HOMOCYSTEINE IS NOT AN INDICATOR OF RESTENOSIS RISK
AFTER PERCUTANEOUS TRANSLUMINAL CORONARY
ANGIOPLASTY
Ö n d er S irik c i, M .D .* / V e d a t A y te k in , M .D .** / G ü ler Topçu, M .D .*
S aide A y te k in , M .D .** / I.C.Cemsid D em iro ğ lu , M .D .***
C em 'i D em iro ğ lu , M .D .**
* D e p a rtm e n t o f B io c h e m is try , S c h o o l o f M e d icin e , M arm ara U n ive rsity, Is ta n b u l, Turkey.
* * D e p a rtm e n t o f C a rd io lo g y, F lo re n ce n ig h tin g a le H o s p ita l, S c h o o l o f M edicine, K a d ir lia s U n ive rsity, Is ta n b u l, Turkey.
* * * D e p a rtm e n t o f C a rd io lo g y, F lo re n c e n ig h tin g a le H o s p ita l, Is ta n b u l, Turkey.
ABSTRACT
O b je c t iv e : E le v a te d h o m o c y s te in e le v e ls h a v e b e e n a s s o c ia te d w ith in c re a s e d ris k o f a th e r o s c le ro tic v a s c u la r d is e a s e . T h e p o s s ib le a s s o c ia tio n o f h o m o c y s te in e w ith re s te n o s is a fte r p e rc u ta n e o u s tr a n s lu m in a l c o ro n a ry a n g io p la s ty (P T C A ) h a s n o t b e e n w id e ly in v e s tig a te d . M e t h o d s : In o rd e r to d e te rm in e if a re la tio n s h ip e x is ts b e tw e e n s e ru m h o m o c y s te in e le v e ls a n d re s te n o s is a fte r P T C A , s e ru m h o m o c y s te in e le v e l w e re d e te r m in e d in 2 0 4 p a tie n ts w h o u n d e rw e n t a s u c c e s s fu l P T C A p ro c e d u re a n d s ta n t im p la n ta tio n . T h e p a tie n ts w e re fo llo w e d w ith c lin ic a l e x a m in a tio n s a n d e x e rc is e te s ts a t 1, 3, a n d 6 m o n th s , a n d a c o n tr o l c o r o n a r y a n g io g r a p h y w a s p e rfo rm e d a fte r 6 m o n th s to e v a lu a te re s te n o s is . H o m o c y s te in e le v e ls w e re d e te r m in e d w ith flu o r e s c e n c e p o la r iz a tio n im m u n o a s s a y . R e s u lt s : O f th e 1 4 6 p a tie n ts w h o u n d e rw e n t a n g io g r a p h ic e v a lu a tio n , 5 7 (3 9 % ) h a d re s te n o s is , w h e re a s 8 9 (61 % ) d id n o t. T h e h o m o c y s te in e d is trib u tio n s w e re c o m p a re d in th e s e tw o g r o u p s o f p a tie n ts . A lth o u g h th e a v e ra g e h o m o c y s te in e le v e ls w e re h ig h e r in th e re s te n o s e d g ro u p , th e d iffe r e n c e w a s n o t s ta tis tic a lly s ig n ific a n t.
Conclusion:
B e c a u s e o f its w id e d is trib u tio n , s e ru m h o m o c y s te in e v a lu e s d o n o t s e e m to be a u s e fu l in d ic a to r fo r th e ris k o f re s te n o s is a fte r P T C A .K ey W o rd s :
H o m o c y s te in e , R e s te n o s is , P T C AINTRODUCTION
H o m o c y s te in e is a n a tu ra lly o c c u rrin g s u lp h u r c o n ta in in g a m in o a c id p r o d u c e d d u rin g m e th io n in e m e ta b o lis m . M e th io n in e is c o n v e rte d to h o m o c y s te in e th r o u g h in te r m e d ia te s S - a d e n o s y l m e th io n in e a n d S -a d e n o s y l h o m o c y s te in e . H o m o c y s te in e c a n be r e m e th y la te d to m e th io n in e b y m e th io n in e s y n th a s e w h ic h r e q u ir e s m e th y le n e te tra h y d ro fo la te (M T H F ) a s a c o fa c to r, b u t th e m a jo r ity o f h o m o c y s te in e g o e s th r o u g h a p y rid o x a l- 5 '-p h o s p h a te (v ita m in B 6) d e p e n d e n t (A c c e p te d 30 M ay, 20 00 ) M arm a ra M e d ic a l J o u rn a l 2 0 0 0 ;1 3 (3 ):1 37 -142 1 3 7Onder Sirikci, et aI
c o n d e n s a tio n w ith s e rin e to fo rm c y s ta th io n in e in a re a c tio n c a ta ly z e d b y c y s ta th io n in e b e ta - s y n th a s e (C p S )(1 ). T h e h o m o c y s te in e in b lo o d is e ith e r fo u n d a s c o v a le n tly b o u n d to p la s m a p ro te in s , o r b o u n d to o th e r th io ls -in c lu d in g its e lf. O n ly a v e ry s m a ll fra c tio n , (~ 1 % ) c irc u la te s in th e fo rm o f fre e th io l.
