Obstructive Sleep Apnea_ the New Cardiovascular Disease

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31.05.2013 Obstructive sleep apnea: the new cardiovascular disease. Part I: obstructive sleep apnea and the pathogenesis of vascular disease

www.ncbi.nlm.nih.gov/pmc/articles/PMC2698951/ 1/16

Obstructive sleep apnea: the new cardiovascular disease. Part I: obstructive sleep apnea and the

pathogenesis of vascular disease

Rami Khayat, Brian Patt, and Don Hayes, Jr.

Abstract

Obstru ctiv e sleep apnea (OSA ) is incr easingly recognized as a nov el cardiov ascular risk factor. OSA

is im plicated in the path ogenesis of hy pertension , left v entricular dy sfunction, coronary artery

disease an d stroke. OSA exerts its negativ e cardiova scular c onsequen ces thr ough its un ique patt ern

of interm ittent hy poxia. Endothelial dy sfun ction, oxidativ e stress, and inflam m ation are all

consequences of OSA direct ly l inked to interm ittent hy poxia an d cri t ica l pathwa y s in the

pathogenesis of cardiov ascular disease in patient s with OSA . This rev iew w ill discuss the kn ow n

m echanism s of v ascular dy sfun ction in patients with OSA and th eir implicat ions for ca rdiov ascular

disease.

Keywords:Keyw ords Obstruct iv e sleep apnea, Hear t fai lure, Endothelial dysfunct ion, Inter m ittent

hy poxia, Oxidativ e stress

Introduction

Obstru ctiv e sleep apnea (OSA) is a respiratory disorder of sleep char acterized by recu rr ent episodes

of com plete or par tial upper airw ay obstruct ion. OSAhas an est imat ed prevalence of 924% in

m iddle-aged indiv iduals [1 , 2 ] and is increasingly emerg ing as a car diov ascular risk factor [ 3 6 ].

Sev eral etiological factors in OSA ov erlap w ith th ose of car diov ascular diseases creat ing difficulty in

distingu ishin g the direct car diov a scula r consequen ces of OSA from its role in ex acerba tin g

concom itant c ar diov ascular disease. Never theless, an in dependent r ole for OSA in ca rdiova scular

m orbidity and m ortal i ty i s now w ell supported [4 6 ].

Th is rev iew w ill discu ss th e path ophy siological responses to episodes of obstr u ctiv e apnea a nd

hy popnea. These responses inclu de sym pathetic activ ation, increased respira tory w orkload, and

interm ittent hy poxia in the im m ediate term . Endothel ia l dysfunction, oxidative stress, an d

inflam m ation are long -term consequen ces tha t m ediate car diov ascular disease in patients with

OSA. A subsequen t rev iew in th is series will attem pt to present th e backgr oun d and ev idence for a

cau sativ e relationship betw een OSA and cardiov ascular disease with focus on hy pertension an d

heart fa i lure.

Presentation and definition of OSA

The t erm Sleep Disordered Breath ing (SDB) encom passes all ty pes of respiratory distur bance dur ing

sleep: obstru ctiv e, central , an d m ixed. Ty pical ly , patients hav e predom inance of ei ther centra l or

obstruct iv e ev ents, so SDB is div ided broadly into two ma in clinical sy ndrom es, centr al an d

obstr uc tiv e sleep disorders.

In n orm al conditions, a tenu ous balan ce between constrictor and dilator forces m ainta ins the

patency of the upper a irw ay during sleep [7 , 8 ] . Obstru ctiv e events occur wh en this balance shi f ts

towar d the constricting forces [9 ]. One of the im porta nt collapsing factors leading to constriction of

the upper a irway is the extra- lum inal pressur e from the t issue surrounding the a irw ay [1 0 ], a

comm on condition in obesity .

The presence of com patible clinical sy m ptom s, inclu ding excessiv e day tim e sleepiness, an d at least

fiv e obstru ctiv e respiratory ev ents, apneas or h y popneas, per hour of sleep defines Obstru ctiv e Sleep

A pn ea Sy n dr om e. Ob st r u ctiv e a pn ea s r esu lt fr om com pl et e colla pse of t h e u pp er a ir w a y r esu lt in g

in cessation of airflow aga inst wh ich th e inspirat ory effort persists. Obstru ctiv e hy popneas result
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from a par tial collapse of the upper airw ay cau sing r eduction in, but n ot cessation of airflow , and

ar e associated w ith in creased respiratory effort.

The m ost effectiv e treatm ent for OSA is contin uous positiv e airw ay pressur e (CPAP), wh ich acts as

pneum atic splint keeping t he air w ay open dur ing sleep. Discussion of treatm ent m odalities for OSA

is elsewh ere in t his special issue.

