Coronary Artery Endothelial Dysfunction Uptodate 2015

8/15/2019 Coronary Artery Endothelial Dysfunction Uptodate 2015

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Coronary artery endothelial dysfunction: Basic conceptsAuthorsFrank W Sellke, MDEmile R Mohler III, MD

Amir Lerman, MDR Jay Widmer, MD, PhDFilippo Crea, MDSection Editor Juan Carlos Kaski, DS, MD, DM !"ons#, FRCP, FESC, FACC,FA"ADeputy Editor $ordon M Saperia, MD, FACC

Contributor disclosures

All %opis are upda%ed as ne& e'idene (eomes a'aila(le andour peer re'ie& proess is omple%e)Literature review current through: Apr *+-) . This topic lastupdated: May -, *+-)

IT!"D#CTI" / 0he oronary ar%erial irula%ion, &hih

onsis%s o1 ondu%ane and resis%ane 'essels, plays a ma2or

role in %he deli'ery o1 (lood %o %he myoardium) 0he endo%helium is

%he layer o1 ells %ha% lines %hese (lood 'essels) 0his layer

main%ains (lood 'essel !'asular# %one, re3ula%es hemos%asis, a%s

as (arrier %o po%en%ially %o4i ma%erials, and re3ula%es

in1lamma%ion) 5o%a(ly, %he me%a(oli re3ula%ion o1 oronary (lood

1lo& %ha% %akes plae a% %he si%e o1 resis%ane 'essels allo&s a

per1e% ma%hin3 (e%&een o4y3en supply and demand) 0he

inrease o1 (lood 1lo& in %he presene o1 an inrease o1 o4y3en

demand is mainly media%ed (y %he release o1 %iny amoun%s o1 1reeo4y3en radials)

Endo%helial dys1un%ion is %he ina(ili%y o1 %he endo%helium %o

op%imally per1orm one or more o1 %hese 1un%ions) Dys1un%ion o1

%he endo%helium is %he prinipal de%erminan% o1 hroni

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miro'asular dys1un%ion (u% also may our in %he lar3er ondui%

ar%eries, espeially &hen a%heroslerosis is presen%) 0he prinipal

linial onse6uene o1 miroirula%ory dys1un%ion is myoardial

ishemia (u% an also inlude 'asular %hrom(osis, inreased'asular permea(ili%y, and dias%oli han3es in %he myoardium)

Endo%helial dys1un%ion plays a key role in de%erminin3 myoardial

ishemia in all linial mani1es%a%ions o1 ishemi hear% disease)

Fur%hermore, %he deremen% in %he nonin'asi'e measuremen% o1

peripheral endo%helial 1un%ion has (een sho&n in a lar3e

sys%ema%i re'ie& and me%a7analysis enompassin3 o'er 8,+++

pa%ien%s %o dou(le %he ardio'asular risk in modera%e7risk

indi'iduals 9:)

0his %opi &ill 1ous on (asi onep%s o1 normal endo%helial

1un%ion and dys1un%ion) More linial aspe%s are disussed

separa%ely) !See ;Coronary ar%ery endo%helial dys1un%ion< Clinial

aspe%s;)#

"!$AL ED"T%ELIAL CTI" / 0he endo%helium is one

o1 %he lar3es% or3ans in %he (ody and i% in%era%s &i%h nearly e'eryo%her or3an or or3an sys%em 9*,=:) I% is a sin3le !mono# layer o1

ells ser'in3 mul%iple purposes<

>Main%enane o1 hemos%asis, %he (alane (e%&een

%hrom(osis and lo%%in3

>Main%enane o1 op%imal 'asular permea(ili%y

>Re3ula%ion o1 in1lamma%ion

>Con%rol o1 'asulo3enesis and an3io3enesis

>Main%enane o1 op%imal 'asular %one, (y on%rollin3

'asoons%ri%ion and 'asodila%ion? ade6ua%e end or3an (lood

per1usion is main%ained in %his &ay)

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Wi%h re3ard %o %his las% 1un%ion, %he endo%helium 1un%ions %o

main%ain %he 'essel in a rela%i'ely neu%ral s%a%e, 1a'orin3 dila%a%ion

o'er ons%ri%ion under (asal ondi%ions) I% has %he apai%y %o

respond %o 'arious s%imuli, inludin3 shear s%ress, %empera%ure,and %ransmural pressure, as &ell as e4%ernal s%imuli suh as

%empera%ure, men%al s%ress, neurohumoral responses, and

media%ions amon3 o%hers) 0he on%rol o1 loal 'asular %one is

media%ed prinipally (y ni%ri o4ide !5@#, al%hou3h pros%aylin

and endo%helium7dependen% hyperpolaria%ion 1a%or play an

impor%an% role in a%heroslero%i ar%eries)

itric o'ide generation / 0he endo%helial7dependen% responseo1 'asodila%ion is prinipally re3ula%ed (y release o1 5@ 1rom

endo%helial ells) I% is syn%hesied 1rom %he amino aid L7ar3inine

(y endo%helial ni%ri o4ide syn%hase !5@S#, &hih leads %o %he

produ%ion o1 in%raellular yli 3uanosine monophospha%e !$MP#

9B:)

5@, a moleular 3as, is enyma%ially 1ormed 1rom L7ar3inine (y

%hree iso1orms o1 5@S< neuronal7%ype !n5@S, 5@S#, y%okine7indui(le or maropha3e 5@S !i5@S, 5@S*#, and %he endo%helial7

%ype !e5@S, 5@S=# 9,-:) All %hree enymes, &hih are

y%ohrome PB+7like pro%eins, 1aili%a%e %he addi%ion o1

%he 3uanidine ni%ro3en o1 %he amino aid ar3inine %o moleular

o4y3en, produin3 5@ and &a%er) 0hese enymes di11er markedly

in %heir loalia%ion and 1un%ion) Many ell %ypes, mos% no%a(ly

endo%helial ells, ons%i%u%i'ely e4press e5@S, 3enera%in3rela%i'ely lo& le'els o1 5@ %ha% are under %i3h% on%rol (y re3ula%ory

1a%ors) In on%ras%, i5@S is normally no% e4pressed, (u% &hen

indued (y in1lamma%ory y%okines, an 3enera%e lar3e amoun%s o1

5@ 1ar in e4ess o1 %hose made (y e5@S)

http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/4http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/5,6http://www21.ucsg.edu.ec:2062/contents/guanidine-drug-information?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/4http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/5,6http://www21.ucsg.edu.ec:2062/contents/guanidine-drug-information?source=see_link


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itric o'ide function / 5@ is a pararine media%or %ha% &orks

di11eren%ly 1rom endorine media%ors, suh as an3io%ensin II and

an%idiure%i hormone) 5@, &hih is produed and released (y

indi'idual ells, readily pene%ra%es %he (iolo3ial mem(ranes o1nei3h(orin3 ells, modula%in3 a num(er o1 si3nalin3 asades)

Sine i% has an e4%remely shor% hal17li1e, i% e4er%s i%s e11e%s loally

and %ransien%ly)

0he mos% reo3nied ellular %ar3e% o1 5@ is heme7on%ainin3

solu(le 3uanyla%e ylase) 0he s%imula%ion o1 %his ompound

enhanes %he syn%hesis o1 yli $MP !$MP# 1rom 3uanosine

%riphospha%e, inreasin3 %he y%osoli le'els o1 $MP) 0he e11e%so1 5@ an (e enhaned (y inhi(i%in3 %he (reakdo&n o1 $MP, a

proess a%alyed (y a 1amily o1 phosphodies%erases)

