ent
12
Watts
etal
200411
Australia
148.9(1.6)
43BM
I$30
kg/m
2equivalent26
AEX:31-hsessions/wk;whole-body
exercise
includingwarm-up,
exercise,and
stretching;
included
dodge-and-tag,jogging,
soccer
atsetHR
(140–180bpm);
intensity
anddurationincreased
astolerated
Exercise
physiologistsa
Crossoverprotocol
(randomly
assigned
toexercise
ornontrainingperiod);asked
todesist
from
activity
for
8wks
during
nontraining
period
8
Watts
etal
200423
Australia
1914.3(1.5)
47BM
I$30
kg/m
2equivalent26
CT:3
1-hsessions/wk;5-min
warm-
up,5-minstretches,22.5-minAEX
oncycleergometer
(65%
–85%
HRmax),22.5-min
RT(55%
–70%
pretrainingstrength
max),5-min
cool-dow
n
Exercise
physiologistsa
Crossoverprotocol
(randomly
assigned
toexercise
ornontrainingperiod);asked
todesist
from
activity
for
8wks
during
nontraining
period
8
Woo
etal
200424
Hong
Kong
82Intervention10.0
(1.0);control
9.9(0.9)
66BM
I$21
kg/m
2accordingto
CentersforDiseaseControl
andPrevention
CT:2
75-min
sessions/week;10-min
warm-up,30-min
RT,10-min
AEX
(60%
–70%
HRmax),10-min
agility
training,5-min
cool-dow
nandshortrest
periods;diet
educationprogram
Physiotherapists
Diet
educationprogram
bydietitian
(2/wkfor6wks,
then
2/mo);balanced
hypocaloricdiet
prescribed
(900–1200
kcal
daily)
6
CT,circuittraining;AEX,aerobicexercise
training;R
T,resistance
training;H
R,heartrate.
aCorrespondence
with
authors.
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males), with 129 and 118 assigned tothe exercise intervention and controlgroups, respectively.
Three of the 6 reviewed studiesexamined FMD in obese participantsonly,11,12,23 whereas the remaining 3studies included both overweight andobese participants.22,24,25 Overweightand obesity criteria varied, with useof the Cole dataset (2000),11,23,26
Centers for Disease Control andPrevention Growth Charts (2000),27
the Must dataset (1991),28 and anEast German dataset developed byKromeyer-Hauschild (2007).12,29
Because of the differing criteria fordefining obesity, these participantswere not meta-analyzed separately.
The World Health Organizationdefines adolescents as young peoplebetween the ages of 10 and 19 years,so 4 of the included studies involvedboth children andadolescents,12,22,24,25 1 involvedchildren only,11 and 1 involvedadolescents only.23 Authors specifiedwhether the population of interestwas prepubertal,11,12 postpubertal,23
or mixed.22,24,25 Two of the 6
investigations were conducted by thesame research group at the Universityof Western Australia, albeit indifferent subjects.11,23
Vascular Assessment Protocols
Vascular assessment protocols variedwith regard to cuff pressure, time inischemia, ultrasound scanningduration, and timing after cuffrelease. All 6 protocols placed the cuffdistal to the region of interest as perguidelines.30 Inflated cuff pressureranged from 200 to 300 mmHg, with1 study inflating pressure to 50 mmHg above resting systolic bloodpressure.25 The cuff was inflated for5,11,22,23,25 4.5,24 or 412 minutes.Timing of artery imaging varied, with2 studies imaging for 30 secondsbefore and 90 seconds after cuffrelease.12,24 In Kelly et al22 and bothstudies by Watts et al,11,23 the arterywas imaged continuously for 180seconds after cuff release, whereasMurphy et al25 imaged the artery for60 seconds after cuff release. Imageanalysis was performed by usingautomated edge detection and walltracking software in 2
laboratories.11,22,23 Farpour-Lambertet al12 did not state FMD analysistechniques; Woo et al24 and Murphyet al25 stated that scans wereanalyzed offline by a trained, blindedobserver, indicating that manualcaliper-based analysis was used. Inreporting reliability of the measure,Murphy et al25 stated their laboratorycoefficient of variation for arterydiameter (0.973, P , .01), whereasWoo et al24 reported established FMDcoefficient of variation values, aspublished by Sorensen et al.31
Participant preparation variedbetween protocols. When participantshad fasted,11,22–25 fasting time rangedfrom 411,23 to 1424 hours. Watts et aland Murphy et al also askedparticipants to abstain from caffeineand exercise for 411,23 and 2425 hoursbefore testing. Additionally, 4protocols stated that participantsrested for a specified time period(15,22 20,11,23 and 3012 minutes)before vascular assessment.
