DTIC ADA489742: Obesity and Obstructive Sleep Apnea: Or is it OSA and Obesity?

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Pathophysiology15(2008)71–77
Obesity and obstructive sleep apnea: Or is it OSA and obesity?
Robert Carter IIIa,b,∗, Donald E. Watenpaughc,d
aCentredeRechercheduServicedeSante´desArme´es,LaTronche,France
bUnitedStatesArmyResearchInstituteofEnvironmentalMedicine,Natick,MA,USA
cSleepConsultantsInc.FortWorth,TX76104,USA
dUniversityofNorthTexasHealthScienceCenter,DepartmentofIntegrativePhysiology,FortWorth,TX76107,USA
Received5March2008;receivedinrevisedform29April2008;accepted30April2008
Abstract
Obstructivesleepapnea(OSA)consistsofrepetitivechokingspellsduetosleep-inducedreductionofupperairwaymuscletone.Millions
ofadultsandchildrenliveunawareofthiscondition,whichcanhaveaprofoundaffectontheirhealthandqualityoflife.Obesity,gender,
genetic, and hormonal factors mediate risk for OSA and interact in a multifaceted manner in the pathogenesis of this disease. Obesity is
themostestablishedandprimaryriskfactorgiventhatbodymassindex,visceralfat,andneckcircumferencearemajorpredictorsinthe
clinicalexpressionofOSA.ManystudieshaveshownweightlossorgainsignificantlyimpactsOSAseverity.Morerecently,accumulating
evidenceindicatesOSApromotesweightgain,obesity,andtypeIIdiabetesinavarietyofways,suchthatobesityandOSAformmultiple
interleavedviciouscycles.Thus,creativestrategiestoincreasephysicalactivity,improvediet,andotherwisefacilitateweightmanagement
becomeparticularlyvitalgiventheepidemicsofobesityandOSAintheUnitedStates.Inthisregard,theAmericanCollegeofSportsMedicine
recentlylaunchedthe“ExerciseisMedicine”(initiativeexerciseismedicine.org).Inthefuture,medicationsmayemergetotreatobesity,OSA,
andtheirsequelaewithminimalsideeffects.However,thereareeffectivewaystoapproachtheseproblemsnowwithoutwaitingfor“the
magicpill”.
PublishedbyElsevierIrelandLtd
Keywords: Physicalinactivity;Exercise;Sleepdisorder;Obese;Ethnicity;Bodyweight
1. Introduction are not diagnosed [3–5] and this proportional may be even
greater in children [6,7]. In recent years, the prevalence of
Obstructivesleepapnea(OSA)isadisordercharacterized OSAhasincreasedespeciallyrapidlyinobesechildren.
by partial or complete narrowing of the pharyngeal airway BasedontheWorldHealthOrganizationandTheNational
during sleep, resulting in repeated episodes of airflow ces- InstitutesofHealthcriteriafordefiningoverweightandobe-
sation,oxygendesaturation,andsleepinterruption.Overthe sity[8],theirprevalencenowconstitutesanepidemic[1,2,9].
past 25 years, the prevalence of overweight and obesity in IntheUnitedStates,∼55%ofmenand50%ofwomenare
developedcountrieshasincreasedsignificantlyacrossallage presentlyoverweightorobese[2,9].Theconnectionbetween
groups and ethnic populations, and consequently has con- OSA and obesity is very complex and likely represents an
tributed to the public health burden of sleep apnea [1]. In interaction of biological (i.e., sex, racial, genetic, and neu-
spiteofthehighandincreasingprevalenceofOSA,mostpri- rohormonal) and lifestyle factors. Therefore, understanding
mary care physicians in the United States under-recognize themechanismsofobesity-relatedOSAisimportantforpre-
the public health impact of this disease [2]. In fact, it has ventionandmedicaltreatment,especiallyinchildren.
beenestimatedthat60–80%ofadultsAmericanswithOSA The purpose of this review is to explore the relationship
of obesity and sleep apnea from epidemiological studies,
describe the complex, interleaved vicious cycles that con-
∗ Corresponding author at: Department of Human Factors, Centre de
nect the two diseases, and raise some intriguing questions
RechercheduServicedeSante´desArme´es,LaTronche,France.
concerningtreatmentofobesityandsleepapneainchildren
Tel.:[phone].