@%her ellular %ar3e%s 1or 5@ also e4is%<

>5@ in%era%s &i%h %hiol 3roups on pro%eins and small

moleules, resul%in3 in %he 1orma%ion o1 S7ni%roso%hiols) 0he

addi%ion and remo'al o1 S7ni%roso%hiols is a hi3hly re3ula%edproess)

>5@ an %ar3e% FeS 3roups a% %he a%aly%i en%ers o1

pro%eins, inludin3 hemo3lo(in 98:

>0he 1orma%ion o1 pero4yni%ri%e 1rom 5@ and supero4ide

radial, &hih ours &hen lar3e amoun%s o1 5@ are

3enera%ed, %ypially (y i5@S, has (een implia%ed in ellular

%o4ii%y 'ia %he propensi%y o1 pero4yni%ri%e %o indue pos%7

%ransla%ional han3es in %he %yrosine residues o1 pro%eins 9:)

Biologic effects / 0he (iolo3i e11e%s o1 5@ depend upon %he

onen%ra%ion o1 5@ produed as &ell as 1ea%ures spei1i %o %he

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loal en'ironmen%, par%iularly %he presene and produ%ion o1

%hiols and supero4ide)

(asodilation / 5@ e4er%s i%s 'asodila%ory e11e%s %hrou3h

s%imula%ion o1 %he solu(le 3uanyla%e ylase) !See 5i%ri o4ide

1un%ion a(o'e)#

Angiogenesis / 5@ and 5@7rela%ed 1a%ors may play a role in

%he 3ro&%h o1 'asular ells and (lood 'essels) 5@ is a physiolo3i

inhi(i%or o1 smoo%h musle 3ro&%h 0he e11e% o1 5@ on 'asular

smoo%h musle 3ro&%h is media%ed (y $MP 987G:) In addi%ion %o

inhi(i%in3 smoo%h musle 3ro&%h, 5@ may also promo%e apop%osis

9+:)

Endothelial cell proliferation / While 5@ and o%her yli $MP7

a%i'a%in3 a3en%s inhi(i% %he 3ro&%h o1 'asular smoo%h musle,

%hey do no% al%er %he ra%e o1 3ro&%h o1 endo%helial ells 9:) @n %he

o%her hand, proli1era%in3 ells !e3, 1ollo&in3 endo%helial

denuda%ion# e4press a(ou% si41old as muh e5@S mR5A as

on1luen% ells 9:) 0he ne% e11e% is %ha% proli1era%in3 endo%helialells %ha% 3ro& (ak %o reo'er e4posed in%ima produe lar3e

amoun%s o1 5@? %he 5@ &ill %end %o minimie pla%ele% adhesion and

'asular smoo%h musle proli1era%ion in %he area (u% &ill no%

in%er1ere &i%h %he endo%helial ell proli1era%ion)

5e& 'essel 3ro&%h in'ol'es se'eral dis%in% s%eps 9*:)

>Inreased 'asular permea(ili%y and dissolu%ion o1 %he (ond

(e%&een %he endo%helium and (asemen% mem(rane

>Mi3ra%ion and rea%%ahmen% o1 endo%helial ells

>Proli1era%ion and mi3ra%ion o1 endo%helial ells and %he

1orma%ion o1 a %u(ule, &hih is %he rudimen%ary 'asular

s%ru%ure)

http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts?source=search_result&search=endotelio&selectedTitle=4~150#H359037870http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts?source=search_result&search=endotelio&selectedTitle=4~150#H359037870http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/7-9http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/10http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/11http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/11http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/12http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts?source=search_result&search=endotelio&selectedTitle=4~150#H359037870http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts?source=search_result&search=endotelio&selectedTitle=4~150#H359037870http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/7-9http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/10http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/11http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/11http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/12


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Almos% uni'ersally, pa%holo3i ondi%ions %ha% an lead %o

an3io3enesis, suh as %issue hypo4ia and in1lamma%ion, are

assoia%ed &i%h %he produ%ion and release o1 3ro&%h 1a%ors,

su33es%in3 %ha% %hese su(s%anes are ri%ial %o %he 1orma%ion o1ne& (lood 'essels) In addi%ion, %he respe%i'e 3ro&%h 1a%or

reep%ors mus% (e upre3ula%ed and inhi(i%ory 1a%ors mus% (e

inhi(i%ed i1 %he 3ro&%h 1a%ors are %o play a role in %he ini%ia%ion and

la%er s%eps o1 'essel de'elopmen% 9*7B:) !See ;Coronary

olla%eral irula%ion;)#

0here is also a s%ron3 rela%ion (e%&een %he release o1 5@ and %he

re3ula%ion o1 (lood 'essel 3ro&%h and de'elopmen%) Su(s%ane Pand 3ro&%h 1a%ors suh as 'asular endo%helial 3ro&%h 1a%or

!HE$F# and 1i(ro(las% 3ro&%h 1a%or !F$F#, all o1 &hih s%imula%e

%he release o1 5@ 9=,,-:, indue ne& 'essel 1orma%ion in 'i'o

and inrease %he permea(ili%y, mi3ra%ion, and proli1era%ion o1 pos%7

apillary endo%helial ells in %issue ul%ure 9-,8:) @n %he o%her

hand, inhi(i%ors o1 5@ syn%hase suppress an3io3enesis, and %he

proli1era%i'e e11e% o1 HE$F)

0here are, ho&e'er, on%radi%ory o(ser'a%ions onernin3 %he

role o1 5@ in an3io3enesis) In di11eren% models, 5@ syn%hase &as

in'ol'ed in an3io3enesis indued (y HE$F (u% no% %ha% indued (y

F$F7* 9: and, parado4ially, an3io3enesis &as inhi(i%ed (y %he

5@ donor sodium ni%roprusside and %he 5@ syn%hase su(s%ra%e L7

ar3inine, and inreased (y inhi(i%ors o1 5@ syn%hase 9G,*+:) I% is

possi(le %ha% %he e11e%s o1 5@ di11er (e%&een speies and(e%&een 'asular (eds &i%hin speies)

In on%ras% %o %he ro(us% an3io3eni response seen in many

animal models o1 hroni myoardial ishemia, %he an3io3eni

e11e%s o1 e4o3enously deli'ered 3ro&%h 1a%ors, suh as F$F7*

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and HE$F, ha'e (een rela%i'ely modes% or ne3a%i'e in human

%rials, espeially &hen 3i'en in%ra'asularly 9*:) 0his di11erene

ould (e rela%ed %o a diminished response %o an3io3eni 3ro&%h

1a%ors in %he se%%in3 o1 a%heroslerosis, hyperholes%erolemia,dia(e%es, and o%her auses o1 endo%helial dys1un%ion 9**,*=:) In

addi%ion, %he e4pression o1 pro7an3io3eni 1a%ors, suh as HE$F,

may (e diminished and %he e4pression o1 an%i7an3io3eni 1a%ors,

suh as endos%a%in and an3ios%a%in, may (e inreased in

ondi%ions suh as hyperholes%erolemia and dia(e%es 9*B,*:)

0his may ne3a%i'ely a11e% (o%h miro'asular and maro'asular

olla%eral 3ro&%h in response %o hroni oronary ar%ery olusion,

and %hus may a11e% o'erall myoardial per1usion)

