Carrmt Vascular Pharmacologlt, 2007, t 000-000
Inflammation, Sleep,Obesity and CardiovascularDisease
M.A. Miller* andF.P.Cappuccio
Clinical SciencesResearch Institute, Ilarwick Medical School, Coventry, UK
Abstract: Evidenceis emergingthat disturbancesin sleepand sleepdisordersplay a role in the morbidity of chronicconditions. However, the relationshipbetweensleepprocesses,diseasedevelopment,diseaseprogressionand diseasemanagementis often unclearor understudied.
Numerouscommon medical conditionscan have an affect on sleep.For example,diabetesor inflammatory conditions
such as arthritis can lead to poor sleepquality and induce symptomsofexcessive daytime sleepinessand fatigue.It has
also beensuggestedthat poor sleepmay lead to the developmentof cardiovasculardiseasefor which an underlying inflammatorycomponenthas beenproposed.It is thereforeimportantthat the developmentand progressionofsuch disease
statesare studiedto determinewhetherthe sleepeffect merely reflectsdiseaseprogressionor whetherit may be in some
way causallyrelated.Sleeploss can alsohave consequences
on safetyrelatedbehavioursboth for the individualsand for
the society,for examplethe increasedrisk of accidentswhen driving while drowsy. Sleepis a complexphenotypeand as
such it is possiblethat there are numerousgeneswhich may eachhave a number of effects that control an individual's
sleeppattern.
This review examinesthe interactionbetweensleep(both quantityand quality) and parametersof cardiovascularrisk. We
alsoexplorethe hypothesisthat inflammationplays an essentialrole in cardiovasculardiseaseand that a lack ofsleep mav
play a key role in this inflammatoryprocess.
Aim: To review currentevidenceregardingthe endocrine,metabolic,cardiovascularand immune functionsand their interactionswith regardto sleep,given the currentevidencethat sleepdisturbances
may affect eachofthese areas.
Keywords: Sleep, obesity, cardiovasculm disease,inflammation, innate immunity.
INTRODUCTION
Sleepis a natural processand yet the exact purposeof
sleepand its effect on healthand diseaseremainsto be fully
elucidated.Both physiologicaland pathologicalsleep is divided into two states: non-rapid-eye-movement(NREM)
sleepand rapid-eyemovement(REM) sleep[]. It has been
suggestedthat it is crucial for the maintenanceand restoration of homeostasis
throughthe regulationof energy,repair
and infectioncontrol and that it may be importantin the programmingof thebrain[l-3]. It is now particularlyrelevantto
understand
the importanceof sleep,as sleepinghabitswithin
our societyhave been changingover a period of yearsas a
resultofdecreaseddependencyon day light hours,increased
shift-work and changesin lifestyle and home environments
[4, 5]. Statistics from the National Sleep Foundation in
America suggestthat approximatelyone-thirdof Americans
sleep6.5 h a nightor lessFig. (l) t5l.
It is well establishedthat sleep disorderssuch as sleep
apnoeacan lead to serioushealthproblemsincluding cardiovasculardisease[6-9]. New datasuggeststhat 'healthy' individualswho do not get enoughsleepmight be at risk of poor
healthin the future [0, 1l]. Moreover,there is increasing
evidenceto suggestthat sleepdisturbancesmay be an impor*Address correspondence
to this author at the Clinical SciencesResearch
Institute, Clinical SciencesBuilding-UHCW Campus, Warwick Medical
School, Clifford Bridge Road, Coventry, Cyz 2DX, UK; Tel: 024 7696
8666;Fax: 024 7696 8660; E-mail: Michelle.Miller@warwick.ac.uk
ts70-t6tt t07$50.00+.00
l*vr:*
**$,
parng{
lAl
EA
;"fi
ti6
n*
'tr*
,&t
,*i
,&I
:,8*
:tfi
n*
Fig. (1).Durationof sleepin theaverage
US population
in thelast
century
tant determinantof diseaseand morbidity andthat inflammatory processes
may play an importantrole [2, 3, 12, l3]. A
decreasein sleepleadsto an increasein inflammatorycytokines which are now believedto be importantin the developmentofcardiovascular
risk progression
[2]. Indeed,there
is an increasedrisk of heart attacksand strokesduring the
early morning and it is possiblethat sleephas an effect on
the endothelialfunction of blood vessels[14]. This review
focuseson risk factors for diabetesand cardiovasculardiseaseandtheir relationshipto sleepand inflammation.
Cardiovascular Disease,Sleepand Inflammation
Individuals who experiencesleep problems have been
shownto be at an increasedrisk ofcardiovascularevents[9],
@ 2007 Bentham SciencePublishers Ltd.
2
Current Vascular pharmacotogt, 2007, Vol S, No. 2
which is reducedfollowing successfultreatrnentwith Con_
tinuous.Positive,Airway pressure(CpAp), surgery (uvulo_
palatopharyngoplasty
(Uppp)) or oral applian.r'fr j]. Within
the.generalpopulation sleep complajnii are ur.y ,o*ron
and are often associatedwith midical, psychologicatand
socia-ldisturbances[16]. Inflammatory pror.rr., aie impor_
tant in the developmentand progresiion of cardiovascular
disease^and_it
is possiblethat disiurbancesin sleeppa$erns
may affecttheseprocessesFig. (2).
$laeplssr
I
,
Frs*inflam
matsry cy{akine*
I
,
I
f
Cardisva$sulsr
di*ease
Fig.(2).Sleeploss,inflammation
andcardiovascular
disease
Patientswith obstructivesleep apnea(OSA) syndrome
who have associatedcardiovasculaidiseasehave significantly elevatedC-reactiveprotein (CRp) comparedto ihose
yjth OSA syndrome but without cardiovasculardisease
(CVD) or thosewirhout OSA syndromeor CVD
[12].
Age,Sleepand Inflammation
Age is a risk factor for cardiovasculardiseaseand ageing
and is associated
with changesin length and quality ofiteei
as well as an increasein the prevalenceof sleepcomplainti
[I3]..S.leepproblemsincreas-e
with age and the deviloped
world.is experiencingan increasein its ageingpopulation.
'illnesses
I .ikewise,the numberof individualswittr ctrronic
is
increasing.It is therefore important that the bidirectional
effect of sleep on diseaseprogressionand developmentis
evaluated.Fufihermore,it has been demonstratedin young
adultsthatsleepdeprivationleadsto metabolic,systemicand
immunechangesthat are similar to thoseobservedin ageing
and age-relateddisorders [13]. However, although treitfri
elderlyadultsspendmore time in bed,they spendlesstime
asleepand are more easily arousedfrom sieepthan younger
individuals[17]. Ageing is associated
with an increasein
Sleep-Disordered
Breathing(SDB), daytimesleepiness
and
Miller and Cappaccio
insomniaas well as loud snoring,difficultiesmaintaining
s1eep,fatigue, mood effects and impairmentof daily activi
ties. These factors can lead to an increasein depression,
memoryproblems,a declinein cognitivefunctioningand
a
lowerqualityof life [18, t9,Z0l.