The physiological response to episodes of obstructive apnea and hypopnea

A ty pi ca l pa tie n t w it h OS A m a y ex pe r ie n ce a n y w h er e fr om fiv e to w el l ov er on e h u n dr ed a pn ea or

hy popnea ev ents per hour. Each of these obstruct iv e respiratory ev ents results in an episode of

hy poxia. Re-oxy gena tion occurs wh en the episode is term inated by an a rousal that r estores the

a i r w a y p at en c y (Fig. 1 ) . The r ecurrence of these respiratory ev ents and their r espectiv e recov ery

phases produces a char acter istic pattern of noctur na l interm ittent hy poxia tha t is un ique to OSA.

General ly , both apnea a nd hy popnea ev ents produce the same pattern of interm ittent hy poxia .

Each episode of hy poxia stimu lates the carotid chem oreceptors resulting in sy m pathetic ner v e

activ ation [1 1 ] an d subsequen t sur ge in blood pressur e [1 2 ]. As a result, patients with OSA spend

their sleep period in a state of interm ittent hy poxia an d a cy cling patter n of recu rr ent surg es of

sy m pathetic act iv i ty and blood pressure.

Fi g. 1

A f r agme nt f r om a ful l ni gh t sl eep st udy r ec or ding (p ol y somnogr ap hy ) of a p at i ent w i th sev er e

OSA. Channels fr om top: LOC: le ft ey e elec tr ooculogram, ROC: ri ght ey e ele ctr ooculogram, Chin

EMG: Ele ct romy ogram of th e chi n, C3-A2 and O2-A1: r ecor dings of...

Signi ficant experimental ev idence has emerged indicating th at interm ittent hy poxia is a u nique

phy siological state w ith a pr ofile of biologica l consequenc es th at is distin ct from oth er ty pes of

hy poxia [1 3 1 6 ]. More im portan tly , interm ittent hy poxia is the cri t ica l elem ent accounting for

m ost of the imm ediate and long -term car diov ascular consequen ces of OSA inclu ding hy pertension

[1 7 1 9 ].

Intermittent hypoxia, sympathetic activation, and the pathogenesis of hypertension

Patients with OSA experience recu rr ent episodes of sy m path etic activ ation an d blood pressure

surges thr oughout the sleep period [2 0]. This sy m pathetic act iva tion, a long with the increased

bl ood pr essu r e pe r sists du r in g th e da y tim e in di ca tin g a lin k be tw een OS A a n d th e pa th og en esi s of

hy pertension [2 0 ]. Sev eral stu dies attem pted to explain this blood pressur e relation to apnea. X ie et

a l . reported that a short (2 0 m in) exposure to hy poxia in h ealthy hu m ans resulted in substantia l

increase in sym pathetic nerv e act iv i ty , which rem ained elev ated 20 min after withdraw al of the

chem ical st imu lus [2 1 ] . In h um ans exposed to interm ittent hy poxia , intact sym pathetic pathw ay

w a s r equ ir ed for th e h y pe r ten siv e r espon se to v olu n ta r y a pn ea [1 2 , 2 1 ]. In other experim ents, the

sam e inv est igators , as wel l as others, confirm ed that interm ittent hy poxia , an d not the respiratory

effort associat ed with a pnea , is responsible for th e sy m path etic act iv ation followin g episodes of

obstru ctive apnea [ 1 1 , 2 2 ]. Addit ional ly , hy poxia , an d not hy percapnea, w as cri t ica l for th e

persistence of sym path etic activ ation followin g episodes of apnea [2 3 ]. Withdra wa l of the inh ibitory

v a g a l sig n a l a ssoc ia ted w it h in spi r a t ion du r in g br ea th h old s w a s n ot im por ta n t for th e sy m pa th et ic

activ ation an d blood pressur e sur ge [2 4 ]. In summ ary , these hum an experiments conf irmed that

interm ittent hy poxia is the critical stimu lus for OSA-associated sy m pathetic activ ation [2 2 ] a nd

sur ge in blood pressur e followin g obstr u ctiv e episodes [1 2 , 2 1 ]. The sym pathetic response to

interm ittent hy poxia is associated with a carr y ov er effect in wh ich sy m pathetic act iv ation an d

bl ood pr essu r e su r g e pe r sist a ft er h y pox ia h a s r esolv ed [2 5 ].

A n im a l m ode ls con fir m ed th e r ole of i n ter m it ten t h y pox ia -in du ced sy m pa th et ic a ct iv a t ion in OS A -

related h y pertension. In a la ndm ar k experim ent, Brooks et al. dev eloped a dog m odel of OSA in
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w h ic h th ey m im ic ked th e u pper a ir w a y occlu sion of O SA . A g a in , in ter m it ten t h y pox ia w a s t h e

m anda tory stimu lus for t he blood pressur e response [1 9 ]. Fletcher et al. dev eloped an a nim al m odel

of OSA in w hich rat s were exposed to a protocol of interm ittent h y poxia design ed to sim ula te the

pattern of nocturna l hy poxia in OSA [2 6 ]. An increa se in blood pressure occurr ed in the r ats

exposed to this inter m ittent h y poxia pr otocol compar ed to contr ol an im als [2 7 ]. Car otid body

denerv ation prev ented the increase in art erial blood pressur e. Additiona lly , either ch em ical or

sur gical sym pathectom y prevent ed the blood pressure response to interm ittent hy poxia [ 1 7 , 2 8 ].