0he diminished po%en%ial o1 an3io3eni 3ro&%h 1a%ors %o indue

olla%eral de'elopmen% may ha'e ad'erse implia%ions 1or %he use

o1 3ene7, pro%ein7 and, ell7(ased %herapies %o inrease per1usion

%o ishemi myoardium 9*-7=+:) I% is possi(le %ha% ad2un%i'e

%herapies suh as s%a%ins and 5@S su(s%ra%e !L7ar3inine# may

impro'e %he an3io3eni po%en%ial o1 %hese 3ro&%h 1a%ors as a

%herapeu%i modali%y 9**:) "o&e'er, %he role o1 s%a%ins in olla%eral

3ro&%h is (iphasi, and some s%udies ha'e su33es%ed %ha% s%a%ins

may no% neessarily impro'e olla%eral de'elopmen% and may

a%ually diminish per1usion 9=:) !See ;0herapeu%i an3io3enesis

1or mana3emen% o1 re1ra%ory an3ina; and ;In'es%i3a%ional and

emer3in3 %herapies 1or hear% 1ailure;, se%ion on Cell

%herapy and ;@'er'ie& o1 %he non7au%e mana3emen% o1 S0

ele'a%ion myoardial in1ar%ion;)#

"ther factors / "ydro3en pero4ide produes 'asodila%ion (y

o4ida%ion o1 %hiols and a%i'a%ion o1 p= MAP kinase) 0hus,

oronary me%a(oli dila%ion appears %o (e media%ed (y redo47

dependen% si3nals 9=*:) @%her 1a%ors also play a role, inludin3

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a(normal au%onomi re3ula%ion o1 'asular %one, han3es in

'asular smoo%h musle rea%i'i%y, al%ered 'ol%a3e73a%ed K

hannel 1un%ion, and impaired 'asodila%ory response %o hypo4ia,

&hih may ha'e si3ni1ian% implia%ions 1or %he me%a(olire3ula%ion o1 (lood 1lo& 9==7=:)

ED"T%ELIAL D)SCTI" / 0he prinipal ause o1

endo%helial dys1un%ion is an im(alane in ni%ri o4ide !5@#

produ%ion and onsump%ion, 1a'orin3 onsump%ion and redued

produ%ion) 0he ma2or onse6uene is ina(ili%y o1 %he 'essel %o

properly dila%e) 0he prinipal linial mani1es%a%ion o1 endo%helial

dys1un%ion in %he oronary irula%ion is myoardial ishemia)When 5@7media%ed 'asodila%ion is ompromised, %he 'asodila%ory

response is %hou3h% %o (e 1aili%a%ed (y y%ohrome7deri'ed

1a%ors, na%riure%i pep%ide, and pros%aylin)

In addi%ion, endo%helial dys1un%ion rea%es ondi%ions 1a'ora(le

1or pla%ele% plus leukoy%e a%i'a%ion and adhesion, as &ell as %he

a%i'a%ion o1 y%okines %ha% inrease %he permea(ili%y o1 %he 'essel

&all %o o4idied lipopro%eins and in1lamma%ion media%ors, 1inallyresul%in3 in s%ru%ural dama3e o1 %he ar%erial &all &i%h smoo%h

musle ell proli1era%ion and a%heroslero%i pla6ue 1orma%ion)

Abnor*al nitric o'ide *etabolis* / iohemial auses o1

a(normal 5@ me%a(olism, &hih on%ri(u%e %o endo%helial

dys1un%ion %hrou3h dereased produ%ion andor inreased

onsump%ion o1 5@, inlude<

>"i3h o4ida%i'e s%ress and in1lamma%ion lead %o a(normal

5@ me%a(olism !(ioa'aila(ili%y, useresponse,produ%ion,

release, and de3rada%ion#, &hih an (e e4aer(a%ed &i%h

o%her ondi%ions !old, men%al s%ress, an3er# %ha% are kno&n

%o produe a 3lo(al 'asoons%ri%ion) Inreased o4ida%i'e

http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/33-35http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/33-35


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s%ress is hara%eried (y a measura(le inrease in rea%i'e

o4y3en speies !R@S#, &hih an resul% 1rom impaired 5@

syn%hase, dereased L7ar3inine up%ake, inreased o4idied

lo& densi%y lipopro%ein holes%erol !@47LDL# 9=-:, or reduedsupero4ide dismu%ase, an enyme pi'o%al in %he learin3 o1

R@S 9=8:) "yperlipidemia is kno&n %o inrease R@S, &hih

&ill redue %he (ioa'aila(ili%y o1 5@? i% an (e ameliora%ed

&i%h orre%ion o1 hyperlipidemia 9=:)

>A derease in %e%rahydro(iop%erin !0"#, &hih is a o7

1a%or 1or endo%helial ni%ri o4ide syn%hase !e5@S# 9=G,B+:)

Replenishin3 0" s%ores appears %o impro'e endo%helial

dys1un%ion, e'en in hyperlipidemi pa%ien%s 9B:)

>De1iienies in L7ar3inine, %he su(s%ra%e 1or e5@S, and %he

o71a%or %e%rahydro(iop%erin lead %o a redu%ion in %he

syn%hesis and release o1 5@)

>A(normali%ies o1 $7pro%ein si3nalin3, resul%in3 in redued

a%i'a%ion o1 e5@S in response %o endo%helial ell reep%or

a%i'a%ion) In addi%ion, %he enyme ar3inase may (e

inreased in a%i'i%y a1%er ishemia7reper1usion, dereasin3

%he a'aila(le L7ar3inine 9B*:)

>Ele'a%ed asymme%ri dime%hylar3inine !ADMA#, &hih is an

endo3enous ompe%i%i'e inhi(i%or o1 5@ 9B=,BB:) ADMA has

(een linked %o redued endo%helial 1un%ion as &ell as

ere%ile dys1un%ion in pa%ien%s a% modera%e risk 1or

ardio'asular disease 9B:) Fur%hermore, @4 LDL an

inrease ADMA, 1ur%her ompoundin3 kno&n risk 1a%ors inpa%ien%s &i%h oronary ar%ery disease 9BB,B-:, e'en leadin3 %o

inreased e'en%s in %hose 1ound %o ha'e ele'a%ed le'els o1

ADMA 9B8:)

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!ole of endothelin / Inreased 'asomo%or %one in

a%heroslero%i oronary ar%eries is par%ly due %o endo%helial

dys1un%ion? ho&e'er, endo%helin7 also on%ri(u%es %o %he

e4a33era%ed 'asoons%ri%or response) Adminis%ra%ion o1 anendo%helin reep%or an%a3onis% produes si3ni1ian% dila%ion in

a%heroslero%i ar%eries, espeially a% s%enoses !-)= and *)-

'ersus 8)= peren% in normal ar%eries#, su33es%in3 %ha% endo%helin

si3ni1ian%ly on%ri(u%es %o %he res%in3 %one in a%heroslero%i

ar%eries !8B 'ersus =G peren% in normal ar%eries# 9B:)