Exercise Mode
Circuit training was used by 3 studiesthat incorporated aerobic exercise
TABLE 2 FMD Protocols and Outcomes
Study Preparation Cuff Pressure,mm Hg
Time inIschemia, min
Postischemiascanning Protocol
Image Analysis Vascular FunctionOutcome
Change
Farpour-Lambertet al 200912
Supine rest 30 min 300 4 30 s before, 90 safter cuff release
Not reported FMD peak, % 20.59
Kellyet al 200422
Fasted (12 h); supinerest 15 min
200 5 180 s after cuff release Semiautomated, walltracking software
FMD peak, % 1.10
FMD AUC, %s 173.00GTN, % 4.80Resting BA diameter 20.06
Murphyet al 200925
Fasted (12 h); no caffeineor exercise for 24 h
50 aboveresting SBP
5 60 s after cuff release Manual offline (trained,blinded observer)
FMD peak, % 5.60a
Resting BA diameter 0.07Watts
et al 200411Fasted (4 h); no caffeine
or exercise; supinerest 20 minb
220b 5 180 s after cuff releaseb Semiautomated, walltracking software
FMD peak, % 1.35c
Resting BA diameter 0.08Watts
et al 200423Fasted (4 h); no caffeine
or exercise; supinerest 20 minb
220b 5 180 s after cuff release Semiautomated, walltracking software
FMD peak, % 3.50c
Resting BA diameter 20.04Woo
et al 200424Fasted (14 h) 250 4.5 30 s before, 90 s
after cuff releaseManual offline (trained,
blinded observer)FMD peak, % 1.20a
GTN, % 0.40
AUC, area under the curve; GTN, glyceryl trinitrate; BA, brachial artery.a P , .01.b Correspondence with authors.c P , .05.
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with other activities.12,23,24 Circuittraining consisted of a combination of(1) aerobic exercise (walking,running, ball games, and swimming)with resistance training;12 (2) aerobicexercise on a cycle ergometer withresistance training;23 and (3) aerobicexercise (modality not stated) withresistance and agility training.24 In 3programs, aerobic exercise alone wasperformed by using (1) a cycleergometer;22 (2) activities includingdodge-and-tag, jogging, and soccer;11
Aerobic exercise intensities weretypically based on baselinemaximal/peak testing data usinga percentage of either maximal heartrate (MHR),23,24 VO2max,12 orVO2peak.22 Watts et al23 prescribeda set heart rate zone (140 to180 bpm), whereas Murphy et al25
did not specify or measure intensityof exercise performed. Whenprescription involved a percentage ofmaximal/peak oxygen consumption,similar intensities were prescribed(55% to 65% VO2max
12 vs 50% to 60%VO2peak
22). When MHR was used todefine intensity, heart rate rangesspecified were 65% to 85%23 and60% to 70%24 MHR. Kelly et al22
stated that intensity was increasedfrom 50% to 60% to “near” 70% to80% VO2peak toward the end of theintervention. Of the 3 trials thatincluded circuit training,12,23,24 only 1specified the intensity of the resistancetraining (55% to 70% of pretrainingmaximum strength).23
Exercise Duration
Farpour-Lambert et al12 and Wattset al11,23 prescribed 60 minutes ofexercise, whereas Woo et al24 used 75minutes. Table 1 outlines thesubduration of activities performed inthis time. In Kelly et al,22 durationprogressed from 30 to 50 minutes inthe last 2 weeks, and Murphy et al25
increased duration from 10 to 30minutes in week 5, by 5-minuteincrements each week.
Circuit training was used toincorporate both aerobic exercise andresistance training. Training time ofeach modality varied, with ratios of 3:2,12 1:3,24 and 1:123 (aerobicexercise:resistance training).
Exercise Frequency
Frequency of training sessions rangedfrom 2 to 5 days/week, with a medianof 3 days/week. Woo et al24
prescribed 2 training sessions eachweek, whereas Farpour-Lambertet al12 and Watts et al11,23 prescribed3 training sessions each week. Theremaining 2 studies prescribedtraining on 422 and 525 days perweek. The largest mean differences inFMD were seen in studies thatprescribed 323 and 525 sessions perweek. Among the 3 interventionsusing a frequency of 3 weeklysessions, the mean difference in FMDvaried from 20.72% to 3.50%. Thisvariation is likely due to disparities inprescribed modality, duration, andintensity between the studies. Thesedisparities add difficulty inattributing improvements in FMD toa particular session frequency.