Similar to hu m an experim ents, these series of experim ents dem onstra ted that ch em oreception-

induced sy m path etic activ ation m ediated the blood pressure response to interm ittent h y poxia. In

particular, intact renal artery , and m edullary sy m pathetic act iv i ty w ere required for the

hy pertensiv e response in th is an im al m odel [2 9 ]. Moreov er, in th is rat m odel, interm ittent hy poxia

not only resulted in increased basal sy m pathetic act iv i ty , but a lso faci l itated enhan ced

sy m pat het ic response to subsequen t episodes of hy poxia [3 0 3 2 ]. Other inv estigators, using a

simi lar rat m odel, confirm ed that interm ittent hy poxia induces long-term facil i tat ion in th e

sy m pathetic act iv ation v ia an effect on the ca rotid chem oreceptors [2 5 ].

Sy m pathetic ov eractiv i ty appears to be the cri t ica l l ink between OSA and hy pertension [ 2 0 , 3 3 ].

The m echanism by wh ich sym pathetic act iv ation contributes to the pathogenesis of hy pertension

in patients with OSA is not y et fully un derstood. Par allels do exist in th e curr ent u nderstan ding of

the path ogenesis of essentia l h y pertension, in w hich sy m pathetic act iv i ty i s centra l [3 4 , 3 5 ].

Incr eased sym path etic tone exerts sy stemic cha ng es tha t prom ote the persistence of elev ated blood

pressur e [3 6 , 3 7 ] and au gm ent th e response to subsequen t sym path etic stim uli [3 8 ]. Youn g

patients with early essentia l hy pertension hav e increased cardiac sym pathetic tone compared to

age m atch ed contr ols [3 9 ]. In a populat ion-based stu dy , incr eased hear t ra te, a m an ifestation of

sy m pathetic act iva tion, correlated with futur e dev elopment of hy pertension [ 4 0]. The sym pathetic

interaction w ith the renin-ang iotensin system m ay be another im portan t elem ent in the

pathogenesis of hy pertension [3 6 , 4 1 , 4 2 ]. In tu rn , a ng iotensin II potentiat es the v asoconstrictor

effects of sym pathetic activ ation v ia post-gan glionic effects [4 3 4 5 ]. In the prev iously m entioned

rat m odel of intermittent hy poxia , Fletcher et a l . showed th at interm ittent hy poxia-induced

hy pertension wa s m ediated by r enal sy m pathetic nerv e act iv i ty [ 1 7 , 4 6 ] and that intact renin-

an giotensin sy stem w as critical for th is blood pressure response to interm ittent h y poxia [ 4 7 ].

A n oth er im por ta n t li n k bet w ee n OS A a n d h y per ten sion is th e r eset t in g of t h e ba r or eflex . Pa tie n ts

an d anim al m odels of hy pertension dem onstra te chan ges in th eir au tonom ic regu lation of blood

pressur e (bar oreflex) consistent w ith adaptat ion of the baroreceptors to a high er blood pressur e set

point [4 8 , 4 9 ]. This adaptation w as reported in patients with OSA both w ith an d without cha nges

in th e sensitivity of the baroreflex [5 0, 5 1 ]. Adapta tion of the bar oreflex in hy pertension r equir es

react iv e oxy gen species (ROS) [5 2 ]. Also, long -term facilitation of sym path etic activ ation in anim al

m odels of interm ittent h y poxia r equir ed ROS [5 3 ], establ ishing another im portan t l ink w ith OSA,

tha t is oxidativ e stress.

Final ly , sym pathetic act iva tion-m ediated v asoconstrict ion m ay induce long last ing structu ral

cha ng es in r esistan ce v essels that contr ibute to the persistence of hy pertension [ 5 4 ]. Anim al m odels

of interm ittent hy poxia demonstrate early stru ctur al and functional changes [5 5 ], a long with

im paired v asodilator r esponse to hy poxia [ 5 6 ]. Th ese local effects of increa sed sy m path etic tone on

the v ascular w all and structur e ma y be mediated by endothel ia l factors . In th e rat m odel of

interm ittent h y poxia, en dothelin-1 w as critical for th e sustain ed increase in blood pressure in

response to interm ittent h y poxia [5 7 , 5 8 ].

In sum m ary , sym pathetic act iv ation is central to the pathogenesis of hy pertension in OSA.