Circulating endothelial progenitor cells +E,Cs- as a *ar.er of

endothelial dysfunction / A measure o1 EPCs has e'ol'ed as ano'el me%hod o1 assessin3 endo%helial dys1un%ion) Rarely 1ound

in %he peripheral (lood o1 heal%hy indi'iduals, EPCs

are res%ora%i'ere3enera%i'e ells, %hou3h% %o possi(ly replae or

rene& dama3ed areas o1 %he 'essel in%ima 9BG:) Fur%hermore,

EPCs possess %he hara%eris%i o1 (ein3 apa(le o1 au3men%in3

re'asularia%ion and endo%helial re3enera%ion 9+:) EPCs may

also (e in'ol'ed in %he re3enera%ion o1 ishemi myoardium (y

modula%ion o1 an3io3enesis and myo3enesis, ardiomyoy%e

apop%osis, and remodelin3 in %he ishemi ardia %issue) EPCs

ha'e addi%ionally (een repor%ed %o par%iipa%e in ere(ral

neo'asularia%ion a1%er ishemi s%roke) 0he si3ni1iane o1 %he

role o1 EPCs in early 'asular in2ury and repair &as undersored

(y a repor% demons%ra%in3 a si3ni1ian% orrela%ion (e%&een %he

num(er and %he 1un%ion o1 EPCs and peripheral endo%helial

1un%ion 9:) 0he assessmen% o1 %he num(er and %he 1un%ion o1

EPCs may ser'e as an impor%an% addi%ional marker o1 endo%helial

1un%ion and aordin3ly an ser'e as a marker 1or %herapy) 0hus,

i% is no% simply %he num(er o1 irula%in3 EPCs 1ound, (u% also %he

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%ype and loa%ion o1 %hese EPCs %ha% mi3h% ha'e an impa% on

disease and po%en%ial %herapies 9*:)

EPC release, indued (y in1lamma%ory y%okines suh as 5Fk

and IL7, has (een doumen%ed a% %he si%e o1 endo%helial in2ury in

animal models) Flo& y%ome%ry s%udies in humans ha'e no%ed an

epidemiolo3ial %rend %o&ard inreased EPCs in pa%ien%s a% hi3h

risk 1or ardio'asular e'en%s 9=,B:) 0he hara%eria%ion o1

os%eo3eni EPCs 1ound a% hi3her num(ers and re%ained in 3rea%er

6uan%i%y &i%hin %he oronary irula%ion in pa%ien%s &i%h endo%helial

dys1un%ion pro'ides some mehanis%i 1rame&ork 1or e4plainin3

%he epidemiolo3ial phenomenon in humans a% risk 1or oronarye'en%s 9:)

E'tracellular *icroparticles / E4%raellular miro'esiles, also

re1erred %o as miropar%iles, are dynami, mo(ile, (iolo3ial

e11e%ors likely ha'in3 a role in media%in3 endo%helial 'asular

ommunia%ion and 1un%ion) 0he release o1 e4%raellular

miro'esiles may indue au%orine and pararine e11e%s on

%ar3e% ells %hrou3h ellular in%era%ions and possi(ly %he deli'eryo1 in%ra7'esiular ma%erial 9-:)

Atherosclerosis / A%heroslerosis is %he mos% ommon linial

en%i%y assoia%ed &i%h endo%helial dys1un%ion) !See ;Pa%ho3enesis

o1 a%heroslerosis;)#

@ne o1 %he 1irs% e4amples o1 an al%era%ion in %he oronary

miroirula%ion in a%heroslerosis &as made in monkeys 1ed ahi3h holes%erol die% 1or mon%hs 98:) 0hese animals de'eloped

impaired 'asodila%ion, and in some ases parado4ial

ons%ri%ions, in lar3er 'essels in response %o ae%ylholine,

(radykinin, and %hrom(in) Impaired 'asodila%ion &as also seen in

%he oronary miro'asula%ure, &here o'er% a%heroslerosis does

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no% de'elop) Similar 1indin3s ha'e (een made in o%her animal

models o1 die%7indued a%heroslerosis)

In a%heroslerosis, %he sero%onin reep%or is upre3ula%ed and

sero%onin produes au3men%ed 'asoons%ri%ion, a resul% o1

alium mo(ilia%ion 9:) @%her s%udies usin3 in 'i'o %ehni6ues

sho&ed %ha% 'asoons%ri%ion aused (y sero%onin

and er3ono'ine, &hih is normally modula%ed (y %he endo%helium,

&as markedly enhaned in %he oronary miroirula%ion o1

hyperholes%erolemi monkeys 9G:) 0hese 1indin3s are s%rikin3

(eause %he oronary miroirula%ion is spared 1rom o'er%

a%heroslerosis) 0hus, 'essels %ha% ha'e (een e4posed %o a hi3hholes%erol milieu, e'en in %he a(sene o1 a%heroslerosis, de'elop

a(normal 'asomo%ion)

Endo%helial dys1un%ion resul%s 1rom %he presene o1 risk 1a%ors

!ie, smokin3, dia(e%es, hyper%ension, or hyperlipidemia# and is

1ur%her po%en%ia%ed (y a%heroslerosis in a 'iious irle)

%yperlipide*ia / Diminished 1lo& responses %o ae%ylholineha'e (een demons%ra%ed in humans &i%h hyperholes%erolemia

9-+,-:, an a(normali%y %ha% an (e orre%ed (y reduin3 %he

serum holes%erol 9-:) !See ;Mehanisms o1 (ene1i% o1 lipid7

lo&erin3 dru3s in pa%ien%s &i%h oronary hear% disease;, se%ion on

Re'ersal o1 endo%helial dys1un%ion)#

%ypertension / Impaired endo%helium7media%ed rela4a%ion has

also (een demons%ra%ed in humans &i%h or e4perimen%al modelso1 hyper%ension 9-*:)

Diabetes *ellitus / Dia(e%es is assoia%ed &i%h 'asular

dys1un%ion) Inreased o4ida%i'e s%ress, &hih is %ypially

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assoia%ed &i%h dia(e%es, may inhi(i% 5@, %hus on%ri(u%in3 %o

endo%helial dys1un%ion)

S*o.ing / 0he po%en%ial impa% o1 smokin3 on %he oronary

miroirula%ion is disussed separa%ely) !See;Cardio'asular risk

o1 smokin3 and (ene1i%s o1 smokin3 essa%ion;, se%ion on

Pa%ho3enesis)#

$yocardial hypertrophy / Pa%ien%s &i%h ardia hyper%rophy

due %o a 'arie%y o1 auses ha'e hes% pain su33es%i'e o1

myoardial ishemia) Ishemia due %o miro'asular disease is an

impor%an% risk 1a%or 1or ardia e'en%s in pa%ien%s &i%h

hyper%rophi ardiomyopa%hy) !See ;"yper%rophi ardiomyopa%hy<

5a%ural his%ory and pro3nosis;, se%ion on

Mor%ali%y and ;"yper%rophi ardiomyopa%hy< Clinial

mani1es%a%ions, dia3nosis, and e'alua%ion;)#

Cardia hyper%rophy is assoia%ed &i%h a redu%ion in %he ma4imal

apai%y o1 %he oronary irula%ion %o dila%e in response %o ei%her

rea%i'e hyperemia or pharmaolo3i s%imuli 9-=7-:)

0&o hypo%heses ha'e (een proposed %o e4plain %his de1e% in

'asodila%or 1un%ion<

>As %he myoardium hyper%rophies, %he oronary resis%ane

irula%ion does no% inrease %o keep pae &i%h %he lar3er

myoardial mass) 0hus, peak 1lo& normalied %o myoardial

mass is redued (eause o1 %he rela%i'e paui%y o1 oronary

ar%erioles)