The_.ageingprocess is associatedwith changesin the
metabolicprocessand diseasedevelopmentand &idence is
accumulatingto suggestthat sleep_deprivation
is associated
with similar-changes.Furthermore,there is an increasin!
body of evidenceto suggestthat the ageingprocess,sleei
andthe inflammatoryprocesses
arerelaiedyZ.i_Z+1.It
is im'_
po.r?nttlat n9! only are sleep regulatorymechanismsstud_
ied but the effect of ageing on ihese processesare deter'boundaries
mined. A better understandingof the
between
normal and abnormalage-relatedchangesin sleepbehaviour
should allow the developmentof inierventionguidelines.
Moreover, the exact nature_of relationshipsanj causality
between sleep, age and inflammation remain to be eluci_
dated.Increasedlevelsof a numberof inflammatorymarkers
in elderly populationhave beenobserved,for exampleCRp
and interleukin-6 (IL-6) increasewith age
[Zt, iZ]. fur_
thermore,partial short term sleepdeprivatiin gives rise to a
similar pattem of CRp response[23]. Sleepieprivation is
also associatedwith an increased-geneexpiessibnof heat_
shockprotein[24l.It is thereforepoisiblethatsleepdeprivation may contribute to the increise systemic inflammation
observedin ageing.The exactprocesshoweverremainsto be
determinedbut may also involveoxidativestress
[25] or the
regufationof growth hormone 126l and its associitedeffect
on theimmunefunction.
Gender,Sleepand Inflammation
Men are at increasedrisk of CVD but it is not clear
whetherthis is associatedwith genderdifferencesin pattems
of sleep.It has also beensuggestedthat the menopausealso
may be a risk for sleep_disordered
breathing(SbB) t271.
Genderdifferencesin inflammatory markershave been ob_
served[28]. We have shownthat certainadhesionmolecule
levels are lower in women than in men
[2g]. Furthermore,it
is possiblethat the associationbetweeniteep anOcardiovas_
cular risk factors such as the Body-Mass_Index
(BMI) may
vary beh.veen
sexes,at leastin adolescents.
Knutsondemon_
stratedthat while short sleepmay have an effect on BMI in
young men this does not appearto be the case in young
women.[29].
Ethnicity, Sleepand Inflammation
SouthAsians have a higher risk of CVD than whites and
individuals of African origin appearto be protectedfrom
coronaryheartdisease(CHD) t301.
^ An increasedprevalenceof insomniahasbeenreportedin
Americanscomp_qgd
with whites,which may in part
,Africal
be attributableto ethnicdifferencesin associated
risk faclors,
:ulh-_3solgsity l3ll. Ir is not known whetherthis is preseni
in UK African individualswho have a much lower risk of
CHD than their American counterpaxts
[30]. It hasbeensug_
gestedthat there may be a genetic componentfor this increase[32] and it would thereforebe importantto studyboth
UK Africans and Africans in Africa. Diibetes and strokeare
high in UK Africans as well as African Americans.Ethnic
Intlammation, Sleep, ObesiE nnd Cardiovascular Disease
differencesin inflammatory markers have been observed
[28] which in part are associatedwith ethnic differencesin
cardiovascular
risk. It is importantthat future studiesinvestigatewhetherethnicdifferencesin CHD, diabetesand stroke
are in any way relatedto differencesin sleepdisordersand
whether or not there may be an underlying inflammatory
component.
Obesity,Sleepand Inflammation
Obesityis associatedwith an increasein SDB and OSA
(SAS) [33]. Obesityis becominga global epidemicin both
adultsand children and is associatedwith an increasedrisk
of morbidityandmortality as well as reducedlife expectancy
[341. It is clear that obesity may have its effect on CVD
through a number of different known and possibly as yet
Theseinclude dyslipidemia,hyperunknownmechanisms.
tension,glucoseintolerance,inflammation,OSAftrypoventilation, and the prothromboticstate [34]. Obesity leadsto a
changein an individual's metabolicprofile and an accumulation of adiposetissue.
Lack of sleepmay have an effect on the developmentof
obesity and subsequentCVD through a number of mecha-
Cunent VascularPharmacolog42007, VoI 5, No. 2
nisms.Spiegelet al, in the first randomizedcross-overclinical trial of short-term sleep deprivation,demonstratedthat
sleep deprivationwas associatedwith decreasedleptin and
ghrelinlevels[35]. This in turn wouldleadto a coincreased
comittantincreasein hunger and appetite,increasedinsulin
resistanceand accumulationof fat and decreasedcarbohydratemetabolismFig. (3). The individualsin this studywere
subjectedto extremeacutesleepdeprivation(<4 h per night)
and further studiesare requiredto determinethe effects on
thesehormonesof more modestsleepdeprivation(<5 h per
night),especiallyin the long-term[35]. A studyof422 children(boysand girls ofprimary schoolage(5-l0years))has
demonstratedan associationbetweensleepdurationand the
risk to developchildhood overweight/obesity [36]. Interestingly, the NursesHealth Study demonstrated
that while short
sleepdurationleadsto an increasein weight with time there
was no evidenceto suggestthat this was the result of an increasein appetite[37]. Thesefindings are in contrastto othersthat havedemonstrated
a clearrelationshipbetweenduration of sleep,ghrelin, leptin and appetite[35,38]. The findings from the NursesHealth Study suggestthat perhapsthe
effectsof sleepon obesity occur as a result of a changein
energy metabolism.Uncoupling proteins are proteins that
L&SKOT SLESF
HYFgTHiLfrII[US
-fitry*lxtlen w,fpfisfgf *lf$
f
*1'^1"1.^i
sro*ffi
""**-;;;
'iAFFeti*i-
" i Carfmydrate uttlbflnfin
.{ Fatutl[zatisn
i$ &a$tfisme{ility
'1&*ifi $*fr*:i{r}
"{.ts{8{ll€t$fg*erry
dffeste Bnsrgysfl endih.re
48{platFs aldocrine fLs'*ctio{t
,xri$nl*ta,]sli$rfl
nmut$rr
4rreutr*rs$tst*ltrs
iT**:AH**i
lc?g{,r}in
4**€s**e. *sllsrt
.t Uptakrofgluc{rse
,t Glycogen
deposlthn
in il.relhrer
'* Ghmose
rc{ease
hyr€ lider
.t F8tr tntake
"f trr!ryWWffiqndi*rr,s
Fig,(3).Effect ofthe lack ofsleep on energyregulatinghormones
3
4
Current Vascularpharmacolog,2007, VoL S, No.2
Miller and Cappuccio
uncoupleproton exchangeald ATp production. polymor_
phjc,variationin these.genes
hasbeenielatedto energyme_
tabo,llsm,
obesityand diabetes[39, 40]. Furthermore,
-irelli
et al demonstratedthat in animal studies,sleep
depiivation
was associatedwith an increasein Uncoupling protein
2
(UCP2) expressionin liver and skeletal .ir"iE
t4tl. Th;
latter is
_thelargest tissue in the body, -O t rn". and in_
UCP2 expressionin this tissue may have a poren_
.:T?":d
uauy targeettecton restingenergyexpenditure
[41].
