Evaluation of C-Reactive Protein, Fibrinogen and Antithrombin-III As

yrigin—l erti™les

iv—lu—tion of gE‚e—™tive €roteinD pi˜rinogen —nd

entithrom˜inEsss —s ‚isk p—™tors for goron—ry ertery hise—se

‰uksel g—vusoglu whD fulent qorenek whD ƒeref elpsoy whD ehmet n—lir whD xe™mi et— wh

—nd filgin „imur—lp wh

hep—rtment of g—rdiologyD ysm—ng—zi niversityD iskisehirD „urkey

uey wordsX gEre—™tive proteinD fi˜rinogenD —ntithrom˜inEsssD ™oron—ry —rtery dise—se

ipidemiologi™—l studies h—ve shown — signifi™—nt —sso™i—tion por iditori—l see p—ge QT

˜etween sever—l risk f—™torsD su™h —s smokingD hypertensionD

dyslipidemi—D di—˜etes mellitusD —nd the p—thogenesis of

™oron—ry —theros™lerosisF gurrentlyD sever—l new risk f—™tors ± e˜str—™t

n—mely elev—ted levels of lipoprotein@—AD homo™ysteinemi—D f—™kgroundX snfl—mm—tion is —n import—nt fe—ture of

elev—ted levels of pl—sminogen —™tiv—tor inhi˜itorD ex™essive —theros™leroti™ lesions —nd in™re—sed produ™tion of the —™uteE

iron lo—d in the ˜odyD —n im˜—l—n™e ˜etween oxid—nt —nd ph—se re—™t—ntF „he ™ontri˜ution of ™o—gul—tion f—™tor to the

—ntioxid—nt spe™iesD —nd —ngiotensinE™onverting enzyme polyE development of ™oron—ry —rtery dise—se h—s not yet ˜een

morphism ± —re ˜eing des™ri˜ed in —theros™lerosis ‘I±T“F ™le—rly est—˜lishedF

purthermoreD experiment—l —nd ™lini™—l studies h—ve provided y˜je™tivesX „o test whether gEre—™tive proteinD fi˜rinogen

eviden™e for the presen™e of ongoing infl—mm—tion in —theroE —nd —ntithrom˜inEsss —re —sso™i—ted with —ngiogr—phi™ gehD

s™lerosis ‘UDV“F sn —dditionD new d—t— suggest th—t ˜—™teri—lD history of myo™—rdi—l inf—r™tion —nd extensive —theros™leroti™

p—r—siti™ or vir—l infe™tion m—y initi—te the infl—mm—tory involvementF

pro™ess ‘W“F wethodsX flood s—mples were tested for g‚€D fi˜rinogen

—nd e„Esss levels from PIW individu—ls undergoing ™oron—ry gEre—™tive protein —nd fi˜rinogen —re e—sily me—sur—˜le —nd

—ngiogr—phyF highly sensitive —™uteEph—se re—™t—nts th—t —re synthesized in

‚esultsX g‚€ w—s higher in p—tients with geh response to proEinfl—mm—tory ™ytokinesD su™h —s interleukinETD

@HFWSCIFQID naIVHD vsF HFQWCHFTI mgGdlD naQWD whi™h is the m—jor determin—nt of —™uteEph—se protein produ™E

€`HFHHHIA —nd in those with — history of ws @IFHUCIFTRD tion ‘IH“F sn™re—sed ™on™entr—tions of g‚€ —ppe—r to ˜e

naWTD vsF HFTSCHFUP mgGdlD naVRD €`HFHSA th—n in ™ontrol predi™tive of higher risk for ™oron—ry events in p—tients with

su˜je™tsF „he p—tients who developed unst—˜le —ngin— h—d st—˜le —nd unst—˜le —ngin—D —s well —s in —symptom—ti™ p—tients

higher g‚€ levels th—n the p—tients with st—˜le geh —t risk for ™oron—ry —rtery dise—se ‘IIDIP“F st h—s ˜een suggested