Exercise Supervision
Three training programs entaileddirect supervision for the duration ofthe intervention. This was provided
by 2 experienced physical educationteachers,12 researchers,22 exercisephysiologists,11,23 and a team ofphysiotherapists.24 A self-administered home program wasused in 1 study for the duration of theintervention, and participants did notreceive any direct supervision.25 Theresearchers used a single trainingsession to teach participants use ofDDR equipment and daily logs. Dailylogs recorded DDR use and stepstaken while playing, which wereconfirmed with parental signature.
Exercise Adherence
When adherence to supervisedtraining sessions was reported, highattendance (83% to 90%) wasnoted.11,12,23 Murphy et al25
administered a home-trainingprogram in which adherenceremained satisfactory, as 75% ofparticipants completed sessions on5 days per week, and 15% completedsessions on $3 days per week.
Vascular Function
Pooling the data from the 6 trials, themean difference in FMD was 1.54%(95% CI 0.24 to 2.84), significantlyfavoring exercise (Fig 3).Heterogeneity between the studieswas displayed, with I2 = 70%, x2 testP = .004, and was accounted for usingrandom effects analysis.32
Watts et al11,23 found that vascularfunction (FMD) in obese children and
FIGURE 3Forest plot illustrating treatment effect of exercise on FMD compared with control. MD, meandifference.
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adolescents was significantly impairedrelative to lean age-matched controlparticipants (6.00% 6 0.69% vs12.32% 6 3.14%, P , .0001; 5.3% 60.9% vs 8.9% 6 0.8%, P , .05,respectively). The improvementresulting from exercise trainingnormalized vascular function in obeseadolescents, with no significantdifferences seen compared withlean age-matched control participants(8.8% 6 0.8% vs 8.9% 6 1.5%,P = NS).23
No significant differences were foundin brachial artery baseline diameterafter the exercise trainingintervention.11,22,23,25 Because of theinfluence of vessel size on FMDresponse, baseline vessel diametershould remain relatively stable forvalid comparisons to beundertaken.33
Body Composition
The mean difference in weight fromthe 6 studies was 20.55 kg (95% CI21.66 to 0.57), favoring exercise(Fig 4). These data were supported bya mean difference of 20.14 kg/m2
(95% CI 20.60 to 0.32) in BMI,favoring exercise (Fig 5). The meandifferences of body compositionvariables were nonsignificant. Theobservations were homogeneousbetween the studies in both analyses,with I2 = 0%, x2 test P = 1.0 and P =.99, respectively, and thereforea fixed-effects analysis wasperformed.32
Cardiorespiratory Fitness
After pooling data from 3 studies thatincluded maximal exercising testingand calculation of VO2peak,12,22,25 themean difference in cardiorespiratoryfitness was 3.64 mL/kg/min (95% CI1.57 to 5.70), significantly favoringexercise (Fig 6). Again, observationswere homogeneous (I2 = 0%, x2 testP = .99).
DISCUSSION
The main finding from this meta-analysis of 219 overweight and obesechildren and adolescents was thatexercise training instigated animprovement in endothelial function.Although exercise training had littleeffect on body composition,significant increases incardiorespiratory fitness were noted.Data pooling from 6 studies showedan increase of 1.54% in FMD,whereas data pooling from 3 studiesshowed an increase of 3.64 mL/kg/min in cardiorespiratory fitness.