Inflammatory processmay also underlie the elfect
.
of
sleepon w_eightgain. Recentitudies have shownthe importanceofadipose tissueasan endocrineorganwhich
is capable of.secreting,€unongothers,inflammato'rycytokines
It is.thereforepossible that a lack of sleep acting via[42].
the
regulatoryhormonesabovemay lead to un ln..eased fut
accumulationand increasedsecretionof pro_inflammatory
cytokines. There is evidence to suggeit that inflammatorv
processes
.may-!e important in obesity and may mediati
some of the effects observedwith intreaseOwiigtrt.
We
demonstrated
that an approximate2yo increasein solubleEselecrlntevetls associated
with a I unit higher BMI and a
0.01 unit greaterWaist-hip_rario (WHR)
J+51.eaiponectln,
which is a protectivecytokine however,'isnot reduced
in
qlt:nll with OSA comparedwith matchedcontrolswithout
OSA [44]. In a separatestudy, individuals with OSA
who
underwentCPAP treatmenthad associatedchangesin in_
flammatorymarkers(IL-6 and ICAM-l)
t451.ih; tevelsof
the inflammatorymarkerswere also associatedwith
resistin
levels. Likewise, CpAp treatmentdecreasedthe levels
of
ICAM-I and IL-8 [46]. prospective,longirudinal
srudies
nowever,are required to examine the causal link
-- between
sleepand obesityand inflammato.ymeaiato.s.
Glucoseand Insulin Regulation,Diabetes,Sleep
and In_
flammation.
Diabetescanleadto the development
of sleepabnormali_
ties. Findings from the SleepHeart Health Stuiy
indicated
thatdiabetesis associated
wiih periodicUr.utfrin!,a respira_
tory abnormalityassociatedwith changesin the ientral
con_
is thousht
fliutotuu.t, maybring
1a7..)...rr
T].:t"y^:ltllllon
about
sleepabnormalities
as a resultof its deleterious
effecti
on centralcontrol of breathing.However, it is also
important
to note.that sleep loss is associatedwith a decrease
in glucosetolerance,a highereveningcortisollevel and
increied
sympatheticactivity Fig. ( ). ireatment for OSA
has also
Deenassocrated
with beneficialchangesin insulinsensitivity
[45]. Furtherstudiesarerequiredto iivestigaG whetirersleep
losscanpredict changesin glucosernrtuUoirrn fr-ui.e
u.rru.
Laboratory
studies
of
healthy
young
adults,
demonstrated
.
that recurrent partial sleep re#iction-wa, ^r*iut.d
,ith
alterationsin glucosemetabolismincludingdecreaseO
glu_
cose tolerance and insulin sensitivity
[4d]. Furtherm6re,
sleeprestrictionled to changesin appeiite'control,in that
the
#legpf*s,#*rant6t$*fi
Seftsvi*ur s|**p rffifrtst*sn
e,g"n$**
e"g",ff
*rfsr$*wsfk*rtgh#ilrs
Sleepdeficit
t
t
I
i
lncreaseds)rnpath€fic
output
lncreasedeor{isol
*
l*sulin re,si* lrw
t
I
*
l$,*ightg*in
Fig, (a). Sleeploss,glucose& insulin regulation
Inflammation, Sleep, Obesity and Cardiovdscular Disease
levels of the anorexigenichormone leptin were decreased,
whereasthe levels of the orexigenicfactor ghrelin were increased(seepreviousFigure (effect ofsleep on energyregulating hormones)).These changeswere associatedwith an
increasein hungerand appetite.Over a long period this may
lead to weight gain, insulin resistanceand Type 2 Diabetes
[48]. A recentlongitudinalanalysisfrom the MONICA study
hasdemonstrated
that in both women and men the difficulty
in maintainingsleepas opposedto the difficulty in initiating
sleepwas associatedwith a higher risk of type 2 Diabetes
during the subsequent
mean follow-up period of 7.5 years
ll0l.
Theseand similar findingshave led to the suggestionthat
sleep and sleep disordersmay have a prominentrole on
metabolicand endocrinefunctions[49, 50]. Thereis a large
body of evidenceto suggestthat oxidative stressand inflammationplay a large role in the developmentof diabetes
and the developmentand progressionofthe associatedcomplications[51]. The exactcausalpathwaysremainto be elucidated and likewise it remains to be seen if the diabetic
complicationsassociatedwith sleep disturbanceshave an
underlyinginflammatorycomponent.
Blood Pressure,Sleepand Inflammation
Blood pressurenormally displays a nocturnaldip of
aboutl0% [52]. Non-dippersare at an inueasedrisk of CVD
and African Americans tend to display more non-dipping
characteristics
comparedto Caucasiansand this is associated
with an increasein sleepdisorderedbreathing[53]. SDB has
been identified as a risk factor for adversecardiovascular
outcomesin the elderly and is also associatedwith an increasein poststrokemortality[54]. Likewiseevidencesuggeststhat OSA palientshave an increasedincidenceof hypertension
comparedwith individualswithoutOSA, andthat
OSA is a risk factor for the developmentof hypertension[7].
Acute deprivationof sleep in healthy subjectsleads to an
increasein blood pressureand SNS activationand evidence
is growing,which suggeststhat there is a causalrelationship
betweenOSA syndromeand hypertension.[8]. A recentlongitudinal study demonstratedthat short sleepduration(<5 h
per night) was associatedwith a significantly increasedrisk
(hazud ratio,2.10;95yoCI, 1.58to 2.79)in
of hypertension
subjectsbetweenthe agesof 32 and 59 years.Furthermore,
adjustmentfor confoundingfactors such as obesity and diabetesonly partially attenuatedthis relationship[11]. Studies
demonstratedan associationbetweenhypertensionand inflammationbut potential causalpathwaysremain to be examinedin more detail. It is however of interestto note that
patientswith OSA exhibit increasedresting heart rate, decreasedtime duration betr.veen
fivo consecutiveR wavesof
the electrocardiogram(R-R interval) variability, and increasedblood pressurevariability. As well as observed
changesin inflammatory mediatorssuch as CRP. OSA is
also associatedwith changesin fibrinogen and plasminogen
activatorinhibitor [7], which are important in the developmentof hypertensionand cardiovasculardisease.
Lipids, Sleepand Inflammation
OSA may leadto hypoxia and the subsequentgeneration
of reactiveoxygenspecies(ROS). Thesein tum can lead to
Currmt VascularPharmacologlt,20M, VoL S, No. 2
5
an increasein lipid peroxidation.Indeed,increasedinflammatory markers and markers of oxidative stresshave been
found in patientswith OSA [55]. Although a recentstudy
concludedthat systemic inflammation is a characteristicof
OSA patientsit failed to find any differencein lipid peroxidation or antioxidantdefence (as measuredby superoxide
dismutase(SOD) betweenparientswith OSA (n=25) and
controls(n=17)[55].