@PFHUCPFQVD naUD vsF HFVHCIFIQ mgGdlD naIUQD €`HFHHIAF th—t fi˜rinogenD whi™h pl—ys — pivot—l role in the ™o—gul—tion

pi˜rinogen w—s signifi™—ntly higher in p—tients with geh th—n in ™—s™—deD is —n independent ™—rdiov—s™ul—r risk f—™tor ‘IQ“F

those without geh @PWVCIHV vsF PSVCTQ mgGdlD €`HFHIAF sn woreoverD —ntithrom˜inEsssD whi™h is —n inhi˜itor of throm˜in

p—tients with gehD me—n e„Esss v—lue w—s less th—n in p—tients —nd of f—™tor ˆ—D m—y h—ve —n import—nt etiologi™ role in the

without gehD ˜ut this differen™e w—s not st—tisti™—lly signifi™—nt prognosis of p—tients with —ngin— pe™toris ‘IR“F „hereforeD in

@€aHFHVAF xo differen™e w—s found in g‚€D fi˜rinogen —nd e„E this study we investig—ted the v—lue of serum levels of g‚€D

sss v—lues —mong the p—tients with singleD dou˜le or triple fi˜rinogen —nd e„Esss in p—tients with st—˜le —ngin— undergoing

vessel dise—seF ™oron—ry —ngiogr—phyF

gon™lusionsX g‚€ is elev—ted in p—tients with geh —nd —

history of wsF ilev—ted levels of g‚€ —t the time of hospit—l wethods

—dmission is — predi™tive v—lue for future is™hemi™ eventsF

€—tient popul—tion

„here is —n —sso™i—tion ˜etween higher levels of fi˜rinogen —nd

„he study popul—tion ™onsisted of PIW ™onse™utive p—tients

gehF „he —sso™i—tion of e„Esss levels with geh needs testing

who h—d suspe™ted or known geh —nd were s™heduled for

in further studiesF

™oron—ry —ngiogr—phy ‘„—˜le I“F „o support the presen™e of

is™hemi™ he—rt dise—seD p—tients must h—ve met —t le—st one of swet PHHIYQXIQEIT

the following ™riteri—X — history of typi™—l myo™—rdi—l

is™hemi™Etype dis™omfortD ele™tro™—rdiogr—phi™ ™h—nges @ƒ„

segment devi—tion or „ w—ve inversionD or ˜othA in geh a ™oron—ry —rtery dise—se

—sso™i—tion with is™hemi™ dis™omfortD — previous positive g‚€ a gEre—™tive protein

exer™ise testD reversi˜le is™hemi— —t myo™—rdi—l perfusion e„Esss a —ntithrom˜inEsss

im—gingD — history of previous myo™—rdi—l inf—r™tionD — ws a myo™—rdi—l inf—r™tion

swe F †ol Q F t—nu—ry PHHI g‚€D pi˜rinogen —nd entithrom˜inEsss in geh IQ t

yrigin—l erti™les

„—˜le IF glini™—l —nd —ngiogr—phi™ ™h—r—™teri™ti™s of study p—tients of new resting ™hest p—in —sso™i—ted with tr—nsient igq signs of

myo™—rdi—l is™hemi—F

€—tients @naPIWA

xoF 7

ƒt—tisti™—l —n—lysis ege @yrA SV IH

w—le IRU TU7 „he st—tisti™—l —n—lysis w—s performed using the ƒt—tisti™—l

ƒystemi™ hypertension IHW RW7 €—™k—ge for ƒo™i—l ƒ™ien™es softw—re @ƒ€ƒƒ for ‡indowsAF

hi—˜etes mellitus QV IU7

gontinuous v—ri—˜les were ™omp—red using t tests for p—ired —nd

ryper™holesterolemi— PW IQ7

unp—ired v—ri—˜lesD —s —ppropri—teF €roportions were ™omp—red

gig—rette smoking WT RQ7

using the ™hiEsqu—re testF „he v—ri—˜les —re expressed —s me—n

p—mily history of geh RR PH7

st—nd—rd devi—tionY € v—lues `HFHS were ™onsidered st—tisti™—lly

€revious ws @b Q monthsA WT

signifi™—ntF

enterior SH

snferior QI

xonE IS ‚esults

€—tients with geh IVH VP7

€—tient groups

ƒingle vessel dise—se WR

glini™—l —nd —ngiogr—phi™ ™h—r—™teristi™s —re summ—rized in

hou˜le vessel dise—se RS

„—˜le IF yf the PIW study su˜je™tsD IVH @VP7A h—d eviden™e of „riple vessel dise—se RI

geh r—nging from bPH7 to signifi™—nt stenoses ˜y ™oron—ry €—tients without geh QW IV7