>0here is a s%ru%ural al%era%ion o1 %he miroirula%ion, due

%o a%ual loss o1 oronary resis%ane 'essels !seen in

hyper%ension or dia(e%es# or due %o medial hyper%rophy o1

%hese 'essels !seen in hyper%rophi ardiomyopa%hy# !pi%ure

http://www21.ucsg.edu.ec:2062/contents/cardiovascular-risk-of-smoking-and-benefits-of-smoking-cessation?source=see_link&sectionName=Pathogenesis&anchor=H7#H7http://www21.ucsg.edu.ec:2062/contents/cardiovascular-risk-of-smoking-and-benefits-of-smoking-cessation?source=see_link&sectionName=Pathogenesis&anchor=H7#H7http://www21.ucsg.edu.ec:2062/contents/cardiovascular-risk-of-smoking-and-benefits-of-smoking-cessation?source=see_link&sectionName=Pathogenesis&anchor=H7#H7http://www21.ucsg.edu.ec:2062/contents/hypertrophic-cardiomyopathy-natural-history-and-prognosis?source=see_link&sectionName=Mortality&anchor=H9#H9http://www21.ucsg.edu.ec:2062/contents/hypertrophic-cardiomyopathy-natural-history-and-prognosis?source=see_link&sectionName=Mortality&anchor=H9#H9http://www21.ucsg.edu.ec:2062/contents/hypertrophic-cardiomyopathy-natural-history-and-prognosis?source=see_link&sectionName=Mortality&anchor=H9#H9http://www21.ucsg.edu.ec:2062/contents/hypertrophic-cardiomyopathy-clinical-manifestations-diagnosis-and-evaluation?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/hypertrophic-cardiomyopathy-clinical-manifestations-diagnosis-and-evaluation?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/63-65http://www21.ucsg.edu.ec:2062/contents/image?imageKey=CARD%2F73467&topicKey=CARD%2F1538&rank=4~150&source=see_link&search=endoteliohttp://www21.ucsg.edu.ec:2062/contents/cardiovascular-risk-of-smoking-and-benefits-of-smoking-cessation?source=see_link&sectionName=Pathogenesis&anchor=H7#H7http://www21.ucsg.edu.ec:2062/contents/cardiovascular-risk-of-smoking-and-benefits-of-smoking-cessation?source=see_link&sectionName=Pathogenesis&anchor=H7#H7http://www21.ucsg.edu.ec:2062/contents/cardiovascular-risk-of-smoking-and-benefits-of-smoking-cessation?source=see_link&sectionName=Pathogenesis&anchor=H7#H7http://www21.ucsg.edu.ec:2062/contents/hypertrophic-cardiomyopathy-natural-history-and-prognosis?source=see_link&sectionName=Mortality&anchor=H9#H9http://www21.ucsg.edu.ec:2062/contents/hypertrophic-cardiomyopathy-natural-history-and-prognosis?source=see_link&sectionName=Mortality&anchor=H9#H9http://www21.ucsg.edu.ec:2062/contents/hypertrophic-cardiomyopathy-natural-history-and-prognosis?source=see_link&sectionName=Mortality&anchor=H9#H9http://www21.ucsg.edu.ec:2062/contents/hypertrophic-cardiomyopathy-clinical-manifestations-diagnosis-and-evaluation?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/hypertrophic-cardiomyopathy-clinical-manifestations-diagnosis-and-evaluation?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/63-65http://www21.ucsg.edu.ec:2062/contents/image?imageKey=CARD%2F73467&topicKey=CARD%2F1538&rank=4~150&source=see_link&search=endotelio


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#) 0hese s%ru%ural han3es an al%er au%ore3ula%ion and %he

per1usion pressure in %he su(endoardium) "o&e'er, &hile

%here is a si3ni1ian% assoia%ion (e%&een dias%oli

dys1un%ion and measures o1 miro'asular 1un%ion inlinial diseases suh as dia(e%es, %he a%ual rela%ionship

(e%&een endo%helial dys1un%ion, onne%i'e %issue on%en%,

and ardia dias%oli 1ailure is no% s%ron3) @%her 1a%ors

pro(a(ly ha'e a more impor%an% role in %he early

pa%ho3enesis o1 su(linial dias%oli dys1un%ion in dia(e%es

and o%her illnesses 9--:)

I% has (een assumed %ha% %he loss o1 ma4imal 'asodila%or reser'ere1le%s a s%ru%ural al%era%ion o1 %he oronary miroirula%ion)

Consis%en% &i%h %his hypo%hesis is %ha% %he de1e% is o(ser'ed

durin3 ma4imal 'asodila%or s%imula%ion? in %his se%%in3, %he resul%an%

1lo& mus% re1le% %he dri'in3 pressure 1or per1usion and %he ross7

se%ional area o1 %he oronary resis%ane irula%ion) I% is unlikely

%ha% %he loss o1 ma4imal 'asodila%or reser'e is due primarily %o

endo%helial 1a%ors sine some o1 %he 'asodila%ors adminis%ered in

pharmaolo3i s%udies !adenosine and papa'erine# lar3ely a%

independen% o1 %he endo%helium)

0he de1e%s in miro'asular 1un%ion %end %o normalie &hen %he

underlyin3 a(normali%y responsi(le 1or hyper%rophy is orre%ed,

as &i%h aor%i 'al'e replaemen% 1or se'ere aor%i s%enosis)

"o&e'er, %he normalia%ion o1 miro'asular 1un%ion is no% losely

orrela%ed &i%h re3ression o1 hyper%rophy in %his se%%in3) Possi(lemehanisms o1 impro'ed myoardial (lood 1lo& a1%er aor%i 'al'e

replaemen% inlude redued e4%ra'asular ompression and

inreased dias%oli per1usion 9-8:)

http://www21.ucsg.edu.ec:2062/contents/image?imageKey=CARD%2F73467&topicKey=CARD%2F1538&rank=4~150&source=see_link&search=endoteliohttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/66http://www21.ucsg.edu.ec:2062/contents/adenosine-drug-information?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/papaverine-drug-information?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/67http://www21.ucsg.edu.ec:2062/contents/image?imageKey=CARD%2F73467&topicKey=CARD%2F1538&rank=4~150&source=see_link&search=endoteliohttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/66http://www21.ucsg.edu.ec:2062/contents/adenosine-drug-information?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/papaverine-drug-information?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/67


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"ther disease associations / @%her 1a%ors leadin3 %o

impairmen% o1 5@ 1un%ion inlude<

>Low/flow vascular states suh as redued ardia ou%pu%,

&hih redues endo%helial shear s%ress in ondi%ions suh as

hear% 1ailure, possi(ly 1rom redued L7ar3inine 9-:) In

addi%ion, 'asular in2ury or olusion an on%ri(u%e %o an

al%era%ion in (ioa'aila(le 5@ and 'aryin3 endo%helial 1un%ion

9-G:)

>Locali0ed infection, par%iularly in %he oral a'i%y, leadin3

%o inreased sys%emi in1lamma%ion and impaired endo%helial

1un%ion, has (een pos%ula%ed %o (e a on%ri(u%or %oardio'asular disease) Chlamydia pneumonia in1e%ions

98+: and immedia%e sys%emi in1lamma%ory s%a%es %ha% &ould

mirror sepsis 98: ha'e (een sho&n %o inrease 3lo(al

in1lamma%ory markers and endo%helial dys1un%ion)