Inter m ittent hy poxia-induced sy m path etic activ ation and blood pressur e incr eases in patients with

OSA persist through the day an d mediate a ca scade of chang es tha t set the stage for persistent

hy pertension, probably sim ilar t o the conditions of initial stages of essentia l hy pertension [ 3 3 ].
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Respiratory effort and the mechanical consequences of OSA

Wh en a n obst r u ctiv e a pn ea occu r s, a n in cr ea se in th e r espi r a tor y ef for t a g a in st th e closed a ir w a y

ensues. This inspira tory effort is a r esult of incr eased respira tory driv e stim ula ted by the associated

hy poxia [5 9 ] and results in a profoun d incr ease in negat iv e intr ath oracic pressure with eac h

inspirat ion. Interest in the m echan ical effects of this negativ e pressure on car diac function ha s been

long present. Howev er, the a v ai lable data sugg est th at h y poxia an d not the r espiratory effort i s

responsible for m ost of the ca rdiov ascular response to respiratory ev ents [6 0]. Nev erth eless, the

effect of this respira tory effort ma y be more importan t in patients with existing car diac dysfunct ion

[6 1 , 6 2 ] than in otherw ise healthy individuals with OSA. Negative intra thoracic pressur e

aug m ents the gradient between the intrav entricular pressur e and the intrath oracic pressur e

result ing in increased left v entricular work an d wa ll stress during sy stole [6 1 ]. Also, this negativ e

intr ath oracic pressure m ay affect the balan ce of forces gov ern ing th e tran sudation of f luid into the

interst i t ia l space result ing in pulm onar y edem a [ 6 3 ]. Final ly , increased v enous return to the right

v en tr ic le is li kel y [6 4 ], wh ich m ay cause an increase in preload. Alternativ ely , som e sour ces

sugg est that th e negative intra thoracic pressure may cause a reduction in v enous return a nd

preload and subsequen tly w ould reduce stroke v olum e [6 1 ]. It is well established th at pa tients with

heart fa i lure and OSA experience imm ediate improv ement in their cardiac w ork index with

elimina tion of OSA ev ents [6 5 , 6 6 ].

Endothelial dysfunction

Endothelial dysfunct ion gen erally denotes im pairm ent in endothelium -dependent v asodilation, a

function m ediated by ni tric oxide. Endothel ia l dysfunction is an im portan t v ascular a bnorm ali ty

tha t precedes the clinical m anifestations of cardiov ascular disease inclu ding hy pertension [6 7 , 6 8 ].

Dy sfun ction prom otes atherosclerotic chan ges and ar terial lesion dev elopm ent w ith subsequen t

clinical com plications [6 9 ]. Flow -mediat ed dilation (FMD) is nit ric oxide-dependen t v asodilat ion

[7 0] tha t r esults from shear -m ediated activ ation of endothelial nitric oxide sy nth esis in r esponse to

an acu te incr ease in blood flow [7 1 ]. Measurem ent of f low -m ediated dilation by non-inv asiv em ethods prov ides an assessment of endothelial fun ction and ca n h elp in th e ev alu ation of

cardiov ascular r isk [7 2 ].

Endothelial dysfunct ion w as dem onstra ted repeatedly in patients with OSA a nd in an im al m odels of

interm ittent hy poxia providing a n im portan t l ink between OSA and ca rdiov ascular diseases. Kato

et al. described im paired endothelial-m ediated v asodilation in a g roup of new ly diagnosed patients

w it h OS A com pa r ed to m a tch ed con tr ols [7 3 ]. Later, Ip et al. ev alu ated flow-m ediated dilation in a

gr oup of OSA patients w ho wer e other w ise free of clinically known car diov ascular disease. These

inv estigators also foun d baseline impairm ent in endothelial fun ction, w hich im proved after

treatm ent of OSA [7 4 ]. A correlation existed betw een the apnea h y popnea index an d the

im pairm ent in f low -m ediated dilation in both studies. A similar correlation between baseline

v a scu la r di a m et er a n d ox y g en de sa tu r a tion in de x w a s a lso r ep or ted in a la r g e pop u la tion ba sed

study of patients with sleep apnea an d cardiova scular disease furt her supporting a cau se-effect

relationship [7 5 ].

In anim al m odels of intermittent hy poxia , endothel ia l dysfun ction occurr ed without a chan ge in

the lev els of endothelial n itric oxide sy nth ase (eNOS) [7 6 ]. To date, howev er, the lev els and

funct ion of eNOS hav e not been directly m easured in patients with OSA. Circu lating lev els of nitr ic

oxide (NO) in patients with OSA w ere reduced at basel ine an d improved w ith treatm ent w ith CPAP

[7 7 ]. Oxidativ e stress play s a m ajor role in disorders of endothelial dy sfun ction a nd NO

bi oa v a il a bil it y [7 8 8 1 ]. Recently , tw o im portan t studies dem onstrated an improv ement in

endothel ia l dysfun ction in patients with OSA with antioxidant tr eatment [8 2 , 8 3 ], sug gesting a

sim ilar role for oxidativ e stress in the m echan ism of reduced NO av ailability in patients with OSA.