The clinical relevance of theimprovement in FMD can beassumed from previous prognosticstudies. A meta-analysis of 5547adults associated a 1% increase inFMD with a 13% decrease incardiovascular events.13 Therefore,an improvement in FMD of 1.54% inthis at-risk pediatric populationwould be expected to amelioratetheir cardiovascular risk profile.Further reduction in risk may be
contributed by the 1-MET (metabolicequivalents) improvement incardiorespiratory fitness found inthe analyzed studies. Myers et al34
demonstrated that in adults, every 1-MET increase in exercise capacitywas associated with a 12%improvement in survival. Whereaselevated BMI, which remainedunchanged over the exerciseintervention, results in an increasedrisk of all-cause morbidity andmortality, increasedcardiorespiratory fitness confersa reduction in this risk.35
Previous studies in adult chronicdisease populations have shown thatexercise training induces changes inFMD. Moderate-intensity exercisetraining improved endothelium-dependent function in adults withhypertension,36 obesity,37 diabetes,38
coronary disease,39,40 and heartfailure,41 whereas no changes wereobserved in endothelium-independent function.42
Mechanistically, it is postulated thatrepetitive exposure to exercise resultsin upregulation of the nitric oxidedilator system.17,43 The endotheliumis activated during bouts of activityowing to mechanical stimulationsecondary to increased blood flowand shear stress.19,43 Improvementsin endothelium-dependent functioncan occur independently ofimprovements in risk factors such asblood lipids, blood pressure, obesity,and glycemic control.44,45
Although exercise training has beenshown to improve vascular functionin both animals and humans, thesechanges are rapidly lost after thecessation of training.46 In patientswith a recent myocardial infarction, 4weeks of exercise training resulted insignificant improvements inendothelium-dependent dilation.However, almost complete reversal ofthe enhancement in endothelium-dependent dilation was reported ina time-equivalent detraining period.47
Woo et al24 examined this effect ina group of participants who withdrew
FIGURE 4Forest plot illustrating treatment effect of exercise on weight compared with control. MD, meandifference.
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from the exercise training witha comparator group who continued toexercise until the 12-month timepoint. In those who withdrew, FMDreturned toward baseline and wassignificantly lower than directly afterthe intervention. Even so, FMD ofthe exercise withdrawal group didremain superior to the controlgroup at 1 year.
Although FMD is diminished in at-riskpopulations, compensation ofvascular structure may occur inoverweight and obese youth. Usingpulse wave velocity and pulse waveanalysis, Charakida et al48 illustratedthat overweight and obesechildren had reduced arterial stiffnesscompared with normal-weightchildren. The authors suggested thatconduit artery adaptation may occur
to subdue the hemodynamic effects ofadiposity.48 Tryggestad et al49
proposed that increased arterycompliance observed in obesechildren may be due to advancedgrowth and maturation comparedwith normal-weight children.Regardless, the current evidencesuggests that overweight andobesity affects vascular function(FMD) and structure (stiffness)dissimilarly. It is also relevant in thiscontext that studies have reportedcompensatory interrelated changesin vascular function and structure,with initial functional changesultimately being superseded bychanges in artery size andremodeling.19,20
The present meta-analysis was unableto extrapolate a relationship between
cardiorespiratory fitness and FMD, asjust 3 of the included studies conductedmaximal exercise tests.12,22,25
Furthermore, the discrepancies inexercise prescription (mode, intensity,duration, and frequency) betweenstudies add complexities whenattempting to ascertain an optimalprescription. Therefore, the exactexercise prescription required to induceclinically significant improvements inFMD cannot be established until moredata become available. It is alsoimportant to reinforce the competingeffects of exercise on body compositionand the consequent difficulty inusing body weight indices such asBMI. Several studies have reportedthat, although body weight and BMIare not decreased by exercisetraining, beneficial countervailingeffects occur through increases inlean body mass and decreases in fatmass.11,23 We recommend thatfuture studies focus on the impactof exercise training on bodycomposition, not BMI or bodyweight.
Limitations
Although this review does illustrate thepositive impact of exercise on FMD,a measure of vascular function, theincluded studies had methodologicallimitations. Heterogeneity of the FMDmeasure was high (x2 = 17.53, I2 =70%, P = .004), perhaps owing tovarying exercise training regimens ortechnical preparation and analyticalapproaches. Although this limitationsuggests that results should beinterpreted with caution owing tovariation in true effect sizes, statisticalheterogeneity was addressed throughrandom effects modeling within themeta-analysis. The optimum exercisetraining protocol to maximize healthbenefits in obese pediatric populationsis yet to be established. As such,current research consists of varyingexercise modes and intensity as well asdiffering session duration andfrequency. Furthermore, heterogeneitymay be due to the different FMDmeasurement protocols used, with
FIGURE 5Forest plot illustrating treatment effect of exercise on BMI compared with control. MD, meandifference.
FIGURE 6Forest plot illustrating treatment effect of exercise on cardiorespiratory fitness (VO2peak) comparedwith control. MD, mean difference.
