Tetrahydrobiopterin improves endothelial function and decreases arterial stiffness in estrogen-deficient postmenopausal women

178A

,dlEI'RACI'S - Oral

The effect of menstrual variation of ondogonotls estrogen and proogosterono on endothelium-depondsnt vasodllntlon has not boon well studied, Methods: We used high.resolution ultrasonography to study flow.medt. ated vasodllatlon of file brachlal artery in 20 healthy women during 3 phases of the menstrual cycle, Flow-mediated vasodllation (FMD), TNG.Induced vasodtlatlon (TNG), sentm Ilplds, estrogen and progesterone levels were compared for the 3 time pha~taawith ANOVA, Lipid levels, estrogen and progesterone levels ware correlated to the degree at flow.mediated vaaodllafion, Resells: Folligt~t~r M,d.cy~l~ L.tonl Dvalue ftMO (%) it,0 10,it 7,0 0,04 TNQ (%) ~4,0 ~fi,~ ~6 000 E~tr~dlol (gruel!L) 4II t 74 15'/ ,0001 Pmge~ter0ne(areal/L) 0? 09 1'1+4 .0,O0t LDL,ghol (mg/(ll) 04,,~ t30,~l 91,3 NS HDL.chol (mg/dl) ,t?,~ 40,5 4a,a NS T(IQI,~eridem (mg/dl) 6'/,3 7 ,',1~ ?t ,(I NB

JACC

levels increased from 7 / t M at bascltna to 26 laM, 8 hours after melhtonino Brschlal artery FMD was significantly atienualod by melhlonine (0,3 ¢ 2,6%) as compared to placebo (6,7 • 13%; P - 0,009 v~, placebo), FMD to nitroglycerin was similar for the 3 study days, Vitamin C levels Increased from 0,90 ± 0,1 mg/dl af baseline to 2,26 ± 0,3 mgldl 8 bouts alter melhtonino= Administration of vitamin C completely normalized FMD of the brachial a~ery (7,0 :~ 1,1%; P ,. 0,01 va, mefhlonine), Conclusion: Experiments,y-Induced HHC rapidly Impairs endofl~llum. dependonf vasodllafaflon in oonduif vasse!a in humans, Thla may be pertinent to the relationship between HHC and afhomsclorosts, Nommltxaflon of Impaired endothelial function by vitamin C suggests that t~cmssed as!dent atmn may play sn Impo,ant role in mediating Iho endofl1~lial elf~ta of homocystoine,

9:15 ImpairedCoronaryVaaodllatlonIn Responseto Sympathetl©Stimulationin I=~tlentoWith O!Obetle AutonomleNaumpathy

~

The enty significant correlate of FMD was the serum progesterone level (R =R ,~ 0 , 2 6 t + p =~0,027),

C~nclt+,~tan; FMD is onl~ancod during mid.cycle ot the menstrual penod when astmoon levels am high, and this effect apgeam to be antagonlted by ondogenott~ pmgsstorono~

8:45 Atofvaatatlnbut Not ImprovesEndothelialFunction In YoungSublaGtaWith InaullnDependentOlebataa

~

Mallltua

MJ, Mullah, A,E, Donald, H, Thomson, G, O'Connor, ~, Tl~ame, D,J, Wright, J,E, Deanfield, Gf, Ormond St Hospital, London, United Kingdom Insulin dependent diabetes metlltus (IDDM) is a major risk factor for coronary adon/disease (CAD), Impaired nlfnc oxide dependent endothelial function has bean demonstrated in young subjects with uncompl~catnd IDDM bur its potential for reversal is unknown, In a double blind 2 w 2 factorial study, 84 Bubl~fa (mean age 34 ym, range 18-46) with uncomplicated IDDM as them Bole dsk factor for CAD, were randomtsed to ato~vastafin 40 mg od (n =~41!, L-~rglntne ? g L',d(n = 43), or marching placebos, Using high resolution ultrasound brachlal artery flow mediated dilation (FMD) (endetholtum dependent) and the response to gtycoryl trinltrato (GTN) (ondethelium independent), were measured at bs~eltna nnd after 6 weeks of treatment. At basel+no, subject chmactertstics wore well marched between the groups (overall mean t: SO FMD 3.4 ~t 31%, low density lipoprotein cholosto,ol [LDL] 2.98 :t 0,89 mmoffl). There was no evidence of a mgnitcant interaction between the interventions In subiocts treated with atorvastatin, LDL decreased by 48 t~ f0% and FMD increased significantly by 1.27 ± 2.56% (p = 0,005, independent t-test vs no atownstalln) There was no mgnilicant change in subjects treated with L.argmmo (0,2 t 24%, p = 0,5), On multiple regresmon analyms improvement in FMD significantly correlated with duration of diabetes (tl = 0,06, p ,~ 0,03), baseline FMD (1¢ ...... 0,37, p = 0,0003) and with allocation to atowastafln (l~ = 1,97, p = 0,01) but not with allocation to L-arginino (,H = 0.06, p = 0,9) or combined therapy (p = 039, p = 0,2) Them was no significant change in dilation to GTN in either group. Those moults indicate that endothelial function in young subjects with IDDM improves significantly following cholesterol reduction by atowastatin, with no benefit from L-arginine therapy.