—ngiogr—phyF „he rem—ining QW p—tients whose ™oron—ry

—rteries were judged to ˜e —ngiogr—phi™—lly smooth were defined

previous ™oron—ry —ngiogr—phy showing SH7 stenosis of —

—s ˜eing free of gehF €—tients with geh —nd those without

m—jor epi™—rdi—l ™oron—ry vesselD previous ™oron—ry —ngioE

geh did not otherwise differ signifi™—ntly in ™—rdiov—s™ul—r

pl—styD or ™oron—ry —rtery ˜yp—ss gr—ft surgeryF ix™lusion

risk f—™torsF eltogether WT p—tients @RQ7A h—d h—d previous wsF

™riteri— wereX unst—˜le —ngin—D —™ute ws within Q monthsD

„here were WR @SP7A p—tients with singleEvessel dise—se —mong

infl—mm—tory ™onditions likely to ˜e —sso™i—ted with —n —™uteE

the p—tients with gehD —nd of these p—tients TR @TV7A h—d left

ph—se response @su™h —s feverD in™re—sed level of leuko™ytesD

—nterior des™ending dise—seD IV @IW7A h—d ™ir™umflex dise—seD

™hroni™ infe™tion —nd infl—mm—tory dise—sesAD ™hroni™ sigE

—nd IP @IQ7A h—d right ™oron—ry —rtery dise—seF

nifi™—nt hep—ti™D pulmon—ry or ren—l dise—sesD —nd neopl—sti™

dise—seF et the time of ™oron—ry —ngiogr—phyD —ll p—tients

g‚€D fi˜rinogenD e„Esss levels in p—tients with geh

were on or—l —spirin —nd isosor˜ide dinitr—teF

we—n g‚€ —nd fi˜rinogen v—lues were signifi™—ntly higher in

p—tients with geh ™omp—red to those without geh flood s—mpling

@€`HFHHHI —nd €`HFHID respe™tivelyAF ilev—ted levels of g‚€ €eripher—l ˜lood s—mples for me—surement of g‚€D fi˜rinogen

were found to ˜e —n import—nt risk f—™tor for gehF sn p—tients —nd e„Esss were t—ken from —n —nte™u˜it—l vein —fter —dmission

with gehD me—n e„Esss v—lue w—s less th—n in p—tients without to hospit—lD ˜efore the ™oron—ry —ngiogr—phy —nd without —ny

gehD ˜ut this differen™e w—s not signifi™—nt st—tisti™—lly intr—venous drug —dministr—tionF

@€aHFHVA ‘„—˜le P“F

v—˜or—tory —ss—ys

g‚€D fi˜rinogenD e„Esss levels in p—tients with history gEre—™tive protein —nd e„Esss were —ss—yed ˜y —n —utom—ted

of ws or unst—˜le —ngin— nephelometri™ immuno—ss—y using — fe™km—n err—y instrument

sn p—tients who h—d previous wsD the g‚€ v—lue w—s @fe™km—n err—y QTH systemD g—n—d—AF pi˜rinogen w—s me—E

signifi™—ntly higher th—n in p—tients without previous wsD —s sured using — photoEopti™ method on the yrg—non „e™hni™—

shown in pigure I @IFHUCIFTR vsF HFTSCHFUP mgGdlD €`HFHSD hurh—m go—Ee instrument @yrg—non „e™hni™—D xorth g—roliE