T h e h o m o c y s te in e le v e ls m a y b e e le v a te d b e c a u s e o f e ith e r g e n e tic c a u s e s , s u c h a s h o m o z y g o u s d e fic ie n c y o f C P S , o r h o m o z y g o u s d e fic ie n c y o f M T H F re d u c ta s e , d ie t (m e th io n in e in ta k e , n u tr itio n a l d e fic ie n c ie s o f fo lic a c id , v ita m in B 12 a n d v ita m in B 6), a g e a n d e s tro g e n s ta tu s . O th e r c a u s e s s u c h a s re n a l im p a irm e n t a ls o e ffe c t h o m o c y s te in e le v e ls b y im p a irin g th e m e ta b o lis m o f h o m o c y s te in e b y th e k id n e y s . E le v a te d h o m o c y s te in e le v e ls h a s b e e n w id e ly a s s o c ia te d w ith a th e ro s c le ro tic v a s c u la r d is e a s e . A lth o u g h th e m e c h a n is m b y w h ic h h o m o c y s te in e c a u s e s v a s c u la r d a m a g e a n d c o n tr ib u te s to a th e ro s c le ro s is is n o t y e t k n o w n , m e c h a n is m s re la tin g to d ire c t (b y d ire c tly re a c tin g w ith c e llu la r c o n s titu e n ts ) a n d in d ire c t (b y a u to -o x id a tio n of h o m o c y s te in e to h o m o c y s tin e a n d h y d ro g e n p e ro x id e ) c y to t o x ic ity o f h o m o c y s te in e to e n d o th e lia l a n d v a s c u la r s m o o th m u s c le c e lls h a v e b e e n p ro p o s e d . V a rio u s s tu d ie s h a v e s u g g e s te d th a t h o m o c y s te in e fa c ilita te s o x id a tiv e a rte ria l in ju ry , a u g m e n ts th e p ro life r a tio n o f s m o o th m u s c le c e lls , a lte r s th e c o a g u la n t p ro p e rtie s o f b lo o d a n d im p a irs e n d o th e liu m d e p e n d e n t v a s o m o to r re g u la tio n . In re s p o n s e to h o m o c y s te in e - in d u c e d in ju r y d a m a g e d e n d o th e lia l c e lls b e c o m e p ro th r o m b o tic w ith d e c re a s e d th r o m b o m o d u lin a n d h e p a ra n s u lfa te s y n th e s is a n d in c re a s e d e x p re s s io n o f tis s u e fa c to r. In c re a s e d le v e ls o f h o m o c y s te in e c a n a ls o in c r e a s e v a s c u la r s m o o th m u s c le c e ll p ro life ra tio n v ia a c tiv a tio n o f p ro te in k in a s e C, c y c lin d e p e n d e n t k in a s e , a n d in d u c tio n o f c -fo s a n d c -m y b . T h e s e h y p o th e s e s a n d re la te d s tu d ie s h a v e b e e n re v ie w e d b y B e rw a n g e r (2), W e lc h (3 ) a n d H a n k e y (4 ). T h e p o s s ib le in te ra c tio n o f h o m o c y s te in e w ith e n d o th e lia l fu n c tio n s , v a s c u la r s m o o th m u s c le c e ll p ro life ra tio n a n d th r o m b o tic p ro p e rtie s o f b lo o d a re a ls o c lo s e ly re la te d to re s te n o s is a fte r P T C A . T h e ro ie o f h o m o c y s te in e in th e d e v e lo p m e n t of re s te n o s is a fte r P T C A h a s n o t b e e n in v e s tig a te d w id e ly . In a ra t c a ro tid e n d a rte re c to m y m o d e l, h y p e rh o m o c y s te in e m ia w a s fo u n d to in c re a s e n e o in tim a l h y p e rp la s ia (5 ), b u t in a p ro s p e c tiv e c a s e -c o n tro l s tu d y p la s m a h o m o c y s te in e w a s n o t a p re d ic tiv e fa c to r fo r re s te n o s is a fte r c o ro n a ry a n g io p la s ty (6 ). T h e re fo r e w e a im e d to o b s e rv e a n y p o s s ib le a s s o c ia tio n b e tw e e n h o m o c y s te in e le v e ls a n d re s te n o s is a fte r P T C A w ith o r w ith o u t s te n t im p la n ta tio n .