~-~

9:00 EndothelialDysfunctionCausedby Experimental Hyperhomooyst(e)lnemla Is Rapidly Normalized by Antioxldant Therapy

P,M. Kanani, C.A, Sinkoy, H.R. Knapp, W.G. Haynes, University of Iowa Hospitals and Clinics. Iowa City,, Iowa, USA

Background: Homocysteine is a putative risk lector for ischemic heart disease, but there is tittle knowledge of its pathophysiologic mechanism(s). We tested whether experimental induction of moderate hyperhomocyst(e)inemia (HHC) using methionine loading causes endothelial dysfunction in humans. To examine the role of oxidant stress in the vascular effects of HHC, we co-administered ascorbic acid (vitamin C) during induced HHC. Methods: Ten healthy human subjects received oral placebo alone (0 hrs), oral methionine alone (100 mg/kg; 0 hrs), or methionine (f00 mg/kg; 0 hrs) plus oral vitamin C (2 gm; +4 hrs), in random order on 3 study days. Ultrasound measured flow-mediated dilatation (FMD) of the brachial artery was performed at +8 hrs as an index of endothelium-dependent dilatation followed by sublingual nitroglycerin administration (400 i~g) as an index of endothelium-independent dilatation. Results: Baseline blood pressure, lipids, vitamins and homocysteine levels were natural tar all subjects on the 3 study days. Plasma homocyst(e)ine

I:cbnmry Ig98

M,F, Oi Cadi, D, Blanc.Dot!tea, G, Gmnberger Wayne State Una'ersity School Ot Medicir~, ~troif, Mch[gan, USA We have shown that cardiac sympathetic signals play an impodanf role in regulating myocardial bk)od flow (MBF)+ The purpose of this SfedY was to assess the dogma to which autonomic oeuropathy (AN) involving efferent sympatholic pathways affects myocardia! pedusien in patients with diabetes. We studied t7 diabolics (ago, 45 t 5 years) who were free el overt cardmvascular complications, and ? age.matched nerma! subl6Cts. Eleven patients had evidence of AN based on their response to standard autonomm ro~,¢ festa, and six did not, PET imaging was used fo delineate ~ t h e t i c in. non/alienwlfh ["C] hydroxyephednno (["C) HED, nompinephnneanalog), and fo measure MBF at rest, dunng adenosine.induced hyperemia+ and in response to sympathoftc sfimulabon by cold presser testing (CPT). using [I:~N] ammonia as a flow tracer+ ["C] HED u:}fake troftecting sympathetic innovation) w a s regionally homogonnous in the diabetics and nemesis, but lower in diabolics with (0.15 ! 0,04) than in those ~,,~,dhout(0.18 t: 0.02) AN and in normats (0,19 i 0.01) ( P . 0,05). Basal MBF in diabatms with AN was similar to that in tooso without AN (1 0 1:O1 vs 0.92 ~ 0,2 mltmtRtg, P = NS) but higher than in nomlals (0,89 ~ 0.2 ml/min g. P < 0.05), mllocling the diffomncos In oxygen demand as assessed by the rate-pressure product. Du,ng hypemmia, the increase in MBF was also simdar in diabofc.s with and without AN (175 .~:71% vs 203 ± 78%,, P = NS b,although it was tower than in normals (284 t 88%, P - 0.05) However, th~ increase in MBF in response fo CPT was markedly lower in diabetics with AN than in those without AN and in normats (9 .t 6% vs 29 ~: 8% and 61 ~ 13%. P - 0.001). Duration at diabetes, giycomic confm$, unnary microalf umin, serum cholesterol, and van Willebrand factor antigen (a marker of end ~thelial cell damage) were not different in both groups of diabetics In conclusion, patients with diabetic AN have an impaired vasodilator response of re.~istance vessels to increased sympathetic stimulation, This abnormal vasomotor response may contribute to the pathogonosis of myocardial ischemia in diabetics with coronary artery disease,