Fur%hermore, ") pylori7posi%i'e pa%ien%s ha'e redued

endo%helial 1un%ion ameliora%ed (y %rea%men% 98*:) "o&e'er,

3lo(al %rea%men%s &i%h an%i(io%is in hi3h7risk pa%ien%s sho&no (ene1i% on ardio'asular disease ou%omes 98=,8B:)

>E'ternal bea* radiation 98:

and che*otherapy !par%iularly do4oru(iin and daunoru(ii

n# 98-: ha'e (een sho&n %o redue endo%helial 1un%ion in

pa%ien%s independen% o1 o%her risk 1a%ors, presuma(ly

%hrou3h endo%helial ell dea%h and redued 5@ a'aila(ili%y)

>1Cardiac syndro*e 23 is a %erm used %o desri(e %he

phenomenon o1 an3ina pe%oris &i%h normal oronary

ar%eries 988:) I% has (een su33es%ed %ha% hes% pain in

pa%ien%s &i%h ardia syndrome is due %o impaired

endo%helium7media%ed 'asomo%ion in %he ardia

miro'asula%ure) For %his reason, ardia syndrome is

http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/68http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/69http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/70http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/71http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/72http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/73,74http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/75http://www21.ucsg.edu.ec:2062/contents/doxorubicin-conventional-drug-information?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/daunorubicin-drug-information?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/daunorubicin-drug-information?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/76http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/77http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/68http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/69http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/70http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/71http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/72http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/73,74http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/75http://www21.ucsg.edu.ec:2062/contents/doxorubicin-conventional-drug-information?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/daunorubicin-drug-information?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/daunorubicin-drug-information?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/76http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/77


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no& alled miro'asular an3ina 98:) 0he pa%ho3enesis and

linial 1ea%ures o1 ardia syndrome are disussed

separa%ely) !See ;Cardia syndrome < An3ina pe%oris &i%h

normal oronary ar%eries;, se%ion on Pa%ho3enesis)#>Inhalation anesthetic agents %ha% are deli'ered durin3

sur3ial opera%ions may ha'e si3ni1ian% in1luene on %he

oronary miroirula%ion) For e4ample, iso1lurane and

halo%hane ha'e (een 1ound %o derease endo%helium7

dependen% responses in %he oronary miroirula%ion 98G:)

Iso1lurane a%%enua%es 1lo&7indued dila%ion, &hereas

halo%hane enhanes i% 9+:) Se'o1lurane main%ains myo3eni

and endo%helial de%erminan%s o1 myoardial (lood 1lo&

dis%ri(u%ion, (u% des1lurane a%%enua%es endo%helium7

dependen% 1lo&7indued dila%ion &hile mildly enhanin3

myo3eni ons%ri%ion 9:) Despi%e %hese e11e%s, myoardial

(lood 1lo& is pro(a(ly ade6ua%e and li%%le han3ed durin3

anes%hesia &hen %he irula%ion is normal) "o&e'er, mos%

anes%he%is may ha'e impor%an% miro'asular in1luenes

under ondi%ions o1 %issue ishemia suh as myoardialin1ar%ion, oronary ar%ery disease, or durin3 ardia sur3ery)

>Ishemia 1ollo&ed (y reperfusion in4ury 9*,=:

>Endo%helial 1un%ion o1 %he oronary miroirula%ion is

al%ered 1ollo&in3 ardiople3i arres% and e4%raorporeal

irula%ion durin3 coronary artery bypass graft

surgery !CA$# 9B,:) 0his a(normali%y persis%s 1or some

%ime a1%er ardiopulmonary (ypass and normalies%herea1%er) A num(er o1 1a%ors may (e in'ol'ed, inludin3

inreased release o1 produ%s o1 C@7* 9,-:)

Suh a de1ii% in endo%helial 1un%ion may ha'e impor%an%

http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/78http://www21.ucsg.edu.ec:2062/contents/cardiac-syndrome-x-angina-pectoris-with-normal-coronary-arteries?source=see_link&sectionName=PATHOGENESIS&anchor=H262633435#H262633435http://www21.ucsg.edu.ec:2062/contents/cardiac-syndrome-x-angina-pectoris-with-normal-coronary-arteries?source=see_link&sectionName=PATHOGENESIS&anchor=H262633435#H262633435http://www21.ucsg.edu.ec:2062/contents/isoflurane-drug-information?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/79http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/80http://www21.ucsg.edu.ec:2062/contents/sevoflurane-drug-information?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/desflurane-drug-information?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/81http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/82,83http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/84,85http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/85,86http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/78http://www21.ucsg.edu.ec:2062/contents/cardiac-syndrome-x-angina-pectoris-with-normal-coronary-arteries?source=see_link&sectionName=PATHOGENESIS&anchor=H262633435#H262633435http://www21.ucsg.edu.ec:2062/contents/cardiac-syndrome-x-angina-pectoris-with-normal-coronary-arteries?source=see_link&sectionName=PATHOGENESIS&anchor=H262633435#H262633435http://www21.ucsg.edu.ec:2062/contents/isoflurane-drug-information?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/79http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/80http://www21.ucsg.edu.ec:2062/contents/sevoflurane-drug-information?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/desflurane-drug-information?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/81http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/82,83http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/84,85http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/85,86


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linial implia%ions (eause o1 %he 1re6ueny &i%h &hih

ardiople3ia is used in ardio'asular sur3ery) I% is no%

unommon 1or pa%ien%s under3oin3 CA$ &i%h omple%e

oronary re'asularia%ion %o e4hi(i% si3ns o1 myoardialishemia durin3 %he hours 1ollo&in3 sur3ery? i% is possi(le

%ha% %he mehanism, in par%, is al%era%ion o1 endo%helial

1un%ion) !See;Early nonardia omplia%ions o1 oronary

ar%ery (ypass 3ra1% sur3ery;)# In addi%ion, i% is likely %ha% %he

ar%eriopa%hy o1%en o(ser'ed a1%er ardia %ransplan%a%ion is in

par% rela%ed %o endo%helial in2ury resul%in3 1rom inade6ua%e

'asular preser'a%ion) !See ;Pa%ho3enesis o1 and risk 1a%ors

1or ardia allo3ra1% 'asulopa%hy;)#

>Chronic heart failure, due %o ei%her an ishemi or

nonishemi ardiomyopa%hy, is assoia%ed &i%h endo%helial

dys1un%ion and impaired endo%helium7media%ed, 1lo&7

dependen% dila%ion o1 oronary and peripheral ar%eries due %o

a redu%ion in %he syn%hesis, release, and response %o 5@

987G:) !See;Coronary ar%ery endo%helial dys1un%ion<

Clinial aspe%s; and ;5i%ri o4ide, o%her hormones,y%okines, and hemokines in hear% 1ailure;)#