M A T E R IA L S A N D M E T H O D S P a tie n ts
F ro m J a n u a ry to D e c e m b e r 1 9 9 7 , 2 0 4 p a tie n ts w e re e n ro lle d in th is p ro s p e c tiv e c lin ic a l tria l w h o u n d e rw e n t a c o ro n a r y in te rv e n tio n b e c a u s e of s ta b le o r u n s ta b le a n g in a p e c to ris . T h e c rite ria fo r c o r o n a r y in te r v e n t io n w a s th e a n g io g r a p h ic a lly d o c u m e n te d s te n o s is o f> 7 0 % in a t le a s t o n e o f th e m a jo r b ra n c h e s o f th e c o r o n a r y tr e e , a n d a c c o m p a n y in g is c h e m ic c h a n g e s in e le c tro c a r d io g ra m s (E C G ) a t re s t o r w ith p ro v o c a tiv e te s ts . A ll p a tie n ts ' w h o le b lo o d c o u n ts , b lo o d g lu c o s e le v e ls , liv e r a n d re n a l fu n c tio n te s ts , E C G a n d c h e s t X -ra y s w e re e v a lu a te d b e fo r e th e in te r v e n tio n . O v e r n ig h t fa s tin g b lo o d s a m p le s w e re o b ta in e d fro m th e p a tie n ts b e fo r e P T C A fo r h o m o c y s te in e d e te r m in a tio n s . A n in fo rm e d c o n s e n t w a s o b ta in e d fro m all p a tie n ts a n d th is s tu d y w a s a p p ro v e d b y th e E th ic a l C o m m itte e o f th e M a rm a ra U n iv e rs ity S c h o o l o f M e d ic in e . P r o c e d u r e a n d f o l l o w - u p P T C A p ro c e d u re s a n d s te n t im p la n ta tio n s o f th e s c h e d u le d p a tie n ts w e r e p e r fo r m e d in th e C a th e riz a tio n L a b o ra to ry o f F lo re n c e N ig h tin g a le H o s p ita l ( K a d ir H a s U n iv e r s ity S c h o o l o f M e d ic in e ). T h e a n g io p la s ty p ro c e d u re s w e re p e rfo rm e d v ia th e fe m o ra l a p p ro a c h w ith a n 8 F re n c h g u id in g c a th e t e r a c c o r d in g to th e s ta n d a rd P T C A te c h n iq u e a s o rig in a lly d e s c rib e d b y G ru n tz ig e t al (7). T h e a n g io g r a p h ic c rite r ia of a s u c c e s s fu l a n g io p la s ty w a s d e fin e d a s an in c re a s e o f g re a te r th a n 5 0 % in lu m in a l d ia m e te r w ith a fin a l s te n o s is o f le s s th a n 3 0 % in lu m in a l d ia m e te r a n d n o m a jo r c o m p lic a tio n s (d e a th , m y o c a r d ia l in fa rc tio n , o r e m e r g e n c y b y -p a s s s u rg e r y ). A s te n t w a s im p la n te d in b a il-o u t s itu a tio n s a n d in c a s e s w h e re a s u b o p tim a l re s u lt w a s o b ta in e d w ith c o n v e n tio n a l P T C A . A ll
Homocysteine is not an indicator of restenosis risk after PTCA
p a tie n ts w h o d id n o t h a v e a h is to ry o f p re v io u s g a s tro in te s tin a l b le e d in g w e re o n a s p irin th e ra p y (1 0 0 - 3 0 0 m g /d a y ) b e fo r e a n d a fte r th e in te rv e n tio n , in tra v e n o u s b o lu s h e p a rin (1 0 ,0 0 0 U in P T C A a n d 1 5 ,0 0 0 U in s te n t p a tie n ts ) w ith a P T T c o n tro l, a n d tic lo p id in e fo r 6 w e e k s (s te n t p a tie n ts ) , c a lc iu m c h a n n e l b lo c k e rs a n d n itro g ly c e rin fo r s ix m o n th s a s a d ju n c tiv e m e d ic a l th e ra p ie s . A n y o f th e p re s e n t ris k fa c to rs s u c h as h y p e r c h o le s te r o le m ia , h y p e r te n s io n a n d d ia b e te s w e r e in te n s iv e ly tr e a te d w ith a p p r o p r ia te th e r a p ie s . T h e p a tie n ts w e re fo llo w e d w ith c lin ic a l e x a m in a tio n s a n d e x e rc is e te s ts a t 1,3 a n d 6 m o n th s a fte r th e in te rv e n tio n . A c o r o n a r y a n g io g r a m w a s s c h e d