E-mailaddress:[email protected](R.CarterIII). andadults.
0928-4680/$–seefrontmatter.PublishedbyElsevierIrelandLtd
doi:10.1016/j.pathophys.2008.04.009
72 R.CarterIII,D.E.Watenpaugh/Pathophysiology15(2008)71–77
2. ObesityandancillaryriskfactorsforOSA
Numerousriskfactorsincludingoverweight/obesity,age,
sex,race/ethnicity,andheritablefactorsarewelldocumented
inthepathogenesisofsleepapnea.Nevertheless,obesityhas
been consistently demonstrated as one of the greatest sleep
apneariskfactors[10].Severalcross-sectionalstudieshave
consistently found a relationship between body mass index
(BMI)andtheriskofOSA.Thereportedprevalenceofsleep
apnearangesfrom40to90%inindividualswithabodymass
index >40kg/m2 (severe obesity) [8,11]. Significant sleep
apnea is present in 40% of obese persons and over 70% of
sleepapneapatientspresentwithobesity[12].
ObesityistheonlymajorOSAriskfactorthatisreversible.
Weightreductionintheshortterm(1–2years)leadstoabetter
metabolic regulation of patients with OSA [5]. A prospec-
Fig.1. Effectsofweightchangeonapneahypoapneaindex(AHI)(from
tivestudyinWisconsinresidentsshowedthata10%weight [11,22]).
loss predicted a 26% decrease in sleep apnea severity (i.e.,
apnea hypoapnea index (AHI)) (Fig. 1) [11]. Furthermore, menareat2–4-foldgreaterriskforsleepapnea,andrecent
reduced apnea frequency followed weight loss in another evidence suggests that this difference may be linked to
cohortstudy[13].Although,theexactmechanismsofweight sex-relateddistributionofadiposetissue[15,16].Ingeneral,
lossanddecreasedOSAsymptomsarenotfullyunderstood, women exhibit less deposition of adipose tissue around the
factorssuchasreducedfatdeposition[14]inandnearairway neckandabdomencomparedtomen,andthishasbeenshown
structuresandimprovedneurophysiologicregulationofres- tocontributetoriskofsleepapnea[17,5,10].Inobeseindivid-
pirationarelikelyimportant[15].Inaddition,obesitymaybe uals,adiposetissuedepositssurroundingtheairwaydecrease
involved in the regulation of chemoreflex function through dimensionsoftheupperairwayandcontributetoincreased
neurohormonal mediators such as leptin, which decreases airflow resistance [14]. In older men and postmenopausal
whensleepapneapatientsloseweight[5].Thus,thesepoten- women,increasedfatintheneckandcraniofacialareasmay
tial mechanisms likely work in concert to act as a vicious increasesleepapneaprevalence[18,19].Differencesinpha-
cycle in the pathogenesis of OSA and weight body gain ryngealanatomy(i.e.,length)andventilatorystability(dilator
(Fig.2). muscle activation) may explain some of the gender differ-
ences,butitislikelycomplexandmultifactorial[14,20].In
2.1. Gender children,however,alinkbetweenpharyngealfatandstruc-
tureandOSAisnotsupportedbytheresultsofarecentstudy
Itisnotentirelyclearwhysleepapneaislesscommonin [21].Furthermore,epidemiologicalstudiesandcasereports
womenthanmen.Nevertheless,severalstudiesindicatethat ofOSAandsnoringfrequencyhavereportedsimilarpreva-
Fig.2. Proposedmechanismsactingasaviciouscycleinthepathogenesisofobstructivesleepapneaandobesityandthepotentialinfluencesofsharedand
non-sharedgenes.
R.CarterIII,D.E.Watenpaugh/Pathophysiology15(2008)71–77 73
lenceratesamongschoolageboysandgirls[22],suggesting 2.4. Geneticsandfamilialfactors
otherfactorslikelyplayaroleinadultgenderdifferences.