MetabolicSyndrome,Sleepand Inflammation
Metabolic syndromeis characterised
by the clusteringof
cardiovascular
and metabolicrisk factorsin a given individual.Theseincludethe presence
ofcentralobesity,an adverse
lipid profile (high triacyglycerols
and low high densitylipoprotein(HDL) -cholesterol),
raisedblood pressure
and insulin resistance
or glucoseintolerance.It has also beensuggestedthat theremay be an increasedpro-inflammatorystate
[56]. Furthermore,Vgontzaset al. [57] clearlydemonstrated
that inflammatorycytokinesareincreasedin individualswith
OSA andthey proposedthat thesecytokineswerethe mediators of excessivedaytime sleepiness
(EDS). They demonstrated the importanceof visceral fat in OSA syndrome.
They suggestedthat sleepapneaand sleepinessin obesepatients may be manifestations
of the metabolicsyndrome.
Indeed in the US, data from the Third National Health and
Nutrition ExaminationSurvey(1988-1994)has shownthat
in the US population the prevalenceof the metabolicsyndromeparallelsthe prevalenceof symptomaticsleepapnoea
in generalrandomsamples[57].
Inflammation and Sleep
Immunemoleculesaltersleeparchitecture
andsleepdeprivation alters neuroendocrine
and immuneresponse[58].
Furthermore,immune systemactivationand neuroendocrine
responses
alter sleep [58]. In addition,sleep quality may
affect susceptibilityto infection,as well as onesability to
frghtoff infection[59]. The concentration
of high-sensitivity
CRP (hsCRP)is predictiveof future cardiovascularmorbidity [60] and at the sametime short sleepdurationand sleep
complaints are associatedwith increased cardiovascular
morbidity [9,23]. CRP levels are elevatedfollowing both
acute total and short term partial sleep deprivation [23].
Comparedwith control subjectsthe levelsof TNF-c, IL-6,
hsCRP,adhesionmolecules,and monocytechemoattractant
protein-l are markedly and significantly elevatedin patients
with sleepapnoea[61]. Short term sleepdeprivationgives
rise to a numberof effectson the immunesystemincludinga
decrease
in cellularimmuneresponseon the following day
to viral challengeis
12,62].Likewise,the immuneresponse
alsoreduced[63]. It remainsto be elucidated
whethersimilar
effects on the immune system are observedin individuals
with long-termsleepdeprivation.
As well as infectious agents,it is known that other diseasescan lead to an increasein systemicinflammationsuch
as arthritis.Studiesin patientswith rheumatoidarthritishave
revealedpattemsof sleepdisturbancesthat arc not associated
with the concomitantpain [64]. The innateimmunesystem
pathway can be activatedby the outer lipopolysaccharide
(LPS) componentof bacterialcell membranes[65]. Such
stimulationof the innateimmunesystemoccursthroughtoll-
6 Carrent Vascularpharmacologt,2007, VoI S, No.
2
like receptorsand can lead to an increasein inflammatory
cytokinesFig. (5).
LPS increasesNREM and reduceREM sleep in rabbits
[66]. In.rats, a 30 day infusion of LpS led ti a loss of
nypocretlnneurons.This suggests
that LpS and the resulting
inflamm.ation
may play a rolJ in the lossof hypocretinneuronswhichoccurin sleepdisorderssuchasnarcolepsy
[62].
^^In humanstudies,Gundersenet al. [6g) investigatedthe
effect of prolonged physical activity with'concomitant
en_
ergy and_
sleepdeprivationon leukocytefunction. They demonstrated.that leukocytesrespondedwith an increasingre_
Ieaseof inflammatorycytokineswhen challengedwith
LpS
as the study-progressed.Furthermore,they fiund that
the
responseto the anti-inflammatoryagenthydrocortisonewas
reduced.Theseresults demonstratethat multifactoral stress
can activateimmune cells and prime their responseto a microbial challenge[63]. However, it is importantto note that
sleep deprivationcan alter catecholamaines
[69], which in
turn may havean effect on white blood cells. The'exactpart
played and the importanceof the sleep deprivation
in rhis
multifactorialstressneedsto be further inu.rtigut.d.
The intermittenthypoxia/reoxygenation
processthat oc_
curs in OSA syndromeis associatedwith a ielective activa_
Miller and Cappuccio
tion of
.inflamm-at9ryprocessesas demonstratedby the increase in circulating tumour necrosis factor_alph; (TNF_
.
{pha) .andNFkappaB levels whereasadaptivepathwaysas
d_etermined
by the measurementof the aOaptiie regulator
HIF-l are not increased[70]. Fr:rthermore,CirAp theiapy
is
ableto normalisethe incieasedTNF_alphat.uet,
JZOI.ilsa
syndrome is associatedwith an increasedmonocyte
NFIuppug activity. Moreover this is also associatedwith an
increasedexpressionof iNOS protein
[71]. Furtherinformation on the links beh.veenthe innate immune system
and
sleepcanbe foundin a recentreview
[3].
Cortisol,-Sleep,the SympatheticNervous System(SNS),
Hylothalam ic pitu itary Adrenocortical (HiA)_axis
anO
Inflammation
Dysfunctionof the HpA axis at any level (corticotrophin
releasinghormone (CRH) receptor,giucocorti.oid r...itor,
or mineralocorticoidreceptor)ian dGrupt sleep
[72]. Sieep,
and.in particular_deep
sleep,has an inniUitoryinfluenceon
rne HrA axts, whereasactivation of the HpA axis leads
to
arousal [72]. Furthermore,excessivedaytime sleepiness,
as presentin sleepapnoea,narcolepsy,and idiopathic
luch
nypersomnla
are associated
with an increasein the secretion
*lrea* h*rmsnsn
Frc**smr?usarii*
Ertsldns*;**r#.ffia rxrn*t*rycaspNrlne,#:
ffi$ergy'regu*nllefxAFpgfftuEfifitr#*
Fig' (5). Possibleinteractionbetweenthe innateimmunesystemand sleepregulation
Inflammation, Sleep, Obesig and Cardiovascular Disease
of inflammatorymarkers[73]. It hasalsobeensuggested
that
HPA axis hyperactivitymay be a consequence
of OSA and
may indeedcontributeto secondarypathologiessuchas hypertensionand insulin resistance.[72]. On awakening,there
is a rise in cortisol levels.The time of awakeningand stress
are thoughtto influencethe magnitudeof the cortisol awakening response(CAR) 1741.A recentstudy which examined
men and women London Underground shift-workerssuggestedthat early-waking,stressearly in the day, and associated cortisol levels often coincide with sleep disturbance.
[74]. In a recentpilot study, which examinedthe sleepand
the stress-induced
cortisol responsein children and adolescents,there were signifrcantassociationsbetweenthe selfreportedsleep quality but not quantity and the cortisol response[75].
Depression,
Sleepand Inflammation
When comparedwith controls depressedpatientshave a
significantnocturnalincreasein circulatingIL-6 and sICAM
[76]. Furthermoreboth sleep latency and REM density are
associatedwith these inflammatory markers [76]. It is of
interestto note that in patientswith depression,total sleep
deprivationleadsto an increasein renin secretionand a concomitanttrend for a decreasein HPA axis activity in the recovery night [77]. lt has been suggestedthat thesechanges
could be a "fingerprint" of a rapidly antidepressive
treatment
1771.