This prov ides para llels to other car diov ascular diseases in w hich oxidativ e stress-induced
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endothelial dy sfun ction is im porta nt [ 8 4 , 8 5 ].

Sev eral m echan ism s hav e been pr oposed to explain th e oxidativ e stress-m ediated reduction in NO in

patients with OSA. Hy poxia-mediated reduction in molecular oxy gen, a substrat e of eNOS, in the

endothelial cell is one possible m echan ism . Th e increa se in free ra dical product ion in OSA m ay

cause superoxide-m ediated scav enging of NO generating peroxy nitri te. Sv atikov a et a l . m easur ed

circulat ing n i troty rosine as an indicator of peroxy nitri te form ation in the v ascular env ironm ent in

hu m ans with OSA and foun d no increase in n i troty rosine levels [8 6 ]. This stu dy , howev er, does not

ru le out th e accum ula tion of peroxy nitr ite in th e endothelial cells. Tetrah y drobiopterin (BH4) is a

cofactor cr itical for NO production by eNOS [8 7 , 8 8 ]. Wh en th is cofact or is depleted in conditions of

incr eased oxidat iv e str ess, eNOS produc es superoxide instead of NO resultin g in endoth elial

dy sfun ction [8 9 ]. Ascorba te is sugg ested to replete BH4 [9 0 ]. In a relevan t study, Gr ebe et a l .

show ed an im provem ent in endothelial dy sfun ction in OSA patients after supplement ation with

v it a m in C, le n di n g su pp or t to t h is pa th w a y [8 2 , 8 3 ]. Sour ces of ROS in the v ascular env ironm ent

ar e nu m erous and inclu de mitochondria, x an thin e oxidoreduct ase (XOR), NADPH oxidase, eNOS,

Cy tochrome P45 0 enzy m es, and the arach idonic acid pathw ay enzy m es l ipoxy genase and

cy clooxy gena se. ROS gener ated from xa nth ine oxidoreduct ase activ ity du ring ischem ia reperfusion

i n ju r y [9 1 , 9 2 ] are im plicated in endothelial dy sfun ction [9 3 , 9 4 ] and h y pertension [ 9 5 , 9 6 ]. XOR

inhibi tors hav e a lready been shown to im prov e endothel ia l fun ction in hu m ans w ith other form s of

endothelial dy sfun ction [9 7 9 9 ]. Recent ev idence also show s im prov em ent in endothelial

dy sfunction w ith xan thine inhibi tor tr eatm ent in patients with OSA [8 3 ].

A sy m m et r ic a l di m et h y la r g in in e (A DMA) a n d NG -m on om et h y l-L-ar g in in e( L-NMMA ) a r e st r u ctu r a l

an alogues of L-Ar ginin e, a substrat e for eNOS, an d can funct ion a s com petitive in hibitors for eNOS

w h en th ei r le v el s a ccu m u la te in th e v a scu la r en v ir on m en t . On ly on e h u m a n st u dy so fa r su g g ests

a cha ng e in the lev el of ADMA in patien ts with OSA w ith tr eatm ent. Th is reduct ion of ADMA

correlated with the im provem ent in FMD in th ese OSA patients [1 00 ]. Figur e 2 sum m ar izes some of

the m echan ism s of oxidativ e stress-m ediated endothelial dy sfun ction th at m ay play a role in

endothelial dy sfun ction in patients w ith OSA.

Fi g. 2

A sc he ma of pot en ti al mec ha ni sms of ox i dati v e st r ess-medi at ed en doth el i al dy sf un ct i on. IH:

inter mittent hy poxia, ADMA: asymmetri cal dimethl argini ne, BH4: tetrahydrobiopteri n, eNOS:

endotheli al nitr ic oxide synthase, NO: nitr ic oxide, O2: oxy gen ONOO-: ...

Intermittent hypoxia and oxidative stress

Oxidativ e stress describes an im balan ce between th e production of ROS an d the an tioxidant

capacity of a biological sy stem. Oxidativ e stress occur s in conditions of ischem ia reperfusion t y picalto ma ny disease states. Oxidativ e stress can be assessed directly by m easurem ent of ROS in

bi olog ic a l sy st em s, or in di r ec t ly by m ea su r em en t of ox id a tion pr odu cts su ch a s l ip id s, pr otei n s, or

DNA. Addit ional ly , increased oxidative stress can be quan ti fied by m easur ing th e av ai lable in v i tro

an tioxidant capacity of a biological sy stem as an indicator of existing oxidativ e stress. Giv en th e

sign ifican t influence of env ironm ental factors on oxidativ e activ ity , large sam ple sizes, v ery

m eticulous techn iques, and sophisticated m easurem ents are usua lly required to ev alu ate the role of

oxidativ e stress in a particu lar disease process [1 01 ].