Independently,thegeneticdeterminantsforobesityhave
2.2. Age beendescribedintheliteratureforseveraldecades[31]and
likelyplayaroleintheviciouscycleofobesityandweight
Aging has been viewed as a major factor in the patho- gaininsomeindividuals(Fig.2).Historically,studiesfrom
genesis of sleep apnea [3,22,15,10]. The highest reported the United States and Europe have reported that the heri-
prevalenceofOSAisinmen45–64yearsoldandinwomen tability of body weight is estimated to be 50–80% [16,26].
over 65 years of old [22,23]. However, accumulating evi- Stunkard et al. found that body weight and size of adopted
denceforincreasedOSAprevalenceinchildrenischanging children was more likely to reflect their biological parents
howcliniciansandscientistsviewageasariskfactor[24]. than their adopted ones [32], further supporting the role of
Recently,onestudyshowedthatalthoughtheprevalence heritabilityindeterminationofbodyweight.Morerecently,
of OSA may be less in younger individuals, the impact of several studies have completed genetic scans in obese and
untreated OSA on behavior, mood, and excessive daytime non-obeseindividualsandidentifiednumerousgenesassoci-
sleepiness may be more severe. In fact, Castronovo et al. atedwithheritabilityofobesity[16].
reported that as many as 13% of children between 3 and 6 Whereas, the significant familial linkage to obesity has
years old snore frequently and the prevalence of OSA may been known for many years, the genetic determinants and
be as higher as 2–5% in middle school-aged children [25]. family history of sleep apnea has been described more
Inobesechildren,evenhigherprevalenceratesofOSAand recently [33,16,26]. Several studies have shown a signifi-
snoring have been reported [26]. Differences in sampling cantfamilialandheritabilitycomponentinthedevelopment
methodology (i.e., questionnaires, respiratory monitoring ofclinicalobstructivesleepapneawithincreasingattention
techniques), definitions of respiratory events, interpretation givenobesechildrenandtheirgeneticsusceptibilitytosleep
ofpolysomnographyfindings,andpopulationsstudiedmake apnea[26].Patelshowedthatindividualswithrelativeswith
it more challenging to accurately predict the prevalence of ahistoryofsleepapneaweremorethantwiceaslikelytothe
OSA in children and adolescent populations. Given that disease[16].
untreatedsleepapneacompromisesphysical,behavioral,and
cognitive development in children, more investigation into
mechanismsofthesesequelaeisneeded. 3. DoesOSApromoteobesity?
2.3. Raceandethnicity The section above summarizes how obesity causes or
exacerbates OSA. Over the last several years, emerging
Mostoftheinter-ethnic/racestudiesofOSAintheUnited evidencesuggeststhatOSApromotesweightgainandobe-
States have compared African Americans and Caucasians. sity.
ExistingdatasuggestthatAfricanAmericansexhibitsignifi- OSArepeatedlyinterruptssleepandtherebymakesadults
cantlygreaterriskforOSAandarediagnosedlaterwithmore sleepy during the day. This daytime sleepiness translates
severeOSA[27,3,28,29].Theprevalenceofoverweightand into inactivity, and these symptoms correlate with OSA
obesityarealsogreaterinAfricanAmericans[1]andalong severity. For example, Basta et al. [34] recently reported
with OSA can contribute to poor health status and quality that logAHI strongly predicted Epworth sleepiness scores,
oflifeintheseindividuals.Ancoli-Israeletal.studiedcom- andself-reportedphysicalactivitydecreasedwithincreasing
munity dwelling adults and found that, after adjusting for sleepiness. They also found increased incidence of depres-
differencesinBMIandotherconfoundingfactors,theodds sion with increased Epworth score in their sample of 365
ofhavinganAHIof30orgreaterwere2.5timesgreaterin women and 741 men. An earlier study by Hastings et al.
AfricanAmericanswhencomparedtoCaucasians[27].Data [35] of congestive heart failure patients demonstrated that
from the Cleveland Family Study showed that shared and thosewithsleep-disorderedbreathingwereobjectivelymuch
unshared genetic factors underlie the susceptibility to OSA sleepier (Oxford Sleep Resistance Test) and were 7% less
and obesity in African Americans, suggesting that genetic activeduringthedaythanthosewithoutsleepapnea.These
determinantsofobesityinthispopulationmayalsodetermine investigatorsalsoobservednegativecorrelationbetweenAHI
apneaseverity[28]. anddaytimeactivity.