SocialEconomicStatus (SES),Sleepand Inflammation
Low SESis frequentlyassociatedwith sleepdeprivation
and ethnic differencesin SES and sleeppatternsexist [78].
African American children have an increasein sleepdisordered breathing compared with white Caucasianswhich
could contributeto an increasein inflammatory processes
and associatedCVD risk [79]. However, further studiesare
requiredto examinethis hypothesis.
Alcohol,Sleepand Inflammation
There is someinconsistencyin the literaturebut in general it is acceptedthat moderate-to-large
quantitiesofalcohol
arecapableofaggravatingsevereOSA [80]. It hasalsobeen
suggestedthat there are inter-relationshipsbetweenalcoholism, sleeplossand ethnicity,which may also operatein a bidirectionalmanner[81]. It has beenpostularedthat disturbed
sleep patternseffect hormonal, autonomic nervous system
and immunefunction and might contributeto the increased
mortalityrateobservedin AfricanAmericanalcoholics[81].
Paediatrics,Sleepand Inflammation
Children with sleep disorderedbreathing have higher
CRP levelsthan childrenwho do not [82]. Furthermore,947o
of the children studied who had elevatedCRP levels also
reportedexcessivedaytimesleepinessor learningdifficulties
as comparedto 620/oof children who had CRP levels in the
normalrange[82].
Genes,Sleepand Inflammation
In the brain the sleep-wakecycle is regulatedby the central circadianoscillator in the hypothalamicsuprachiasmatic
nuclei (SCN) [83]. This oscillator is composedof many
Catmt
VasculdrPharmacolog420M, VoL S, No. 2
7
genesand proteins which interact together and have both
positiveand negativefeedbackloops [83]. Among others,
the CLOCK and BMALI elementspromotethe expression
of the Period(pefl, 2 and 3) and Crytochrome(Cryl | & 2)
genes.It is known that geneticvariationin someof these
genes,includingPeriod2, is importantin the development
of
somesleepdisorders[84].
Ifit is possibleto identift genesandgeneproductswhich
contributeto sleepdisordersit would be interestingto study
their associationsin children,as well as adults,as the former
are less likely to be influenced by age-associatedcomorbidities, which are present in the adult populations.
However,sleepdisordersdo exist in some childrenwhich
needto be excludedor diagnosed
in suchstudies.
A recent literaturereview led to the suggestionthat inflammatory cytokines such as TNF-alpha and Interleukin 1(L-1) perform neural functions in normal brainsAs such
they shouldbe regardedas both neuromodulators
as well as
inflammatory mediators [85]. The genes coding for these
cytokinesand their accessoryproteinsare expressedby glial
cells and neuronesin the normal brain [85]. Receptorsfor
thesecytokinesarepresenton neuralcells[85]. Patientswith
OSA syndromehave elevatedTNF-alphalevels [86]. The 308,4.TNF-alphagenepolymorphismis responsible
for increasedTNF-alphaproduction.Individualswith OSA syndrome and their siblings are more likely to carry this polymorphism than population controls; once more indicating
that an increasein inflammatorymediatorsmay be important
in thepathogenesis
of OSA syndrome[87].
Genetic and environmentalfactors may act togetherto
influencethe set-pointat which a given individual'sneroendocrine stressresponsesand cytokine production pattems
respondto different pathogensor antigens[S8]. It is therefore possiblethat geneticdeterminantsof sleepactingon the
oxidativeand immune pathwaysmay also be of importance
in determining an individual's subsequentcardiovascular
risk.
Sleepand PharmacologicalTreatments
OSA is characterizedby a collapse of the airway that
occursduringsleep[89]. As a resultthereis a lack ofoxygen
to the brain and the individual wakesup so that breathingis
resumed[89]. This canbe repeatedseveraltimesin onenight
and results in fragmentedsleep.One of the most common
treatrnentsfor this condition is CPAP [89]. This maintains
the airway during sleep.However, in some individualsthe
daytimesleepinessassociatedwith OSA and othersleepdisordersis not always eliminatedby this treatment.Although
the exact mechanismsthat govern the sleep-wakecycle and
the processare unknown.It is of interestto note that a relatively new drug, Modafinil is effective against excessive
daytimesleepiness[90]. It would appearthat this drug exerts
someof its action in the hypothalamus,which is an areaof
the brain that regulatessleep-wakefunctioning[90].
5-hydroxytryptophan
(5-HT) increasesserotoninlevels
and is usedto treat depression[91]. Therehas been some
suggestionthat it may improve sleeppatternsand aid weight
loss. A recent study, which investigatedthe effect of sleep
deprivation on 5-HT tumover, indicated that REM sleep
8
Current Vascular Pharmacologt, 2007, VoL S, No. 2
modulatedthe 5-HT tumover in the brain in a region_specific
manner[92].
Given the suggestionthat poor sleep may have cardiovascularconsequences
as a result of its effect on the inflam_
m?tor7ard oxidativepathway,it is possiblethat the pharmacologicalmanagement
of sleepdisordersmay need to in_
cludeanti-inflammatory
andantioxidantagentjaswell.
Miller and Cappuccio
It2l
tl 3 l
ll4l
Ilsl
The Importanceof Sleep
_ 91..p is a fundamentalrequirementfor living individuals.
In this review we discussedhow changesin sleep, acting
through inflammatorymechanisms,may be associatedwith
an increasedrisk of CVD. Changesin working pattemsand
increaseddemandson individual'stime ,"quire that more
individualsare awakefor longerperiodsoltime. Unfortu_
nately, increasesin shift work, on-call rotas and prolonged
working hours result not only in a potentially increasedcardiovascularrisk but also an increasedrisk of fatigue and ac_
cidentse.g. road traffic accidents,commutertra]n disasters
and pilot error as well as medical enors [93,94J.Driving
while drowsy has a similar effect to driving-undeithe influl
ence of alcohol. It is believed that substantialnumbersof
medicalerrorsresult from fatigue due to adversesleeppat_
terns in nursesand doctors[4]. Theseproblemstravea ]iigtr
cost both in terms of human life and economic factois.
Hence,it can be seenthat sleephas a major impacton our
healthandwell-being and needsto be researched
ihoroughly.
Some of theseproblems associatedwith the lack of Jleen
cou.ldbe_addressed
by improving our understandingof the
biologicalbasisof sleep;the biochemicalmechaniims;inv.olve.d,by-increasingawaxeness
both among health professionalsand amongthe lay public, and by making changesto
work patternsand accessto sleep recovery (naps/timi offl
aswell as improveddiagnosisandtreatmentresimes.
REFERENCES
tll
t21
t3l
t4l
t51
t61
l7l
t8l
t9l
UOl
tl ll
Siegel JM. Clues to the functions of mammalian sleep. Nature
2005;437:1264-71.
Irwin M. Effects of sleep and sleep loss on immuni8 and cytoki_
nes.BrainBehavImmun 2002:5:503-lZ.