u le d a fte r 6 m o n th s ' c o n tro l to e v a lu a te re s te n o s is , in w h ic h , p a tie n ts w ith g r e a t e r th a n 5 0 % s te n o s is in lu m in a l d ia m e te r a t th e a n g io p la s ty s ite w e re a c c e p te d to h a v e re s te n o s is . B o th a n g io p la s ty a n d c o n tro l a n g io g r a p ie s w e re re c o rd e d w ith c in e a n g io g ra p h y fo r d o c u m e n ta tio n . D e t e r m in a t io n o f h o m o c y s t e in e S e ru m h o m o c y s te in e le v e ls w e re d e te rm in e d w ith flu o r e s c e n c e p o la r iz a tio n im m u n o a s s a y (A b b o tt D ia g n o s tic s ) (8 ,9 ). T h e h o m o c y s te in e a d d u c ts in s a m p le s w e re re d u c e d to fre e h o m o c y s te in e w ith th e a d d itio n o f d ith io th re ito l a n d th e to ta l fr e e h o m o c y s te in e w a s e n z y m a tic a lly c o n v e rte d to S A H . T h e a m o u n t of S A H w e re d e te r m in e d w ith a flu o re s c e in a te d tr a c e r la b e le d a n ti-S A H a n tib o d y . T h e re s u lts w e re e x p re s s e d a s to ta l h o m o c y s te in e in p m o l/L . D a ta a n a ly s is
T h e d iffe r e n c e in th e d is trib u tio n o f d ic h o to m o u s c h a ra c te ris tic s in o u tc o m e g ro u p s w e re e x p lo re d w ith th e c h i-s q u a re te s t. T h e p re s e n c e o f a s ta tis tic a lly s ig n ific a n t d iffe re n c e in h o m o c y s te in e d is trib u tio n s a m o n g p a tie n ts g ro u p e d a c c o rd in g to o u tc o m e o r v a r io u s c h a r a c te r is tic s w e re e x p lo re d w ith th e t-te s t, u s in g o n e -ta ile d p- v a lu e s . T h e s ta tis tic a l te s ts w e re d o n e u s in g M S - E x c e l 9 7 s o ftw a re .
RESULTS
O f th e 2 0 4 p a tie n ts in c lu d e d in th e s tu d y , 146 p a tie n ts (7 2 % ) h a d a c o n tr o l a n g io g r a p h y p e rfo rm e d a t th e e n d o f th e fo llo w -u p p e rio d . T h e m e a n tim e in te rv a l fo r c o n tro l a n g io g ra p h y w a s 6 .9 ± 3 .6 m o n th s . T h e m e a n a g e o f th e s e 111 m a le (7 6 % ) a n d 35 fe m a le (2 4 % ) w a s 5 6 ± 1 0 y e a rs . A c c o rd in g to th e a n g io g ra p h ic e v a lu a tio n , 5 7 o f th e p a tie n ts (3 9 % ) w e re d e c id e d to h a v e re s te n o s is , w h e re a s 8 9 p a tie n ts (6 1 % ) d id not. T h e h o m o g e n e ity o f th e re s to n o s is a n d n o n s te n o s is g ro u p s w e re a n a ly z e d fo r th e d is trib u tio n o f g e n d e r, le s io n n u m b e r, o r ty p e of in te rv e n tio n (P T C A v s . s te n t) a p p lie d , a n d th e n u m b e r o f d ia b e tic a n d h y p e rte n s iv e p a tie n ts w ith th e c h i-s q u a re te s t. T h e d is trib u tio n of th e s e c h a ra c te ris tic s w e re n o t s ig n ific a n tly d iffe re n t (T a b le I) in re s te n o s is a n d n o n -s te n o s is g ro u p s . T h e a p p lic a tio n o f P T C A w ith o r w ith o u t s te n t im p la n ta tio n to p a tie n ts h a v in g o n e , tw o o r th re e le s io n s a ls o w a s n o t d iffe r e n t s ig n ific a n tly (p = 0 .6 2 2 ). T h e a g e , a n d b lo o d lip id p a ra m e te rs o f th e re s te n o s is a n d n o n -s te n o s is g ro u p s are p re s e n te d in T a b le II. T h e m e a n a g e (p = 0 .133), to ta l c h o le s te r o l ( p = 0 .2 8 0 ) , L D L - c h o le s te r o l ( p = 0 .4 3 8 ), H D L - c h o le s te r o l ( p = 0 .3 7 7 ), a n d tria c y lg ly c e ro l (p = 0 .6 6 0 ) le v e ls o f p a tie n ts p rio r to P T C A w e re n o t s ig n ific a n tly d