0here is e'idene 1or inreased 1ree radial 1orma%ion in

hear% 1ailure, and i% is possi(le %ha% %hese speies ina%i'a%e

5@) Suppor% 1or %his hypo%hesis omes 1rom one s%udy in

&hih 'i%amin C impro'ed endo%helial 1un%ion in pa%ien%s

&i%h hear% 1ailure in assoia%ion &i%h an inreased a'aila(ili%yo1 5@ 9G+:) !See;5u%ri%ional an%io4idan%s in oronary hear%

disease;)#

>%eart transplantation an normalie peripheral endo%helial

1un%ion in pa%ien%s &i%h nonishemi ardiomyopa%hy, (u%

http://www21.ucsg.edu.ec:2062/contents/early-noncardiac-complications-of-coronary-artery-bypass-graft-surgery?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/early-noncardiac-complications-of-coronary-artery-bypass-graft-surgery?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/pathogenesis-of-and-risk-factors-for-cardiac-allograft-vasculopathy?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/pathogenesis-of-and-risk-factors-for-cardiac-allograft-vasculopathy?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/87-89http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-clinical-aspects?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-clinical-aspects?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/nitric-oxide-other-hormones-cytokines-and-chemokines-in-heart-failure?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/nitric-oxide-other-hormones-cytokines-and-chemokines-in-heart-failure?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/vitamin-c-ascorbic-acid-drug-information?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/90http://www21.ucsg.edu.ec:2062/contents/nutritional-antioxidants-in-coronary-heart-disease?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/nutritional-antioxidants-in-coronary-heart-disease?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/early-noncardiac-complications-of-coronary-artery-bypass-graft-surgery?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/early-noncardiac-complications-of-coronary-artery-bypass-graft-surgery?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/pathogenesis-of-and-risk-factors-for-cardiac-allograft-vasculopathy?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/pathogenesis-of-and-risk-factors-for-cardiac-allograft-vasculopathy?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/87-89http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-clinical-aspects?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-clinical-aspects?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/nitric-oxide-other-hormones-cytokines-and-chemokines-in-heart-failure?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/nitric-oxide-other-hormones-cytokines-and-chemokines-in-heart-failure?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/vitamin-c-ascorbic-acid-drug-information?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/90http://www21.ucsg.edu.ec:2062/contents/nutritional-antioxidants-in-coronary-heart-disease?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/nutritional-antioxidants-in-coronary-heart-disease?source=see_link


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has no e11e% in %hose &i%h prior ishemi ardiomyopa%hy

9G:) Endo%helial dys1un%ion in pa%ien%s &i%h a nonishemi

ardiomyopa%hy is pro(a(ly a onse6uene o1 hemodynami

al%era%ions %ha% are re'ersi(le a1%er %ransplan%a%ion, &hileendo%helial dys1un%ion is also due %o %he presene o1

sys%emi a%heroslerosis in pa%ien%s &i%h ishemi

ardiomyopa%hy) Persis%en% endo%helial dys1un%ion also may

resul% 1rom 'asular in1lamma%ion assoia%ed &i%h 'iral

myoardi%is 9G*:)

0he presene o1 endo%helial dys1un%ion a1%er hear%

%ransplan%a%ion is assoia%ed &i%h %he de'elopmen% o1

%ransplan% 'asulopa%hy) In one s%udy, 1or e4ample,

peren% o1 %ransplan% pa%ien%s &i%h suh endo%helial

dys1un%ion de'eloped an3io3raphi e'idene o1

ar%erioslerosis a% one year ompared &i%h only = peren% o1

%hose &i%h normal 1un%ion 9G=:) 0he de'elopmen% o1

miro'asulopa%hy in hear% %ransplan% pa%ien%s is assoia%ed

&i%h redued lon37%erm sur'i'al 9GB:) !See ;Pa%ho3enesis o1and risk 1a%ors 1or ardia allo3ra1% 'asulopa%hy;)#

>Pa%ien%s &i%h cyanotic congenital heart disease mani1es%

a si3ni1ian% inrease in (asal oronary (lood 1lo&) "o&e'er,

oronary ar%ery 1lo& reser'e remains normal) In neropsy

speimens s%udied 1rom hear%s o1 pa%ien%s &i%h 'arious

on3eni%al anomalies !inludin3 Eisenmen3ers syndrome,

s%ru%urally a(normal hear%s &i%h 'en%riular hyper%rophy,s%ru%urally normal hear%s &i%h 'en%riular hyper%rophy, and

normal hear%s# remodelin3 o1 %he oronary miroirula%ion

&as no%ed %o (e %he key mehanism 1or preser'a%ion o1 1lo&

reser'e in yano%i on3eni%al hear% disease) 0he inrease in

'asular diame%er ompensa%ed 1or lo&er ar%eriolar len3%h

http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/91http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/92http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/93http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/94http://www21.ucsg.edu.ec:2062/contents/pathogenesis-of-and-risk-factors-for-cardiac-allograft-vasculopathy?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/pathogenesis-of-and-risk-factors-for-cardiac-allograft-vasculopathy?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/91http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/92http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/93http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/94http://www21.ucsg.edu.ec:2062/contents/pathogenesis-of-and-risk-factors-for-cardiac-allograft-vasculopathy?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/pathogenesis-of-and-risk-factors-for-cardiac-allograft-vasculopathy?source=see_link


19/22

densi%y and &as %he prinipal ana%omi (asis 1or

main%enane o1 normal 1lo& reser'e 9G:)

>0he de'elopmen% o1 collateral vessels si3ni1ian%ly al%ers

oronary 'asular rea%i'i%y) !See ;Coronary olla%eralirula%ion;)# When a oronary ar%ery is 3radually oluded,

1lo& %o %he su(%ended myoardium persis%s 'ia per1usion

%hrou3h olla%eral 'essels) When %hese 'essels 1ully de'elop,

%hey are apa(le o1 pro'idin3 normal res%in3 per1usion %o %he

re3ion pre'iously ser'ed (y %he oluded 'essel, al%hou3h a%

a lo&er per1usion pressure)

Sine olla%eral 'essels represen% ;ne&; 'essels, %here has

(een in%eres% in 1a%ors %ha% mi3h% modula%e %heir rea%i'i%y)

For %he mos% par%, %hese 'essels ha'e normal endo%helium7

dependen% 'asular rela4a%ion and normal responses %o mos%

a3en%s s%udied in 'i'o) Endo%helial release o1 5@ may (e

responsi(le 1or %he 'asodila%ion o1 oronary olla%erals 9G-:)

0he 1a%ors responsi(le 1or %he impaired miro'asular

endo%helium7dependen% rela4a%ion in %he olla%eral7dependen% re3ion ha'e no% (een de%ermined) 0his

a(normali%y may (e rela%ed %o inreased loal le'els o1 5@

resul%in3 1rom enhaned e4pression o1 indui(le 5@S, as

ours durin3 ishemia 9G8:? suh a han3e ould lead %o

redued a%i'i%y o1 endo%helial 5@ syn%hase 9G:) @%her

possi(le on%ri(u%in3 1a%ors %o impaired olla%eral 1lo&

inlude han3es in shear s%ress or pulsa%ile 1lo& in %heolla%eral7dependen% miro'asula%ure 9GG: and inreased

e4pression o1 heparan sul1a%e ma%ri4 pro%eins, suh as

syndean7B, %ha% an a11e% 'asular rea%i'i%y 9++,+:)

http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/95http://www21.ucsg.edu.ec:2062/contents/coronary-collateral-circulation?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-collateral-circulation?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/96http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/97http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/98http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/99http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/100,101http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/95http://www21.ucsg.edu.ec:2062/contents/coronary-collateral-circulation?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-collateral-circulation?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/96http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/97http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/98http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/99http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/100,101


20/22

>Colla%eral 3ro&%h and oronary miro'essel 1un%ion an (e

al%ered (y %he dire% peri'asular applia%ion or in1usion o1

an3io3eni 3ro&%h 1a%ors suh as 1i(ro(las% 3ro&%h 1a%ors

or 'asular endo%helial 3ro&%h 1a%or) 0hese %herapeu%iin%er'en%ions impro'e myoardial 1un%ion and per1usion in

hroni ishemi models and an normalie endo%helium7

dependen% rela4a%ion in %he olla%eral7dependen% 'asula%ure

9+*7+B:) "o&e'er, %here is li%%le e'idene %ha% 3ro&%h 1a%or

%herapy or 3ene %herapy impro'es myoardial per1usion in

any linial si3ni1ian% manner in linial %rials 9*G,=+:)