The r esemblance betw een the pattern of intermittent hy poxia associated with OSA and ischemia

reperfusion pattern s leads to the postu lation th at OSA w ould also be associated w ith oxidativ e stress.

Potentia l m echanisms for oxidative stress in OSA m ay be related direct ly to interm ittent hy poxia in

a fashion s imi lar to ischem ia reperfusion inju ry , or indirect ly v ia inf lamm atory response. The

increased sy m pathetic tone an d elev ated catecholam ine levels , a ha l lmar k of OSA, m ight a lso be

associated w ith incr eased ROS production.
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Despite the biological plausibility , sev eral earlier studies prov ided conflicting inform ation

rega rding the presence of increased oxidativ e stress in patients w ith OSA [ 1 0 2 1 05 ]. In some of

these stu dies, the nega tiv e results m ay ha v e been due to inadequa te contr olling, sma ll sam ple size

or u se of less-refined techniques tha n w ha t is av ailable cur rent ly [1 0 2 1 0 4 ]. Recent studies,

part icularly ones that inv olv ed larger nu m bers of patients, w ere able to demonstrate th at OSA is

indeed associated w ith in creased ma rker s of oxidativ e stress. Lav ie et al. [1 06 ] m easur ed plasm a

lev els of thiobarbitu ric rea ctiv e substan ces (TBARS), a m ar ker of lipid peroxidation, and th e levels

of paraxonase-1 , a m arker of antioxidant capaci ty , in 1 1 4 OSA patients and a group of norm al

controls. The inv estigat ors foun d an in crease in lipid peroxidation an d a redu ction in ant ioxidant

capaci ty in patients with OSA, w hich correlated with the severi ty of their OSA, and subsequently

improved with t reatm ent. Simi larly , Barcelo et a l . [1 0 7 ] foun d incr eased lipid peroxidation

(oxidized LDL) in patients with OSA compa red to contr ols. Treatm ent w ith CPAP reduced th e

susceptibility of LDL to oxidation.

Sev eral studies ev alu ated direct or indirect m easurem ents of incr eased ROS production in patients

w it h OS A . Ch r ist ou et a l. , in a ser ies of ex pe r im en ts, ev a lu a ted th e pr esen ce of ox id a tiv e st r ess in

bl ood sa m pl es of p a t ien ts w it h OS A [1 08 1 1 0 ]. In one experim ent, th ey m easured lev els of Diacron

react iv e oxy gen m etabolism (D-ROM). Diacron indicates the ability of m etals to cata ly ze the

form ation of free radicals in th e presence of peroxide. They foun d increa sed lev els of react iv e oxy gen

m etaboli tes which correlated with the severi ty of OSA [1 08 ]. In a later study , the sam e group foun d

a r eduction in th is m easure of oxidativ e stress (D-ROM) after tr eatm ent w ith CPAP. Carpag na no et

al. found in creased lev els of 8-isoprostan e in exha led breath condensate a nd blood of patients w ith

OSA com pared to controls [1 1 1 , 1 1 2 ]. Isoprostan e is another m easure of lipid peroxidation t ha t m ay

be li n ked to t h e pa th og en esi s of a th er osc le r osis [ 1 1 3 1 1 5 ]. Tan et a l . recently described a l ink

be tw een th e lip id a bn or m a li ty in OS A a n d a th er osc le r osis. Th ese in v est ig a tor s fou n d th a t HDL w a s

dy sfun ctional in prev enting LDL oxidation in patients with OSA [ 1 1 6 ]. Other inv est igators

ev alu ated products of oxidized DNA a s a m easure of increased ROS product ion. These inv estigat ors

foun d increased oxidized DNA products in patients with OSA w hich c orr elated with the desatur ation

index [1 1 7 ]. Takah ashi et al. ev alu ated thioredoxin lev els in patients with OSA. Th ioredoxin is a

protein t ha t is released from cells in r esponse to oxidativ e stress and m ay be implicated in

m y oca rdia c in jury [1 1 8 ] an d ath erosclerosis. Th e inv estigat ors foun d incr eased lev els of

thioredoxin a nd a correlation between t hese lev els and sev erity of OSA [1 1 9 ].

Other studies evalu ated cellular antioxidant capaci ty in patients with OSA. T his antioxidant

capacity can ch an ge in the presence of sign ificant oxidativ e load and is a potential m easurem ent or

m ark er of existing oxidativ e stress in th e sy stem. Using T rolox Equiv alent A ntioxidant Capa city

assay , Chr istou et al. foun d that t he an tioxidant capacity in th e blood of patients with sev ere OSA

w a s r ed u ced in com pa r ison to n or m a l con tr ols [ 1 09 ]. An other study a lso foun d that the an tioxidant

capaci ty of the serum in 47 patients with OSA w as reduced com pared to norma l controls and

improved with t reatm ent of OSA [1 2 0]. Together , these studies indicated an im pairm ent in the

protective sy stem from oxidativ e stress in patients with sleep apnea.