iffe r e n t in th e re s te n o s is a n d n o n -s te n o s is g ro u p s w ith th e t- te s t. N o n e of th e s e ris k fa c to rs w e re fo u n d to be a s s o c ia te d w ith re s te n o s is o u tc o m e w ith u n iv a ria te a n a ly s e s . A lth o u g h th e a v e ra g e h o m o c y s te in e le v e l in th e re s te n o s is g ro u p w a s h ig h e r th a n th e a v e ra g e h o m o c y s te in e le v e l of n o n -s te n o s is g ro u p , th e d iffe re n c e w a s n o t s ig n ific a n t w ith th e t-te s t (1 2 .0 6 vs. 1 0 .6 0 p m o l/L ; p = 0 .1 2 ) (T a b le III). In o r d e r to s e e if th e e le v a tio n in th e m e a n h o m o c y s te in e le v e l in th e re s te n o s is g ro u p c o u ld
T a b l e I. T h e distribution of g e n d e r, type of intervention u se d , n u m b er of p a tie n ts with single or multiple lesions and n u m b er of p a tie n ts with d ia b e te s a n d h ypertension in th e re ste n o s is an d n o n -ste n o sis g roups.
^R e ste nos is N o n-stenosis Total
Male 47 64 111 Female 10 25 35 PTCA 37 53 90 Stent 20 36 56 Single lesion 37 61 98 Multiple lesion 20 28 48 DM 5 6 11 Hypertension 10 24 34 1 3 9
Önder Sirikci, et at
Table II. T h e a g e a n d blood lipid p a ra m e te rs of th e re ste n o s is a n d n o n -ste n o s is g roups.
restenosis, (n=57) non-stenosis, (n=89)
mean median min max SD mean median min max SO
Age 57.2 58 38 76 9.8 54.8 55 32 78 9.5 Total cholesterol 212.5 213 122 313 45.4 221.1 220 123 399 45.6 Triacylglycerols 200 171 60 690 130.3 208.6 184 61 573 100.1 HDL-cholesterol 46.4 48 30 56 5.5 45.5 47 24 58 6.1 LDL-cholesterol 127.9 125.9 51.2 238 43.3 133.9 134 42.6 313.2 44.7 Table III. T h e a v e r a g e h o m o c y s te in e le v e ls (± 1 s ta n d a rd deviations) in re s te n o s is a n d n o n -ste n o s is g ro u p s. H o m o cy ste in e , pmol/L restenosis N o n-stenosis Whole group 12.06+4.51 10.60+6.43 Male 12.92+4.31 11.34±7.20 Female 7.36±2.17 8.79±3.56 PTCA 12.10±4.29 9.26±2.73* Stent 11 97±5.12 12.27±8.95 Single lesion 11.78±5.34 10.57±7.57 Multiple lesion 12.51±2.80 10 81 ±3.02 • p=0,002
h a v e b e e n m a s k e d w ith th e w id e d is trib u tio n o f h o m o c y s te in e le v e ls , th e 9 5 th p e rc e n tile v a lu e of th e n o n -s te n o s is g ro u p w a s re g a rd e d a s a c u t-o ff v a lu e fo r th is c o h o rt, a n d th e p e rc e n ta g e o f v a lu e s e x c e e d in g th is c u t- o ff v a lu e w e re c o m p a re d a n d fo u n d to b e v e ry s im ila r in th e re s te n o s is a n d n o n -s te n o s is g ro u p s (6.1 % a n d 6 .2 % re s p e c tiv e ly ). W h e n th e h o m o c y s te in e le v e ls in o u tc o m e g ro u p s w e re c o m p a re d a c c o rd in g to g e n d e r, m e n h a d a n o n -s ig n ific a n t e le v a tio n in th e re s te n o s is g ro u p (1 2 .9 2 v s . 1 1 .3 4 p m o l/L , p = 0 .1 5 2 ) , w h e re a s w o m e n p re s e n te d a n o n -s ig n ific a n t e le v a tio n in th e n o n -s te n o s is g ro u p (7 .3 6 v s 8 .7 9 p m o l/L ; p = 0 .2 0 2 ). T h e h o m o c y s te in e v a lu e s of re s te n o s is a n d n o n -s te n o s is g ro u p s w e re a ls o c o m p a re d a m o n g s u b s e ts a c c o rd in g to th e ty p e o f in te rv e n tio n a p p lie d (P T C A v s s te n t), a n d a c c o rd in g to p a tie n ts h a v in g s in g le o r m u ltip le le s io n s . T h e h o m o c y s te in e le v e ls o f p a tie n ts w ith c o n v e n tio n a l P T C A w e re s ig n ific a n tly e le v a te d in th e re s te n o s is g ro u p (1 2 .1 0 vs. 9 .2 6 , p = 0 .0 0 2 ), b u t th is p a tte rn w a s n o t o b s e rv e d in p a tie n ts to w h o m a s te n t w a s im p la n te d (1 1 .9 7 v s . 