Majde JA, Krueger JM. Links betweenthe innate immune svsrem
and sleep.J Allergy Clin Immunol2005; 116: I 188-98
Horrocks N, PounderR; RCp Working Group. Working the night
shift: preparation,survival and recovery--aguide forjunior doctors.
Clin Med 2006:6: 6l-7.
Ngtignll SleepFoundation.Sleep In America poll ..05: Summary
of Findings. Washington,DC: National Sleep Foundation: 200j.
http://www.sleepfoundation.
org/_content/hottopics/Slee
p_Segment
s.pdf
CaplesSM, Gami AS, SomersVK. Obstructive sleep apnea.Ann
IntemMed 2005; 142.187-97.
KasasbehE, Chi DS, Krishnaswamy G, Inflammatory asDectsof
sleep apnoeaand their cardiovascularconsequences,
South Uea .l
2 0 0 6 ; 9 9 : 5 8 - 6 7q;u i z6 8 - 9 ,8 1 .
Narkiewicz K, Wolf J, Lopez-JimenezF, SomersVK. Obstructive
sleep.apnoea
and hypertension.
Cun CardiolRep2005;7:435_40.
Resnick HE, Howard BV. Diabetes and cardiovasculardisease.
Annu Rev Med 2002: 53:245-67.
Meisinger C, Heier M, Loewel H; MONIC{KORA Augsburg
Cohort Study. Sleep disturbanceas a predictor of type 2 diabetes
mellitus in men and women from the general population. Diabetologia 2005; 48: 23 5-41.
GangwischJE, Heymsfield SB, Boden-AlbalaB, Buijs RM, Kreier
F, Pickering TG, et al. Short Sleep Duration as a Risk Factor for
Hypertension.Analyses of the First National Health and Nutrition
ExaminationSurvey.Hypertension2006; 47: g33-9.
[16]
I17l
ttsl
llel
[20]
121l
122)
Kokturk O, Ciftci TU, Mollarecep E, Ciftci B. ElevatedC_reactrve
protein levels and increasedcardiovascularrisk in patientswith
ob_
structivesleepapnoeasyndrome.Int Heart J 2005;46:901-9
Prinz PN. Age impairmentsin sleep,metabolic and immune functions.Exp Gerontol2004; 39: 1739-43.
Strike PC, SteptoeA. New insights into the mechanismsof temporal variation in the incidence of acute coronary syndromes.Clin
Cardio2003;26: 495-9.
Peker Y, Hedner J, Norum J, Kraiczi H, CarlsonJ. Increasedincidenceof cardiovasculardiseasein middle_agedmen with obstruc_
lyg-d*_p apnea:a 7-year follow-up. Am J-RespirCrit Care Med
2002; 166: 159-65.
Redline S" Strohl K, Recognitionand consequences
of obstructlve
Ilfopnea syndrome.OtolaryngolClin North Am 1999;
1t3eg^1n19a
32:303-31.
Bliwise DL, King AC, Hanis RB. Habitual sleep durations and
health in a 50-65 ye:r old populatron.J Clin Epidimiol 1994; 47:
35-4r.
Vgontzas AN, Kales A. Sleep and its disorders.Annu Rev Med
1 9 9 9 t5 0 :3 8 7 - 4 0 0 .
Lugaresi E, Cirignotta F, Zucconi M, Mondini S, Lenzi pL, Coc_
cagnaC..Goodand poor sleepers: an epidemiological
surveyofthe
Jan Manno populatton.In : Sleep_Wake
Disorders: NaturalHis_
tory, Epidemiology and long-termEvolution. C. Guilleminaultand
E. Lugaresi(eds).New york, Ravenpressl9g3: 1_12.
K,alesA, SoldatosCR, Kales JD. Taking a sleephistory. Am Fam
Physicianl980;22: I 01-108.
Hak AE, Pols HA, StehouwerCD, Meijer J, Kiliaan AJ, Hofman
A, et al. Markers of inflammation and cellular adhesionmolecules
in relation to insulin resistancein nondiabeticelderly: the Rotterdam study.J Clin EndocrinolMetab200t; 86: 4398-4b5
Roubenoff R, P1riry H, payette HA, Abad LW, D'Agostino R,
JacquesPF, et al. Cytokines, insulin-like growth factoi I, sarcopenia, and mortality in very old community_dwellingmen
and
women: the FraminghamHeart Study. Am J Med 2003: ll5:429J)
[231
I24l
t2sl
t26l
I27l
[28]
I2el
t30l
[31]
t32l
t33l
134)
Meier-Ewert HK, tudker pM, Rifai N, Regan MM, price NJ,
Dinges DF, et al. Effect of sleep loss on C-reictive protein, an in_
flammatory marker of cardiovascularrisk. J Am Coll'Cardioi 2OO4:
43 678-83.
Stsininger TL, Hyder K, Apte-DeshpandeA, Ding J,
I:r.": 4,
RishipathakD, et al, Differcntial increasein the ixpression of heat
shock ptotein family membersduring sleepdeprivationand ourrng
sleep.Neuroscience2003 116: lg7-200.
Roy AK, Oh T, Rivera O, Mubiru J, Song CS, ChattedeeB. Im_
pactsoftranscriptional regulationon aging and senescenie.Ageing
ResRev 2002t 1:367-80.
Everson CA, Crowley WR. Reductions in circulating anabolic
hormones induced by sustainedsleep deprivation in its. em J
PhysiolEndocrinolMetab2004;286:El06b_70.
RestaO, Bonfitto P, SabatoR, De pergola G, BarbaroMp. preva_
lence ofobstructive sleepapnoeain a sampleofobese women: effect of menopause.
DiabetesNutr Metab20b4| 17:296_303.
Miller MA, SagnellaGA, Kerry SM, Srrazzullop, Cook DG, Cappuccio FP. Ethnic differencesin circulatingsolubleadhesionmole_
cules: the Wandsworth Heart and Stroke Study. Clin Sci (Lond)
2003; 104:559-60.
Knutson KL. Sex differencesin the associationbetweensleeDand
bodymassindexin adolescents.
J pediatr2005: I 47: g30_4.
BalarajanR. Ethnicity and variarionsin the nation'shealth.Health
Trends1995-96;27:114-9.
Scharf SM, Seiden L, DeMore J, Carter-pokrasO. Racial differ_
ences in clinical presentationof patients with sleeD_disordered
breathing.SleepBreath2004;8: | 73-83.
Buxbaum SG, Elston RC, Tishler pV, Redline S. Geneticsof the
apnea hypopnea index in Caucasiansand African Americans: I.
Segregationanalysis.GenetEpidemiol 2002:22: 243-53.
Poulain_M,D-oucetM, Major GC, DrapeauV, SeriesF, Boulet Lp,
et,al..T,heeffect of obesity on chronic respiratorydiseases:patho_
physiology and therapeuticstmtegies.CMAJ 2006; 174: l29i-g
Poirier P, Giles TD, Bray GA, Hong y, SternJS, plsunyer FX, er
al American Heart Association;Obesity Committeeof the Council
on Nutrition, PhysicalActivity, and Metabolism.Obesi8 and cardiovascular disease: pathophysiology, evaluation, and effect of
weight loss: an update of the 1997 American Heart Association
Scientific Statementon Obesity and Heart Diseasefrom the Obe_
InJlammation, Sleep, Obesity and Cadiovascular Diseose
t35l
[36]
137)
[38]
l39l
sity Committeeof the Council on Nutrition, PhysicalActivity, and
Metabolism.