In sum m ary , oxidative stress in patients with OSA is central to the cardiov ascular m orbidity of

OSA. Most recent stu dies in patients with OSA an d anim al m odels of inter m ittent h y poxia confirm

tha t OSA is associated with oxidativ e stress, wh ich gener ally correlated with t he sev erity of sleep

apnea, an d improv ed with t reatm ent. The conf l ict ing r esults of som e of the earl ier hu m an studies

ar e likely a r esult of m ethodology or contr ol of patient v ar iables. Meticulous controlling for

env ironm enta l and cir cadian fact ors along w ith th e contr olling of subjects is required for

ev alu ation of oxidativ e stress in OSA pat ients. The m echan ism of increased oxidativ e stress in

patients with OSA an d its consequen ces rema ins incom pletely u nderstood. Oxidativ e stress provides

an important l ink in u nderstanding the car diov ascular consequences of OSA. Reactiv e oxy gen

species ar e requir ed for th e mem ory effect of the sy m path etic activ ation in an im al m odels of

interm ittent hy poxia . Increased oxidative stress in the v ascular m i l ieu is inv olv ed in the
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pathogenesis of endothelial dy sfun ction [8 2 , 1 2 1 ] . Fur therm ore, cognit iv e im pairment [ 1 2 2 , 1 2 3 ],

inf lam m ation [1 2 4 , 1 2 5 ], a th erosclerosis [1 1 6 ], hy pertension [1 2 6 ]a nd m y oca rdia l i n jury [1 1 8 ]

m ay all be direct consequen ces of the oxidativ e stress in OSA.

OSA and inflammation

A li n k bet w ee n OS A a n d in fla m m a tion is a n in tr ig u in g a n d in cr ea sin g ly lik el y com pon en t of t h e

pathophy siology of OSA. Several s tudies sugg ested that systemic inf lamm ation m ay be inv olv ed in

the in creased ROS product ion in OSA [1 1 1 , 1 2 4 ]. Schu lz et al. [1 2 4 ] reported a m ar ked increase in

neu trophil superoxide generat ion in OSA patients w hen c om pared to contr ols. Enh anc ed superoxide

gener ation by n eutr ophils decreased with CPAP treatm ent. Th e neutr ophil chem okines, IL-8 an d

gran ulocy te chem otactic protein-2, were s igni ficantly higher in OSA patients com pared to healthy

contr ols [1 05 ].

Htoo et al. assessed nu clear fact or kappa B (NF-kappaB) activ ity in OSA patients compar ed to contr ol

subjects. They determ ined that n eutr ophils in OSA patients demonstrat e sev eral fold increase in

NF-kappaB binding act iv ity com pared w ith control subjects. There w as a positiv e corr elation

be tw een th e de g r ee of NF-k a ppa B a ct iv a tion a n d in di ces of O SA sev er it y . CPA P t r ea tm en t de cr ea sed

neu trophil NF-kappaB activ ation to contr ol lev els [1 2 7 ].

In a n a nim al m odel of OSA, Ncher a nd colleagues determined that recurr ent a irw ay obstru ction

leads to rapid endothelial cell activ ation. They noted endothelial cell activ ation and sy stemic

leukocy te recrui tm ent in the m icrocirculat ion, w ith the apnea group hav ing s igni f icantly

increa sed flux of leukocy te activ ation wh en compar ed with th e sha m gr oups. P-selectin, an

adhesion m olecule foun d in endothelial cells an d activ ated platelets, w hich play s an essential r ole in

leukocy te recrui tm ent, was up-regulated only in the apnea group [1 2 8 ].

Other stu dies established that pa tients with OSA ha v e eleva ted levels of tum or n ecrosis factor-

(TNF-), a pro-inf lam m atory cy tokine that play s an im portan t role in neutr ophi l act iva tion [ 1 2 9 ,

1 3 0]. Vg ontzas et al. also demonstrat ed that Interleu kin-6 (IL-6), a nother pr o-inflam m atorycy tokine, was eleva ted in OSA patients com pared to norm al controls. The primar y factor

influencing TNF- levels w as the degr ee of sleep disturba nce, a nd th e m ain factor affecting IL-6

lev els was body m ass index (BMI) [1 2 9 ]. In a recent study, patients with OSA w ere foun d to hav e

elev ated serum levels of neopterin, a pro-inf lam m atory m arker for m acrophage a ct iv ation, w hich

play s a role in th e pathogenesis of cardiov ascular disease. In th is study , th e elev ated lev els of

neopterin a lso correlated with the sev eri ty of the u nderly ing severi ty of sleep apnea a nd w ith th e

degr ee of sleep disru ption [1 3 1 ].