1 2 .2 7 , p = 0 .4 4 9 ). P a tie n ts w h o h a d a s in g le le s io n in te rv e n tio n (1 1 .7 8 v s . 1 0 .5 7 p = 0 .2 5 9 ) a n d an In te rv e n tio n to m o re th a n o n e le s io n (1 2 .5 1 vs. 1 0 .8 1 , p = 0 .0 6 2 ) b o th h a d n o n - s ig n if ic a n t e le v a tio n s in th e ir re s p e c tiv e re s te n o s is g ro u p s . D IS C U S S IO N A fte r its d is c o v e ry in 1 9 6 0 's , e le v a te d le v e ls o f h o m o c y s te in e w e re re g a rd e d a s a ris k fa c to r fo r a th e ro s c le ro s is . M o re th a n 1 2 ,0 0 0 p a tie n ts w e re in v e s tig a te d in m o re th a n 1 0 0 c ro s s -s e c tio n a l, c a s e -c o n tro l, a n d p ro s p e c tiv e c o h o rt s tu d ie s to d e te r m in e th e ro le o f e le v a te d h o m o c y s te in e le v e ls a s a n a th e r o s c le ro tic ris k fa c to r (4 ). T h e P h y s ic ia n s ’ H e a lth S tu d y (1 0 ), th e B ritis h U n ite d P ro v id e n t A s s o c ia tio n s tu d y (1 1 ), th e T ro m s o s tu d y (1 2 ), th e B ritis h R e g io n a l H e a rt S tu d y (1 3 ), a n d th e la rg e E u ro p e a n C o lla b o ra tiv e S tu d y (1 4 ) w e re a m o n g th e m o s t p ro m in e n t s tu d ie s w h e re e le v a te d h o m o c y s te in e le v e ls w e re fo u n d to b e a s s o c ia te d w ith c o ro n a r y h e a rt d is e a s e . In a m e ta -a n a ly s is o f 2 7 o b s e rv a tio n a l s tu d ie s w h ic h in c lu d e d 4 0 0 0 p a tie n ts , a n e le v a te d h o m o c y s te in e le v e l w a s a s s o c ia te d w ith an in c r e a s e d r is k o f fa ta l a n d n o n - fa ta l a th e r o s c le ro tic v a s c u la r d is e a s e in th e c o ro n a ry , c e re b ra l, a n d p e rip h e ra l c irc u la tio n s (1 5 ). B u t o th e r p r o s p e c tiv e s tu d ie s , - in c lu d in g fu r th e r re p o rts fro m th e P h y s ic ia n s ' H e a lth S tu d y -, h a v e fa ile d to d e m o n s tra te a s ig n ific a n t a s s o c ia tio n b e tw e e n e le v a te d h o m o c y s te in e le v e ls a n d n e w a n g in a , n o n - fa ta l m y o c a r d ia l in fa r c tio n (M l), d e a th fro m c o ro n a r y h e a rt d is e a s e (C H D ), a n d is c h e m ic s tro k e (1 6 -2 0 ). In o rd e r to d e te r m in e if h o m o c y s te in e le v e ls a t th e tim e o f a n g io p la s ty w o u ld b e a p re d ic to r of r e s te n o s is a fte r P T C A , w e e v a lu a te d th e h o m o c y s te in e le v e ls o f 1 4 6 p a tie n ts u n d e rg o in g P T C A w ith o r w ith o u t s te n t im p la n ta tio n . In o u r p ro s p e c tiv e c o h o rt, th e o v e ra ll h o m o c y s te in e d is trib u tio n o b ta in e d is s im ila r to th e d is trib u tio n s o b ta in e d in la rg e -s c a le e p id e m io lo g ic s tu d ie s (1 0 ,1 3 ,1 4 ,2 0 ). A lth o u g h th e h o m o c y s te in e le v e l w a s e le v a te d in th e r e s t e n o s is g r o u p , th e d iffe r e n c e d id n o t r e a c h s ig n if ic a n c e . T h e p e rc e n ta g e o f v a lu e s w h ic h e x c e e d a n a rb itra ry c u t-o ff v a lu e (th e 9 5 th p e rc e n tile v a lu e o f th e n o n s te n o s is g ro u p ) w e r e a ls o s im ila r in th e re s te n o s is a n d n o n -s te n o s is g ro u p s (6 .1 % a n d 6 .2 % re s p e c tiv e ly ), w h ic h in d ire c tly s h o w e d th a t e le v a te d v a lu e s w e re e q u a lly d is trib u te d . W h e n
Homocysteine is not an indicator of restenosis risk after PTCA