respe™tivelyAD where—s fi˜rinogen —nd e„Esss v—lues were not n—D ƒeAF

different ˜etween these two su˜groups @PWSCIIP vsF PVSCWQ

mgGdlD €bHFHS —nd PUFUICQFSP vsF PUFSRCQFUP mgGdlD €bHFHSD goron—ry —ngiogr—phy

respe™tivelyAF purthermoreD in the su˜group of p—tients with

„he pro™edure w—s performed using st—nd—rd ™oron—ry

™hest p—in —sso™i—ted with tr—nsient igq signs of myo™—rdi—l

™—theters vi— the femor—l routeF ‡e defined — p—tient —s h—ving

geh if there w—s —ny —ngiogr—phi™ eviden™e of —theros™lerosisD

„—˜le PF vevels of g‚€D fi˜rinogenD e„Esss in p—tients with —nd without

ex™luding `PH7 stenoses or —ny lumin—l w—ll irregul—rity of the

geh

epi™—rdi—l ™oron—ry treeF e p—tient w—s defined —s ˜eing free of

€—tients € v—lue €—tients geh if —ll ™oron—ry —rteries were judged to ˜e —ngiogr—phi™—lly

with geh without geh smoothF ell p—tients were o˜served for RV hours —fter the

g‚€ @mgGdlA HFWSCIFQI HFQWCHFTI `HFHHHI ™oron—ry —ngiogr—phyD ˜efore hospit—l dis™h—rgeF sn the period

pi˜rinogen @mgGdlA PWVCIHV PSVCTQ `HFHI

˜etween ™oron—ry —ngiogr—phy —nd hospit—l dis™h—rgeD — p—tient

e„Esss @mgGdlA PUFQWCQFTP PVFRUCQFRV a HFHV w—s ™onsidered to h—ve unst—˜le —ngin— if there w—s re™urren™e

IR ‰F g—vusoglu et —lF swe F †ol Q F t—nu—ry PHHI t

yrigin—l erti™les

„—˜le QF vevels of g‚€D fi˜rinogenD e„Esss in p—tients with single vessel

dise—se ™onsidering lesion lo™—liz—tion

veh dise—se gˆ dise—se ‚ge dise—se

g‚€ @mgGdlA IFIICIFVQ HFSPCHFSIB HFSPCHFSIB

pi˜rinogen @mgGdlA PVVCIHH QHVCIIW QIVCIQR

e„Esss @mgGdlA PTFWHCQFUI PVFQRCQFUT PWFRPCQFUR

B €`HFHS vsF g‚€ level of vehF

not with history of ws —nd future unst—˜le —ngin—F „here w—s —

we—ker positive rel—tion with de™re—sed levels of e„Esss —nd

geh @€aHFHVAD —nd no rel—tion with e„Esss levels —nd history

of wsD nor future unst—˜le —ngin—F

snfl—mm—tion is —n import—nt fe—ture of —theros™leroti™

lesions —nd in™re—sed produ™tion of the —™uteEph—se re—™t—ntsF

huring the —theros™leroti™ pro™ess the presen™e of lo™—l

pigure IF we—n levels of g‚€ in p—tients without previous ws —nd infl—mm—tory response with mono™ytesD m—™roph—ges —nd „

with previous wsF €`HFHSF lympho™ytes in the —rteri—l w—ll h—s ˜een in™re—singly re™ogE

nized —nd do™umented ‘VDIS“F ‚ele—se of key ™ytokinesD su™h —s

interleukinETD result in stimul—tion of hep—ti™ produ™tion of is™hemi— ˜efore dis™h—rge @U p—tientsAD g‚€ w—s found to ˜e

—™uteEph—se re—™t—nts ‘IT“F „husD —™uteEph—se re—™t—nts h—ve signifi™—ntly higher th—n in p—tients without —ny eviden™e of

˜een proposed —s — potenti—l indi™—tor of underlying —theroE is™hemi— @PFHUCPFQV vsF HFVHCIFIQ mgGdlD €`HFHHID respe™E

s™leroti™ dise—seF gEre—™tive protein —nd fi˜rinogen —re highly tivelyAF „here w—s no differen™e ˜etween these two su˜groups

sensitive —nd widely me—sur—˜le —™uteEph—se re—™t—nts ‘IH“F reg—rding fi˜rinogen —nd e„Esss @QRVCIPV vsF PVWCIHQ mgGdlD

gEre—™tive protein —nd fi˜rinogen h—ve ˜een found to ˜e €bHFHS —nd PSFQSCRFWQ vsF PUFTSCQFSV mgGdlD €bHFHSD