LimitedevidencealsosuggeststhatincreasedOSApreva- Effects of sleep disturbance on energy metabolism con-
lence may exist in American Indians and Hispanic adults, stitute another possible mechanism for how OSA causes
due to increased prevalence of childhood and adult obesity obesity. The first reports of how inadequate or poor-quality
[29,9]. High prevalence of OSA has also been reported to sleep, and sleep apnea in particular, adversely affected glu-
significantlyimpactAsiancommunities[29,30].Thepreva- cosemetabolismappearedintheearly1990s[36–38].Since
lenceratesofOSAhaveonlybeenrecentlydescribedinmany then, accumulating data reinforce this finding [39–41]. For
otherWesterncountries[3,22,25,29]andarenotestablished example, Tasali et al. [42] recently documented that selec-
inmanypartsoftheWorld. tivereductionofdeltasleepcompromisesinsulinsensitivity.
74 R.CarterIII,D.E.Watenpaugh/Pathophysiology15(2008)71–77
Hormonesknowntoimportantlyregulateenergymetabolism, Nevertheless, some links are more hypothetical than others
such as growth hormone, are secreted during delta sleep. depending on the number and type of published works that
Therefore, the degree to which OSA interferes with delta testspecificpathophysiologicrelationships.
sleep may in part determine propensity for developing dia-
betesfromOSA.OSAappearstoincreasesecretionofand/or 3.1. DoestreatingOSAwithpositiveairwaypressure
alterresponsivenesstotheadipocytehormoneleptinandthe (PAP)reduceweight?
orexigenichormoneghrelin,andtheseeffectsandtheirpatho-
physiologicimplicationsremainsubjectsofstudy[43–47]. GiventheevidenceabovethatOSApromotesweightgain,
Medicationsforco-morbiditiesofobesityandOSAcon- itisreasonabletoexpectthatsuccessfullytreatingOSAfacil-
stituteaniatrogenicsourceofpathophysiologicexacerbation. itatesweightreduction.Indeed,Harschetal.[45]observed
For example, type II diabetes and depression are each thatPAPtreatmentreducedelevatedlevelsoftheorexigenic
extremely common in obese patients with OSA, and sev- hormoneghrelinby66%within2daysoftreatmentonset,and
eralclassesofdrugscommonlyprescribedfordiabetesand the same group recently demonstrated a 68% improvement
depression promote weight gain as a side effect [48–52]. ininsulinsensitivityafter∼3yearsofsuccessfulPAPtreat-
Therefore, such medications unfortunately help “close the ment [71]. Kajaste et al. [72] compared weight loss in two
loop”oftheviciouscyclebetweenOSAandobesity.Excel- groupsofobesemaleOSApatients:bothgroupsunderwenta
lentalternativestomedicationexist:regularphysicalactivity standardized2-yearweightlossprogram,butonegroupused
providesimmediate,ongoing,andexcellentbenefitfortreat- CPAPtreatmentduringtheprogramwhiletheotherdidnot.
ment of both diabetes [53] and depression [54–57], offers Surprisingly,CPAPusersexhibitedsimilarweightlosstothe
myriad other health benefits, and imposes virtually no neg- untreatedgroup.
ative side effects. In this regard, it would be interesting to As we follow patients long-term after they successfully
knowhowmanydoctorssincerelyrecommendandstrongly initiateandmaintainPAPtherapy,ourgeneralimpressionhas
encouragedailyenjoyablephysicalactivitybeforeturningto beenthattheydonotloseweight.Asacursoryassessment,
medications.Depressedpatientsareoftenapatheticandlack we reviewed follow-up data for 28 randomly selected OSA
motivationtoexercise,butthissimplyemphasizestheneed patients (13 women, 15 men) at 8–126 months (mean=42)
forimaginativewaysoffacilitatingenjoyableactivityinsuch afterinitiationofsuccessfulPAPtreatment.OSAwassevere
patients. in 71% of the group. Treatment success was defined as
OSAelicitscyclichypoxemiaandhypercapniawitheach nightly all-night PAP use confirmed by PAP machine data
respiratory event, and these synergistically interact to stim- uploads, along with stable arterial oxygen saturation as
ulateacute,andeventuallychronicelevationofsympathetic demonstratedbyin-homenocturnaloximetry.Amongother
nervoussystemactivity(SNA)[58,59,18].Chronicandinap- queries, our follow-up questionnaire asks patients whether
propriatesympathoexcitation,inturn,isanestablisheddriver PAP negatively or positively affects their daytime energy
ofhypertensionandcardiovasculardiseaseaswellasenergy levels,physicalactivity,andexertionaldyspnea.