th e a n a ly s e s w e r e p e r fo r m e d a c c o r d in g to g e n d e r th e s a m e p a tte rn w a s o b s e rv e d in m e n w h e r e a s w o m e n e x h ib ite d a n o n - s ig n ific a n t e le v a tio n in th e n o n -s te n o s is g ro u p ; b u t th e s m a lle r s iz e o f th e fe m a le p a tie n t g ro u p (n = 1 0 in th e re s te n o s is g ro u p , 2 5 in th e n o n -s te n o s is g ro u p ) a n d th e n o n -s ig n ific a n c e o f th e d iffe re n c e le a d s us to q u e s tio n th e s ig n ific a n c e o f th e c h a n g e in p a tte rn . W h e n th e p a tie n ts w e re g ro u p e d a c c o rd in g to th e ty p e o f in te rv e n tio n a p p lie d (P T C A v s s te n t), th e h o m o c y s te in e le v e ls o f p a tie n ts w ith c o n v e n tio n a l P T C A w e re s ig n ific a n tly e le v a te d in th e re s te n o s is g ro u p (1 2 .1 0 vs. 9 .2 6 , p = 0 .0 0 2 ), b u t th is p a tte rn w a s n o t o b s e rv e d in p a tie n ts to w h o m a s te n t w a s im p la n te d (1 1 .9 7 vs. 1 2 .2 7 , p = 0 .4 4 9 ). P a tie n ts w h o h a d a s in g le le s io n in te rv e n tio n (1 1 .7 8 vs. 1 0 .5 7 p = 0 .2 5 9 ) a n d a n in te rv e n tio n to m o re th a n o n e le s io n (1 2 .5 1 vs. 1 0 .8 1 , p = 0 .0 6 2 ) b o th h a d n o n - s ig n ific a n t e le v a tio n s in th e ir re s p e c tiv e re s te n o s is g ro u p s .T h e in te rp re ta tio n o f th e c o n flic tin g re s u lts of e p id e m io lo g ic a n d o th e r c lin ic a l s tu d ie s re g a r d in g th e ro le o f h o m o c y s te in e in th e d e v e lo p m e n t o f a th e r o s c le ro tic v a s c u la r d is e a s e is c o m p lic a te d b y th e d iffe re n c e s in s tu d y d e s ig n , th e s e le c tio n c rite r ia a n d n u m b e r o f c a s e s a n d c o n tro ls , th e d iffe r e n c e in fo llo w -u p m e th o d a n d d u ra tio n , th e a n a ly tic a l m e th o d u s e d in th e d e te rm in a tio n o f h o m o c y s te in e , th e d iffe re n c e in th e ty p e a n d s e le c tio n o f o u tc o m e (M l, C H D , fa ta l M l, s tro k e e tc .), a n d th e s ta tis tic a l a n a ly s e s u s e d (2 ,4 ). A lth o u g h th e a th e ro s c le ro tic p ro c e s s a n d th e fo rm a tio n o f n e o in tim a l h y p e rp la s ia d u rin g re s te n o s is s h a re m a n y s im ila r fe a tu re s ,th e ro le of h o m o c y s te in e a s a n in d ic a to r o f re s te n o s is risk, a n d its p o s s ib le c o n trib u tio n to th e fo rm a tio n of n e o in tim a l h y p e rp la s ia h a s n o t b e e n e x te n s iv e ly s tu d ie d . In o u r c o h o rt, s e ru m h o m o c y s te in e le v e ls a t th e tim e o f a n g io p la s ty d o e s n o t s e e m to b e a n in d ic a to r o f re s te n o s is ris k a fte r P T C A . It is p o s s ib le th a t s e ru m h o m o c y s te in e le v e l is n o t a g o o d in d ic a t o r o f h o m o c y s te in e ’s p ro b a b le c y to to x ic ro le a t th e c e llu la r le v e l. T h e ro le of h o m o c y s te in e a s a n in d ic a to r o f re s te n o s is risk, a n d th e e x te n t o f its c o n trib u tio n to th e fo rm a tio n o f n e o in tim a l h y p e rp la s ia n e e d s to b e fu rth e r e v a lu a te d . In c o n c lu s io n , a lth o u g h th e re is in v itro e v id e n c e fo r th e a th e r o g e n ic a n d th ro m b o tic p ro p e rtie s of h o m o c y s te in e , s e ru m h o m o c y s te in e le v e l d o e s n o t s e e m to b e a u s e fu l in d ic a to r of re s te n o s is ris k a fte r P T C A in o u r p a tie n t c o h o rt.