Expan ding litera tu re connecting both IL-6 a nd C-Reactiv e Protein (CRP) to OSA is ver y im porta nt,

as both of these inflam m atory m ar kers are risk factors for cardiov ascular disease, including

ath erosclerosis and corona ry hear t disease [1 3 2 1 3 7 ]. Sham suzzam an et a l . reported that plasm a

CRP lev els wer e significantly high er in OSA patients com pared to age an d weight m atch ed contr ols.

In their study , m ult iv ariate an aly sis demonstrated that CRP lev els were independently associated

w it h th e sev er it y of O SA [1 3 8 ]. In a study assessing adolescents (ages 13 1 8 y ears, an d free of

known car diov ascular disease), an AHI 5 w as associated w ith incr eased lev els of CRP. The au thors

concluded tha t OSA in adolescents confers additiona l car diov ascular risk bey ond th at of obesity

[1 3 9 ]. Another study exam ining 6 9 m en w ho were free of cardiov ascular disease dem onstrated a

strong association betw een th e sev erity of OSA an d CRP lev els [1 3 1 ]. Monocy te pr oduction of IL-6

w a s h ig h er in pa tie n ts w it h OS A com pa r ed to ob ese con tr ol su bje cts. In th ose pa t ien ts w it h OS A , th e

factors influencin g CRP lev els w ere OSA sev erity an d BMI, an d the factors affecting IL-6 lev els wer eBMI an d nocturn al hy poxia. Tr eatm ent w ith n asal CPAP significantly decreased lev els of CRP an d

production of IL-6 [1 4 0 ].

A ctiv a ted leu kocy tes pl a y a n im por ta n t r ole in th e in fla m m a tor y r espon se to in ju r y r esu lt in g fr om
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hy poxia/reoxy gena tion th at m ay set off the ather ogenic processes [1 4 1 ] . Dy ugov askaya et a l .

inv estigated th e link between cert ain a dhesion molecules expression on leukocy tes an d their ability

to generate ROS in OSA patients. They foun d tha t OSA w as associated with incr eased expression of

the adh esion m olecules CD1 5 an d CD1 1 c by m onocy tes, incr eased adherence of m onocy tes in

cultu re to hu m an endothelial cells, and increased intr acellula r ROS production in som e monocyt e

an d gran ulocy te subpopulations. Nasal CPAP rev ersed m ost of these inflam m atory activ ities.

Minoguch i et a l . exam ined carotid int ima-media th ickness (IMT) a long w ith inf lamm atory m arkers

associated w ith car diov ascular disease (CRP, IL-6, an d IL-1 8). Ca rotid IMT corr elated w ith seru m

CRP lev els, IL-6, a nd IL-1 8, dur ation of OSA-related hy poxia, a nd sever ity of OSA. The prim ar y

factor influencing car otid IMT w as dura tion of hy poxia du ring total sleep tim e [1 4 2 ]. Th ese findings

indicate tha t patients with OSA a re exposed to ath erogenic insult night ly [1 4 3 ].

Therefore, OSA a ppears increasingly l inked to cardiov ascular m orbidity v ia a dist inct

inflam m atory response. This response is complex and inclu des sev eral hu m ora l and cellular

pathw ay s that are only m inimally un derstood so far. This inf lamm atory response direct ly l inks

OSA with the pathogenesis of atherosclerosis.

Summary

In otherw ise health y indiv iduals, OSA constitut es a significant r isk factor for th e development of

car diov ascular disease or t he progression of existent car diov ascular disorders towa rd h eart fai lure,

stroke, or death . OSA exerts its nega tiv e cardiova scular consequen ces thr ough its un ique patter n of

interm ittent hy poxia. Endothelial dy sfun ction, oxidativ e stress, and inflam m ation are all

consequences of OSA direct ly l inked to interm ittent hy poxia an d cri t ica l pathwa y s in the

pathogenesis of cardiov ascular disease in pat ients with OSA.

Article information

Heart Fail Rev. Author man uscript; available in PMC 2009 September 1.

Published in final ed ited form as:

Heart Fail Rev. 2009 September; 14(3): 143 153.

Published online 2008 September 20. doi: 10.1007/s10741-008-9112-z

PMCID: PMC2698951

NIHMSID: NIHMS110824

Rami Khayat, Brian Patt, and Don Hayes, Jr.

The Ohio State University Sleep Heart Program, The Ohio State University, 473 W 12th Ave, Suite 105 , Columbus, OH 43210, USA e-mail:

brian.patt/at/osumc.edu

Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, 473 W 12th Ave, Suite 10 5, Columbus, OH 43210 , USA

Departments of Pediatrics and Internal Medicine , University of Kentucky College of Medicine, L exington, KY, USA

Corresponding author.

Copyright notice and Disclaimer

The publishe r's final edited version of this article is available at Heart Fail Rev

See other a rticles in PMC that cite the published article.

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Obstructive Sleep Apnea_ the New Cardiovascular Disease

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