elev—ted in p—tients with gehF wend—ll et —lF ‘IP“ reported respe™tivelyAF

elev—ted levels of g‚€ in p—tients with gehD —nd enderson et

—lF ‘IU“ reported more th—n twofold elev—tions of g‚€ in ‚el—tionship ˜etween g‚€D fi˜rinogenD or e„Esss levels

p—tients with geh ™omp—red with ™ontrol su˜je™ts without —nd extensive geh

gehF sn the ƒ™ottish re—rt re—lth ƒtudy ‘IV“D fi˜rinogen w—s xo differen™e w—s found in g‚€D fi˜rinogen —nd e„Esss v—lues

found to ˜e —n import—nt risk f—™tor for geh in men —nd —mong the p—tients with singleD dou˜le or triple vessel dise—se

wom—nD with —nd without preEexisting gehF „he pu˜lished @g‚€ levels HFWSCIFSUD HFVUCIFHPD IFIICHFWSY fi˜rinogen

results from — met—E—n—lysis h—ve indi™—ted — signifi™—nt levels PWTCIHUD QHQCIIUD PWTCWWY e„Esss levels PUFSICQFUVD

—sso™i—tion ˜etween geh —nd in™re—sed levels of ˜oth fi˜rinoE PUFSSCQFRRD PTFWSCQFRUD —ll €bHFID respe™tivelyAF roweverD in

gen —nd g‚€ ‘IW“F „hese results —re ™omp—ti˜le with our the WR p—tients with single vessel dise—seD in™luding vehD gˆ

findingsF e„Esss —s — risk f—™tor h—s h—rdly ˜een investig—ted —nd ‚ge dise—seD g‚€ w—s signifi™—ntly higher in p—tients with

until nowF „hompson et —lF ‘IR“ reported — neg—tive rel—tion veh dise—se th—n with gˆ or ‚ge dise—se @—ll €`HFHSAF „here

˜etween the risk of ™—rdi—™ events —nd e„Esss levelF ƒimil—rlyD w—s no differen™e ˜etween gˆ —nd ‚ge dise—se for g‚€F sn

we found lower e„Esss levels in p—tients with gehD ˜ut it w—s —dditionD no differen™e w—s o˜served —mong vehD gˆ —nd

not st—tisti™—lly signifi™—nt @€aHFHVAF ‚ge dise—se for fi˜rinogen —nd e„Esss ‘„—˜le Q“F

ƒtudies h—ve supported the —sso™i—tion ˜etween g‚€ or

fi˜rinogen —nd —n in™re—sed risk of ™—rdi—™ eventsF sn the his™ussion

€hysi™i—ns re—lth ƒtudy ‘PH“D the in™re—sed level of g‚€ w—s

sn this studyD we demonstr—ted —n —sso™i—tion ˜etween elev—ted found to ˜e —n independent signifi™—nt predi™tor for wsF

levels of g‚€ —nd gehF „he —sso™i—tion w—s m—rked @twofold „hompson et —lF ‘PI“ showed th—t p—tients with st—˜le —ngin—

elev—tionA —nd highly signifi™—nt @€`HFHHHIAF g‚€ ™on™entr—E were —t gre—ter risk of su˜sequent ws if g‚€ w—s elev—tedF

tion w—s —lso strongly —sso™i—ted with history of ws @€`HFHSA r—verk—te —nd ™olle—gues ‘II“ reported — positive ™orrel—tion

—nd future unst—˜le —ngin—D whi™h ™ould ˜e o˜served during the ˜etween elev—ted levels of g‚€ —nd history of wsD —nd

hospit—l period —fter the ™oron—ry —ngiogr—phy @€`HFHHIAF ™onfirmed the predi™tive v—lue of g‚€ for ™oron—ry events in

elsoD our findings suggested th—t the in™re—sed levels of ˜oth st—˜le —nd unst—˜le —ngin—F st h—s —lso ˜een reported th—t

fi˜rinogen were positively ™orrel—ted with geh @€`HFHIAD ˜ut high fi˜rinogen levels were —sso™i—ted with in™re—sed risk of

future ws —nd history of ws ‘PPDPQ“F roweverD we ™ould not

est—˜lish — signifi™—nt rel—tion ˜etween fi˜rinogen —nd history of veh a left —nterior des™ending