dysmetabolismanddiabetes[60–62].Relativetohypoxemia, Seventy-ninepercentofpatientsreportedincreasedday-
the role of hypercapnia in OSA pathophysiology remains timeenergyrelativetopre-treatment,64%reportedincreased
muchlessstudied:medlinecitationsofthelatterequalabout activity,and36%reportedreducedexertionaldyspnea.Anec-
one-third of those for the former. Interactions between the dotes include an elderly patient who was delighted that he
two are interesting and complex; hypercapnia in fact may nowmowedhisentireyardwithoutstoppingtorest(before
counteract some deleterious effects of hypoxemia [63,64]. startingPAP,hehadtositevery10–15min),awomanwho
In addition to sympathoexcitation, hypoxemia accentuates refinishedherkitchencabinetsin1day(anunthinkablechore
free radical formation, which in turn incites the inflam- priortoPAPtreatment),andafatherwhoexhaustedhisyoung
matory response [19]. Growing bodies of work implicate children with activity at the local park (pre-treatment, he
chronictissueinflammationasakeypathophysiologicmedi- couldnotbeconvincedtogotothepark).Inspiteofpatient
ator of cardiovascular disease, diabetes, dementia, arthritis, perceptions of increased energy and activity, mean weight
andOSAitself[65–69]. increased 4% from 106.1kg (S.D. 23.9) kg at baseline to
Sequelae of obesity and OSA cross all organ systems. 110.1kg (S.D. 23.1) after at least 8 months of chronic suc-
For example, chronic excessive musculoskeletal loading cessfulPAPtreatment.Harschetal.sawnoweightreduction
from excess weight coupled with sustained tissue inflam- withPAPtreatmentofOSAintwodifferentstudies:onewith
mation cause arthritis [66]. The associated pain limits follow-upat2months[45],andanotherwithfollow-upat2.9
activity, which promotes further weight gain. Also, OSA years[71].
promotes edema formation which of course adds body Therefore,currentreportsandourclinicalimpressionsdo
weight in the form of water [70]. The above discussion notsuggestthatsuccessfultreatmentofOSAwithPAPleads
summarizes isolated cause–effect relationships that, when toweightloss.FortheobesepatientwithsevereOSA,associ-
linked and integrated into a “big picture”, form multiple atedinactivity,andstrongmotivationtoloseweight,itseems
interwoven vicious cycles between obesity and OSA certainthatsuccessfulPAPtreatmentwouldfacilitateweight
(http://www.sleepconsultants.com/motherdiagram.html). loss,butthisremainstobedemonstrated.
R.CarterIII,D.E.Watenpaugh/Pathophysiology15(2008)71–77 75
3.2. TheconundruminchildrenwithOSA adopt more aggressive, early approaches to weight control,
to preempt initiation of pathophysiologic vicious cycles.
Unlike adults with OSA, who usually experience exces- In this regard, the American College of Sports Medicine
sive daytime sleepiness, children with OSA commonly recentlylaunchedthe“ExerciseisMedicine”initiative(exer-
develop hyperactivity [7]. In fact, ADHD in children often ciseismedicine.org).Inthefuture,medicationsmayemerge
results at least in part from chronic sleep restriction and/or totreatobesity,OSA,andtheirsequelaewithminimalside
sleep pathology such as OSA, restless legs syndrome, or effects.However,thereareeffectivewaystoapproachthese
periodiclimbmovementdisorder[6,73,74]. problemsnowwithoutwaitingfor“themagicpill”.
Roemmich et al. [7] performed an illuminating study of
outcomes following successful treatment of OSA in chil-
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