!See ;0herapeu%i an3io3enesis 1or mana3emen% o1

re1ra%ory an3ina;)#

>S%ress7indued ardiomyopa%hy !0ako%su(o

ardiomyopa%hy# is %hou3h% %o resul% 1rom miro'essel

myoardial ons%ri%ion &i%h resul%in3 ishemia) 0here are

no%ed redu%ions in endo%helial 1un%ion %o men%al s%ress in

pa%ien%s &ho ha'e e4periened s%ress7indued

ardiomyopa%hy 9+:? ho&e'er, %here are no prospe%i'e

da%a india%in3 peripheral endo%helial dys1un%ion an predi%%hose &ho &ill de'elop %his en%i%y)

>"ypo%hyroidism has (een sho&n %o (e assoia%ed &i%h

oronary endo%helial 1un%ion 9+-:) "is%orial o(ser'a%ional

da%a on nearly B++ pa%ien%s &i%h nono(s%ru%i'e oronary

ar%ery disease demons%ra%e %ha% &omen &i%h hypo%hyroidism

ha'e si3ni1ian%ly &orse oronary 1lo& responses %o

ae%ylholine ompared &i%h %hose &ho are normal oreu%hyroid) While mehanis%i reasonin3 &as no% o11ered,

%hese hypo%hesis73enera%in3 da%a should (e 1ur%her e4plored)

>Pa%ien%s &i%h hear% 1ailure &ho under3o le1% 'en%riular

assis% de'ie !LHAD# implan%a%ion ha'e (een sho&n %o ha'e

http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/102-104http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/29,30http://www21.ucsg.edu.ec:2062/contents/therapeutic-angiogenesis-for-management-of-refractory-angina?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/therapeutic-angiogenesis-for-management-of-refractory-angina?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/105http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/106http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/102-104http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/29,30http://www21.ucsg.edu.ec:2062/contents/therapeutic-angiogenesis-for-management-of-refractory-angina?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/therapeutic-angiogenesis-for-management-of-refractory-angina?source=see_linkhttp://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/105http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/106


21/22

han3es in endo%helial 1un%ion, &hih are assoia%ed &i%h an

inreased e'en% ra%e 9+8:) In%eres%in3ly, %he lak o1 pulsa%ile

1lo& %hrou3h %he ar%eries likely has an impa% on %he

endo%helial 1un%ion and assessmen% %hereo1) 5e'er%heless,%his small s%udy does pro'ide o'er si4 mon%hs o1 1ollo&7up,

and pro'ides some mehanis%i ideas re3ardin3 endo%helial

dys1un%ion in pa%ien%s &ho under3o LHAD implan%a%ion and

some o1 %he a%as%rophi onse6uenes o1 'asular e'en%s in

%his e4eedin3ly %enuous pa%ien% popula%ion) In%eres%in3ly, a

preliminary s%udy in o&s omparin3 assis% de'ie pulsa%ile

and non7pulsa%ile per1usion did no% demons%ra%e a si3ni1ian%

di11erene in 'asular permea(ili%y (e%&een 3roups 9+:)

>@s%eoporosis has also (een linked &i%h poor endo%helial

1un%ion, &i%h endo%helial dys1un%ion (ein3 a predi%i'e %ool

india%in3 &hih &omen mi3h% de'elop linial and

symp%oma%i os%eoporosis 9+G:)

S#$$A!)

>0he ar%erial oronary miroirula%ion, &hih onsis%s o1

prear%erioles and ar%erioles, plays a ma2or role in %he deli'ery

o1 (lood %o %he myoardium) 0he endo%helium, &hih lines

%hese 'essels, main%ains (lood 'essel !'asular# %one,

re3ula%es hemos%asis, a%s as (arrier %o po%en%ially %o4i

ma%erials, and re3ula%es in1lamma%ion) !See 5ormal

endo%helial 1un%ion a(o'e)#

>Endo%helial7media%ed 'asodila%ion is a(normal in a 'arie%yo1 pa%holo3i ondi%ions, inludin3 a%heroslerosis,

hyperholes%erolemia, dia(e%es, hyper%ension, i3are%%e

smokin3, ishemia reper1usion, and a3in3) !See Endo%helial

dys1un%ion a(o'e)#

http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/107http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/108http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/109http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts?source=search_result&search=endotelio&selectedTitle=4~150#H359033407http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts?source=search_result&search=endotelio&selectedTitle=4~150#H359033407http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts?source=search_result&search=endotelio&selectedTitle=4~150#H359038804http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts?source=search_result&search=endotelio&selectedTitle=4~150#H359038804http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/107http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/108http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts/abstract/109http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts?source=search_result&search=endotelio&selectedTitle=4~150#H359033407http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts?source=search_result&search=endotelio&selectedTitle=4~150#H359033407http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts?source=search_result&search=endotelio&selectedTitle=4~150#H359038804http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts?source=search_result&search=endotelio&selectedTitle=4~150#H359038804


22/22

>Pa%ien%s &i%h miro'asular an3ina or &i%h ardia

hyper%rophy due %o a 'arie%y o1 auses ha'e hes% pain

su33es%i'e o1 myoardial ishemia) Ishemia due %o

miro'asular disease is an impor%an% risk 1a%or 1or ardiae'en%s) !See Myoardial hyper%rophy a(o'e and ;Cardia

syndrome < An3ina pe%oris &i%h normal oronary ar%eries;,

se%ion on "is%ory)#
http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts?source=search_result&search=endotelio&selectedTitle=4~150#H359037604http://www21.ucsg.edu.ec:2062/contents/cardiac-syndrome-x-angina-pectoris-with-normal-coronary-arteries?source=see_link&sectionName=History&anchor=H352465069#H352465069http://www21.ucsg.edu.ec:2062/contents/cardiac-syndrome-x-angina-pectoris-with-normal-coronary-arteries?source=see_link&sectionName=History&anchor=H352465069#H352465069http://www21.ucsg.edu.ec:2062/contents/cardiac-syndrome-x-angina-pectoris-with-normal-coronary-arteries?source=see_link&sectionName=History&anchor=H352465069#H352465069http://www21.ucsg.edu.ec:2062/contents/coronary-artery-endothelial-dysfunction-basic-concepts?source=search_result&search=endotelio&selectedTitle=4~150#H359037604http://www21.ucsg.edu.ec:2062/contents/cardiac-syndrome-x-angina-pectoris-with-normal-coronary-arteries?source=see_link&sectionName=History&anchor=H352465069#H352465069http://www21.ucsg.edu.ec:2062/contents/cardiac-syndrome-x-angina-pectoris-with-normal-coronary-arteries?source=see_link&sectionName=History&anchor=H352465069#H352465069http://www21.ucsg.edu.ec:2062/contents/cardiac-syndrome-x-angina-pectoris-with-normal-coronary-arteries?source=see_link&sectionName=History&anchor=H352465069#H352465069

Coronary Artery Endothelial Dysfunction Uptodate 2015

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Coronary Artery Endothelial Dysfunction Uptodate 2015