Circulation2006; 113:898-918.
SpiegelK, Tasali E, PenevP, Van CauterE. Briefcommunication:
Sleep curtailment in healthy young men is associatedwith decreasedleptin levels, elevatedghrelin levels, and increasedhunger
and appetiteAnn Intem Med 2004; l4l:846-50.
Chaput JP, Brunet M, Tremblay A. Relationship between short
sleepinghours and childhood overweighVobesity:resultsfrom the
'Quebecen Forme'Project.Int
J Obes(Lond) 2006; [Epub aheadof
printl.
PatelSR, Malhofra A, White DP, Gottlieb DJ, Hu FB. Short Sleep
Is a Risk Factor for Weight Gain, [Publication Page: A733 (Absrracr;ISS SanDiego)1.
Taheri S, Lin L, Austin D, Young T, Mignot E. Short sleepduration is associatedwith reduced leptin, elevated ghrelin, and increasedbody massindex. PLoS Medicine 2004; l: e62.
Dhamrait SS, StephensJW, Cooper JA, Acharya J, Mani AR,
Moore K, et al. Cardiovascular risk in healthy men and markers of
oxidative stressin diabeticmen are associatedwith common variation in the gene for uncoupling protein 2. Eur Heart J 2004;25:
Current Vascalar Pharmacologr, 2007, VoL 5, No. 2
t58l
t59l
[60]
16l]
t62l
t63l
t64l
468-7s.
[40]
l4ll
I42l
t43l
t44l
l45l
[46]
t47l
t48l
[49]
[50].
t5ll
t521
t53l
t54l
l55l
[56]
l57l
DAdamo M, Perego L, Cardellini M, Marini MA, Frontoni S,
Andreozzi F, et al. The -866NA genotype in the promoter of the
human uncoupling protein 2 gene is associatedwith insulin resistance and increasedrisk of type 2 diabetes.Diabetes 2004; 53:
I 905-t0.
Cirelli C, Tononi G. Uncoupling proteins and sleep deprivation.
Arch Ital Biol 2004; 142:541-9.
Trayhum P, Bing C, Wood IS. Adipose tissue and adipokinesenergy regulation from the human perspective. J Nutr 2006;
136(Suppl):
I 935S-l939S.
Miller MA, CappuccioFP. Cellular adhesionmoleculesand their
relationshipwith measuresof obesity and metabolicqyndromein a
multiethnicpopulation.Int J Obes(Lond) 2006; Mar 7 [Epub ahead
ofprintl.
Wolk & Svatikova A, Nelson CA, Gami AS, Govender K, Winnicki M, et al. Plasma levels of adiponectin,a novel adipocytederivedhormone,in sleepapnea.ObesRes2005; l3: 186-90.
Harsch IA, Koebnick C, Wallaschofski H, SchahinSP, Hahn EG,
Ficker JH, el a/. Resistin levels in patientswith obstructivesleep
apnoeasyndrome-the link to subclinical inflammation?Med Sci
Monit 2004: l0: CR510-5.
Ohga E, Tomita T, Wada H, Yamamoto H, NagaseT, Ouchi Y.
Effects of obstructive sleep apnea on circulating ICAM-I, IL-8,
and MCP-I . J Appl Physiol 2003;94: 179-84.
ResnicklIE, Redline S, ShaharE, Gitpin A, Newman A, Walter R,
et al. Sleep Heart Health Study. Diabetesand sleep disturbances:
findings from the Sleep Heart Health Study. DiabetesCare 2003;
26'.702-9.
SpiegelK, Knutson K, Leproult R, Tasali E, Van CauterE. Sleep
loss: a novel risk factor for insulin resistanceand Type 2 diabetes.J
Appt Physiol2005;99: 2008-l9.
Boethel CD. Sleep and the endocrinesystem:new associationsto
old diseases.
Cun Opin Pulm Med 2002;8: 502-5.
ScheenAJ, Van CauterE. The roles oftime ofday and sleepquality in modulating glucose regulation: clinical implications. Horm
Res 1998;49: l9l-201.
Ceriello A. Oxidative stressand diabetes-associated
complications.
EndocrPract.2006; 12 (Suppl): 60-2,
Mallion JM, Baguet JP, Siche JP, Tremel F, De GaudemarisR.
Clinical value of ambulatory blood pressuremonitoring. J Hypert e n s1 9 9 9 ;l 7 : 5 8 5 - 9 5 .
PickeringTG, Kario K. Noctumal non-dipping:what doesit augur?
Cun OpinNephrolHypertens2001; 10:611-6.
BassettiCL, Milanova M, Gugger M. Sleep-DisorderedBreathing
and Acute Ischemic Stroke. Diagnosis, Risk Factors, Treatment,
Evolution, and Long-Term Clinical Outcome. Stroke 2006; 37:
967-72.
Alzoghaibi MA, Bahammam AS. Lipid peroxides, superoxide
dismutaseand circulating IL-8 and GCP-2 in patientswith severe
obstructivesleepapnoea:a pilot study. SleepBreath 2005; 9: I l9Vega GL. Obesity and the metabolic syndrome.Minerva Endocrinol2004;29: 47-54.
VgontzasAN, Bixler EO, ChrousosGP. Sleepapneais a manifestationof the metabolicsyndrome.SleepMed Rev 2005;9:211-24.
t65l
t66]
167l
168l
t69l
t70l
tTll
172)
l73l
174)
I75l
176l
t77l
t78l
t79l
t80]
9
Payne LC, Obal F Jr, Krueger JM. Hypothalamic releasinghormones mediatingtlte effects of interleukin-l on sleep.J Cell Bioc h e m1 9 9 3 ; 5 3 : 3 0 9 - 1 3 .
Edell-GustafssonUM. Sleep quality and responsesto insufficient
sleepin women on different work shifts.J Clin Nurs 2002; I l: 2807; discussion
288.
Clearfield MB. C-reactive protein: a new risk assessment
tool for
cardiovascular
disease.
J Am Osteopath
Assoc2005;105:409-16.
Teramoto S, Yamamoto H, Ouchi Y. IncreasedC-reactiveprotein
and increasedplasma interleukin-6 may synergisticallyaffect the
progressionof coronary atherosclerosisin obstructivesleep apnea
syndrome.Circulation 2003; 107: E40.
Bom J, Lange T, HansenK, Molle M, Fehm. Effects of sleepand
circadian rhythm on human circulating immune cells. J Immunol
1997;158:4454-64.
Lange T, PerrasB, Fehm HL, Bom J. Sleepenhancesthe human
antibody responseto hepatitis A vaccination. psychosom Med
2 0 0 3 ; 6 5 :8 3 1 - 5 .
Majde JA, Kruegar JM. Neuroimmunologyof sleep.In: D'haenen
H editor. Textbook of biological psychiatry.London: John Wiley
&Sons Ltd; 2002; p 1247-57.