A C K N O W L E D G E M E N T
T h is w o rk w a s s u p p o rte d b y T U B IT A K (S B A G - 1 8 2 3 ) a n d M a rm a ra U n iv e rs ity R e s e a rc h F u n d (1 9 9 8 /2 9 )
REFERENCES
1. M in e r SES, E v r o v s k i J , C o le DEC. C lin ic a l c h e m is t r y a n d m o l e c u la r b io lo g y o f h o m o c y s t e in e m e t a b o lis m : A n u p d a te . C lin B io c h e m 1 9 9 7 ; 3 0 : 1 8 9 - 2 0 1 . 2. B e r w a n g e r CS, J e r e m y J Y , S t a n s b y Q. H o m o c y s te in e a n d v a s c u la r d is e a s e . B r J S u rg 1 9 9 5 ;8 2 : 7 2 6 - 7 3 1 . 3 . W e lc h GH, L o s c a iz o J . H o m o c y s te in e a n d a t h e r o t h r o m b o s is . H e w E n g l J M e d 1 9 9 8 :3 3 8 ; 1 0 4 2 - 1 0 5 0 . 4. H a n k e y GJ, E ik e lb o o m JW . H o m o c y s te in e a n d v a s c u la r d is e a s e . L a n c e t 1 9 9 9 ;3 5 4 :4 0 7 - 4 1 3 . 5 . S o u t h e r n EH, C r u z H , E in k LM , e t a l. H y p e r h o m o c y s t e in e m ia in c r e a s e s in t i m a i h y p e r p la s ia in a r a t c a r o t id e n d a r te r e c to m y m o d e l. J Vase S u rg 1 9 9 8 ;2 8 : 9 0 9 - 9 1 8 . 6. B e n o it C, E u r b e r A , L e B o u il A , e t al. P la s m a h o m o c y s t e in e is n o t a p r e d ic tiv e f a c t o r o f r e s te n o s is a f t e r c o r o n a r y a n g io p la s ty . A rc h M a l C o e u r V a iss 1 9 9 9 ; 9 2 : 1 4 5 7 - 1 4 6 0 . 7. G r ü n tz ig AR, S e n n in g A , S ie g e n th a le r WE. H o n o p e r a tiv e d ila t a t io n o f c o r o n a r y a r te r y s te n o s is . H E n g l J M e d 1 9 7 9 3 0 1 :6 1 - 6 8 . 8 . E io re M, M it c h e ll J , D o a n T, e t al. T he A b b o t t IM x A u t o m a t e d B e n c h t o p Im m u n o c h e m is t r y A n a ly z e r S y s te m . C lin C h e m 1 9 8 8 : 3 4 : 1 7 2 6 , 1 7 3 2 . 9. S h i p c h a n d le r M. R a p id , f u l l y a u t o m a t e d m e a s u r e m e n t o f p la s m a h o m o c y s t e in e w ith t h e A b b o t t IM x A n a ly z e r . C lin C h e m 1 9 9 5 ;4 1 : 9 9 1 - 9 9 4 .
10. S t a m p fe r M J, M a lin o w R, W ille tt WC, e t al. A p r o s p e c tiv e s t u d y o f p la s m a h o m o c y s te in e a n d r is k o f m y o c a r d ia l in f a r c t i o n in US p h y s ic ia n s . J A M A 1 9 9 2 :2 6 8 :8 7 7 - 8 8 1 . 11. W a ld H J, W a tt HC , L a w MR, W e ir DG , M c P a rtlin J , S c o tt J M . H o m o c y s te in e a n d is c h e m ic h e a r t d is e a s e : r e s u lts o f a p r o s p e c tiv e s t u d y w ith im p lic a t io n s r e g a r d in g p r e v e n tio n . A r c h In te r n M e d 1 9 9 8 ,1 5 8 :8 6 2 - 8 6 7 . 1 4 1