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evolving guidelines and technologythe primary source of thisvariability. Discrepancies werepresent in image acquisitionalongside analysis techniques, ie,automated software11,22,23
compared with user-dependentmanual measurements,12,24,25
which are likely to influence theoutcome. A recent guidelinesdocument was produced toovercome some of the technicaldifficulties between laboratoriesusing the FMD approach.30 Thecurrent review did not includestudies of vascular structure,measured as arterial stiffness,because of a limited number ofstudies reporting both vascularfunction (FMD) and structure(arterial stiffness) measures.Furthermore, publication bias mayhave been introduced by limiting themeta-analysis to studies in theEnglish language.
Whereas the mean difference ofFMD% was 1.54%, this value lieswithin the range of variability of thedifferent protocols. It is importantto note, however, that 5 of the6 studies reported improvementsgreater than the clinicallysignificant value of 1.0%.11,22–25
Furthermore, 3 of thesestudies11,22,23 used the goldstandard automated analysisapproach, suggesting greaterreliability and validity of findings.30
Most studies reviewed involved smallsample sizes, with a total of 219participants included in the meta-analysis, and male-to-female ratioswere unequal in 2 of 6 studies.12,24
Differing study and participantcharacteristics such as chronologicaland maturational age are confoundingfactors that may have influencedFMD results. Not only did the criteriafor overweight and obesity varybetween reviewed studies, but 3 of 6studies presented pooled FMD datafor overweight and obeseparticipants, therefore restricting themeta-analysis to the entire
population. Combining overweightand obesity may result in varyingstages of vascular dysfunctionamong the population studied. Theinfluence of exercise at each stage ofvascular remodeling and dysfunctionis currently unknown. Furtherresearch concentrating on specificpopulations with particular exerciseinterventions will allow for moreconcise prescription guidelines tobecome available.
Feasibility
Strong adherence to any exerciseprogram is required for short- andlong-term efficacy. In the studiesidentified in this review, adherencewas high, ranging from 83% to 90%in supervised programs. However,long-term adherence to theintervention was not examined, ie,whether individuals continue theexercise program after thesupervised exercise-training period.Previous examinations of theeffectiveness of lifestyleinterventions in pediatric obesitysuggest that these interventionsare effective in improvingcardiometabolic outcomes for #1year.50 Again, uncertainty surroundsthe effectiveness of such programsover a longer period of time.
Practitioners and public healthofficials face much difficulty inencouraging regular exercise amongchildren and adolescents. Currentworldwide data suggest that only5% to 50% of children andadolescents are meeting physicalactivity guidelines (60 minutes eachday), implying that permanentadoption of daily physical activityand exercise in these populationsmay be difficult.51–56 Supervisionand enjoyment are componentspositively related to adherence, andconsideration must be made whendesigning a training program. Wattset al11 designed a game-basedexercise program involvingactivities such as dodge-and-tag,jogging, and soccer, which resultedin a high attendance rate. Educating
children and adolescents aboutways to incorporate regular exerciseinto daily routines may be helpful inestablishing appropriate lifestylebehaviors from an early age. Large,longitudinal studies are required tofurther investigate this notion.Although the current evidenceregarding physical activity trackingthroughout life is mixed, severalstudies suggest that physicalactivity behaviors in late childhoodand early adolescence can track intoadulthood, emphasizing theimportance of early-lifeinterventions.57–60
CONCLUSIONS
This meta-analysis indicates thatexercise is able to induceimprovements in FMD in overweightand obese children and adolescents.The magnitude of increase (∼1.5%)would be expected to restorediminished vascular functionreported in this at-risk pediatricpopulation. This review thereforesupports the notion that exercise canbe used as a therapy in pediatricobesity to reverse reduced vascularfunction, restoring FMD to levelscomparable to those observed innormal-weight children andadolescents. Considering theheterogeneity and small sample sizeof this analysis, further research iswarranted to establishdose–response effects together withoptimal exercise modality. Extendedpostintervention follow-up willascertain the long-termsustainability of exercise in thetreatment of diminished vascularfunction.
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FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: This work was supported by St Olav’s Hospital, the Norwegian University of Science and Technology (grant #9527), and the Wesley St Andrew’s Research
Institute (grant #2014-01).
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
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originally published online August 10, 2015; Pediatrics Coombes
Katrin A. Dias, Daniel J. Green, Charlotte B. Ingul, Toby G. Pavey and Jeff S.Exercise and Vascular Function in Child Obesity: A Meta-Analysis
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