RosenfeldY, Shai Y. Lipopolysaccharide(Endotoxinlhosr defense
antibacterialpeptidesinteractions:Role in bacterialresistanceand
preventionofsepsis. Biochim Biophys Acta. 2006; [Epub aheadof
printl.
Kruegar JM. Somnogenicactivity of immune responsemodifiers.
TrendsPharmacolSci 1990:11:122-6.
GerashchenkoD, ShiromaniPJ. Effects ofinflammation produced
by chronic lipopolysaccharideadministrationon the survival of
hypocretinneuronsand sleep.Brain Res2004; 1019 162-9.
GundersenY, OpstadPK, ReistadT, Thrane I, Vaagenesp. Seven
days' around the clock exhaustivephysicalexertioncombinedwith
energy depletion and sleep deprivation primes circulating leukocytes.Eur J Appl Physiol2006;97: 151-7.
Irwin M, Thompson J, Miller C, Giltin JC, Ziegler M. Effects of
sleepand sleepdeprivationon catecholamineand interleukin-2levels in humans:clinical implications.J Clin EndocrinolMetab 1999;
84:1979-85.
Ryan S, Taylor CT, McNicholas WT. Selectiveactivation of inflammatory pathwaysby intermittenthypoxia in obstructivesleep
apnoeasyndrome.Circulation 20051'll2: 2660-7.
GreenbergH, Ye X, Wilson D, Htoo AK, HendersenT, Liu SF.
Chronic intermittent hypoxia activates nuclear factor-kappaBin
cardiovasculartissues ,n vryo. Biochem Biophys Res Commun
2006;343 591-6.
Buckley TM, SchatzbergAF. On the interactionsof the hypothalamic-pituitary-adrenal(HPA) axis and sleep:normal HpA axis activity and circadian rhythm, exemplarysleepdisorders.J Clin EndocrinolMetab2005t90: 3106-14.
Vgontzas AN, PapanicolaouDA, Bixler EO, Kales A, Tyson K,
ChrousosGP. Elevation of PlasmaCytokines in Disordersof ExcessiveDaytime Sleepiness:Role of Sleep Disturbanceand Obesity. J Clin Endocrinol Metab 19971'82:1313-6.
Williams E, Magid K, SteptoeA. The impact of rime of waking
and congurrentsubjectivestresson the cortisolresponseto awakening. Psychoneuroendocrinology
2005;30: 139-48.
Capaldi Ii VF, HandwergerK, RichardsonE, Stroud LR. Associations betweensleepand cortisol responsesto str€ssin children and
adolescents:
a pilot study.BehavSleepMed 2005;3:177-92.
Motivala SJ, Sarfatti A, Olmos L, Irwin MR. Inflammatorymarkers and sleep disturbancein major depression.PsychosomMed
2005'.67:187-94.
Murck H, Uhr M, ZiegenbeinM, Kunzel H, Held K, Antonijevic
IA, et al. Renin-angiotensin-aldosterone
system, HPA-axis and
sleep-EEGchangesin unmedicatedpatientswith depressionafter
total sleepdeprivation.Pharmacopsychiatry
2006;39: 23-9.
Van Cauter E, Spiegel K. Sleep as a mediator of the relationship
betweensocioeconomicstatusand health: a hypothesis.Ann N Y
Acad Sci 1999; 896 254-61.
Redline S, Tishler PV, Hans MG, TostesonTD, Strohl KP, Spry K.
Racial differences in sleep{isordered breathing in AfricanAmericansand Caucasians.Am J RespirCrit CareMed 1997; 155:
186-192.
Heath M. Management of obstructive sleep apnoea.Br J Nurs
1993:2'.802-4.
l0
t8ll
t82l
[83]
t84l
t85l
t86l
_,
t87l
[88]
Current Vascular Pharmucologt, 2007, VoL S, No. 2
Irwin M, Rinetti G, Redwine L, Motivala S, Dang J, Ehters C.
Noctumal proinflammatory cytokine-associated
sleep disturbances
in abstinent African American alcoholics. Brain Behav Immun
2 0 0 4 :l 8 : 3 4 9 - 6 0 .
TaumanR, Ivanenko A, O'Brien LM, Gozal D. plasma C-reactive
protein levels among children with sleep_disordered
breathing.pe_
diatrics2004; 113:e564-9.
Leloup JC, GoldbeterA. Modeling the mammaliancircadranclock:
sensitivity analysis and multiplicity of oscillatory mechanisms.J
Theor Biol 2004t 230:541-62.
Tafti M, Maret S, Dauvilliers y. Genesfor normal sleepand sleep
disorders.Ann Med 2005; 37: 580-9.
Vitkovic L, Bockaert J, JacqueC. ,'Inflammatory"cytokines:neu_
romodulatorsin normal brain? J Neurochem2000;74:457-71.
Krueger JM, Majde JA. Humoral links betweenileep and the im_
mune system:researchissues.Ann N y Acad Sci. 2003;992,.9_20.
fuha RL, Brander P, Vennelle M, McArdle N, Ken SM, Anderson
NH, et al. Tumour necrosisfactor-alpha(_30g)genepolymorphism
in-otstructive sleep apnoea-hypopnoeasyndr6me.'Eur Reipir J
2005;26:673-8.
Kunz-EbrechtSR, Mohamed-Ali V, Feldman pJ, Kirschbaum C,
St€ptoeA. Cortisol responsesto mild psychologicalsress are ln_
Rseived: July 26,2m6
Rwiscdr July 3 1,2006
AccepcdtAugust04,20(b
Miller and Cappuccio
.
[89]
t90l
[91]
t921
[93]
194)
versely associatedwith proinflammatory cytokines. Brain Behav
Immun2003; 17: 373-83.
Victor LD. ObstructiveSleepApnea.Am Fam physicran1999:60:
2279-86.
Lin JS, Hou Y, Jouvet M. potential brain neuronaltargetsfor amphetamine-,methylphenidate-,and modafinil_inducedwakefulness,
evidenced by c-fos immunocytochemistryin the cat. hoc Natl
Acad Sci USA 1996;93: 14128-t4133.
Birdsall TC. s-Hydroxytryptophan:a clinically-effectiveserotonin
precursor.AlternMed Rev 1998;3:271-g0.
SenthilvelanM, Ravindran R, SamsonJ, Devi RS. Serotonintumover in different duration of sleep recovery in discreteregions of
young rat brain after 24h REM sleepdeprivation.Brain DJv 2006;
28:526-8.
Landrigan CP, Rothschild JM, Cronin JW, KaushalR, Burdick E,
Katz JT, et al. Effect of reducing intems, work hours on serious
medicalerrorsin intensivecare units. N Engl J Med 2004;351:
I 838-48.
Lockley SW, Cronin JW, Evans EE, Cade BE, Lee CJ, Landrigan
CP, et al. Harvard Work Hours, Health and SafetyGroup.Effeciof
reducing intems, weekly work hours on sleep and attentionalfail_
ures.N Engl J Med 2004: 351: lt29-37.