wsF „he —˜ility of g‚€ to predi™t future events w—s gˆ a ™ir™umflex

demonstr—ted ˜y viuzzo et —lF ‘PR“D who showed th—t g‚€ in ‚ge a right ™oron—ry —rtery

swe F †ol Q F t—nu—ry PHHI g‚€D pi˜rinogen —nd entithrom˜inEsss in geh IS t

yrigin—l erti™les

IHF f—um—nn rD q—uldie tF ‚egul—tion of hep—ti™ —™ute ph—se pl—sm— protein p—tients with unst—˜le —ngin— predi™ted re™urrent is™hemi™

genes ˜y hep—to™yte stimul—ting f—™tors —nd other medi—tors of infl—mm—tionF

eventsF fe™ker —nd ™oEworkers ‘PS“ reported th—t elev—tion of

wol fiol wed IWWHYUXIRU±SWF

fi˜rinogen —t the time of hospit—l —dmission is —sso™i—ted with

IIF r—verk—te pD „hompson ƒqD €yke ƒhwD q—llimore t‚D €epys wfF

™oron—ry is™hemi™ events in p—tients with unst—˜le —ngin—F yur €rodu™tion of gEre—™tive protein —nd risk of ™oron—ry events in st—˜le —nd

study popul—tion did not in™lude p—tients with unst—˜le unst—˜le —ngin—X iurope—n gon™erted e™tion on „horom˜osis —nd hisE

—˜ilities engin— €e™toris ƒtudy qroupF v—n™et IWWUYQRWXRTP±TF is™hemi—D ˜ut in those who developed unst—˜le is™hemi™ ™hest

IPF wend—ll weD €—tel €D f—ll—m vD ƒtr—™h—n hD xorthfield „gF g re—™tive p—inD only ˜—seline g‚€ levels were found to ˜e higherD not

protein —nd its rel—tion to ™—rdiov—s™ul—r risk f—™torsX — popul—tion ˜—sed

fi˜rinogen nor e„EsssF

™ross se™tion—l studyF fr wed t IWWTYQIPXIHTI±SF

yne study found no ™orrel—tion ˜etween the degree of

IQF irnst iF €l—sm— fi˜rinogen ± —n independent ™—rdiov—s™ul—r risk f—™torF t

—theros™lerosis —nd the —™uteEph—se response in p—tients with sntern wed IWWHYPPUXQTSF

™hroni™ st—˜le —ngin—D despite mu™h more extensive —theroE IRF „hompson ƒqD pe™htrup gD ƒquire iD reyse D freith—rdt qD v—n de voo

tg‡D uien—st tF entithrom˜in sss —nd fi˜rinogen —s predi™tors of ™—rdi—™ s™leroti™ involvement ‘PR“F yn the other h—ndD —nother study

events in p—tients with —ngin— pe™torisF erterios™ler „hrom˜ †—s™ fiol

demonstr—ted th—t g‚€ w—s positively ™orrel—ted with the

IWWTYITXQSU±TPF

extent of ™oron—ry stenosis ‘II“F sn our studyD no rel—tion w—s

ISF ƒh—h €uD p—lk iD f—dimon ttD pern—ndesEyrtiz eD w—ilh—™ eD †ill—re—lEvevy

found ˜etween —™uteEph—se response —nd extent of gehD ˜ut in qD p—llon t„D ‚engstrom tD puster †F rum—n mono™yteEderived m—™roE

™ontr—st to other studies we found signifi™—ntly high levels of ph—ges indu™e ™oll—gen ˜re—kdown in fi˜rous ™—ps of —theros™leroti™ pl—quesX

potenti—l role of m—trixEdegr—ding met—lloprotein—ses —nd impli™—tions for g‚€ in veh dise—se —mong p—tients with single vessel dise—seF

pl—que ruptureF gir™ul—tion IWWSYWPXISTS±WF

sn ™on™lusionD the present rese—r™h demonstr—tes the

ITF fi—su™™i vwD †itelli eD viuzzo qD elt—mur— ƒD g—ligiuri qD won—™o gD

—sso™i—tion of elev—ted g‚€ levels with geh —nd extends this

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