9:30 ~

T e t r a h y d r o b l o p t e r l n I m p r o v e s E n d o t h e l i a l Function In Patients W i t h C o r o n a r y A r t e r y Disease

w, Major t , F. Cosentino ;, FI. LutolP, M. Fleisch 1, C, Seller t , O.M. Hess t , B, Meiers, T.F. LLischeF:. Cardiology, University Hospital, Stwtzerland; ~Bem, Switzerland, ;'Zurich. Switzerland

Backgmuna: Tetrahydrobiopterin (BH4) is an essential cofactor tot nitric oxide synthase (NOS), A relative BH,vdeficiency leads to reduced NO production and increased superoxide formation by NOS. Atherosclemsis is associated with reduced NO and increased O~ productio,+. The purpose of the present study was to evaluate tho effect of exogenously administered BH4 on endothelial function of patients with coronary artery diseaso. Method_ h; patie.ts undergoi.g single vessel PTCA were studied by quantitative c~.,+onary angiography. Data were obta!ned in an angiographically normal vessel at baseline, after intracoronary (i.c.) inlusien of acetylcholine (ACh; 10 ~ M), BH.~ (10 4 M), and after coinlusion of Ach and BH.~. respectively. At the end o~ the procedure 30014g nitroglycerin (NTG) i.c. was administeroa. Results: ACh induced coronary vasoconstriction (-18 ~ 3% el luminal area, p < 0,001) in 15 patients, but vasodilafien (+39 ~- 20%, p < 0.01) in 4 patients. BH,~ alone did not change vasomotion, but prevented the vasoconstriction to Ach (+22 -~ 6% area change, compared to Ach, p < 0,005). NTG induced maximal vasodilation in all patients (+31 ± 6%). Conclusions: Tetrahydrobiopterin prevents acetylcholine-induced vasoconstriction of angiographically normal coronary aderies ir~ patients with endothelial dysfunction. Thus, substitution of this essential ¢ofactor of m~

JACC

Fcbni,,~, I~),~

A B S T R A ( ' r ~ ~ (~r;d

179A

$41,320 OvOrall moff~ltffy was 34% with ~gn~hcant ,rK~reases m moff~af~ for females (4.6% vs 28% in mates, p ,- 0,01), pat~m~ --62 y ~ of age (46% v~ 15% in petient~ .62., p 001L Patmnt~ w~t,~~.ule MI as the admiP,ing d~agnosis (6,75% vs 18% m patmnt~ without ~¢ute MI, p ~ 0,01) an(l patients with CHF (li ,7% vs 2 , ~ . in patients wttt~0ttl CHF p ~ 0.01), In 1995 PO0 PTCAs were pertotmed in ~ o! the 146 (19,0%) m~!1~lon~ pedon'rmg PTCA The monal~y ~t PTGA m i n s t n m ~ ~ ~ ¢~ m !995 wi~ 13,9% r e m i t t e d to 33% in in~t~l~ns ~ ]~L:~0 ca~es ip < 0,01) lt~t ye~r~ n : PTCA in Calltomi~ i~ ~ l a l e ~ wlth ; ~ moflahly in women, 1!~ eldedy, peiti~lt~, admitted with I~ute MI, ~ ~lt~mts procedures am p e d / o ~ at lnstit~K~ns pedOrming less than ,200 PTCAs annually, A(II I

Bill

I~lllg ~tek I

lt;~

NO-sy~thase may represent a new therapeutic c _ ~ t e ~ t h a l i a ! ~/Sl~n~mn

tor the treatment 0l

8:45 Pmdlct!n9Moftlllly FollowingPTCA: Results From NCN "

~

E D Petemon, D. Moore, L H Muhlbaier, E.R DeLong, R, OresswalO. Duke

~

9:45 CoronaryVas~u!arE I f ~ of Pltysi~l Exen:iu and Dobutam!n~:Comparisonof Physiologicand PharmacologicStmSsOrS

A. P~asad. G Zalos, W H Schenke, E. Amegash~e, A N Kffsiou, A.A. OuyyumL NHLBI, B.etttescla. MD~ USA A I ~ dubutamine (D) ~s rout~m~lyused as a surmrjate tot exemise, Ihere is often (tscor~mce belween exercise and O slmss tes~, ~ l l y in pts with n~M Coronary a~lery disease (CAD). While physral exeeCtse causes myocardial ~:hemia by a com~natmn el mcrease in demand and el~'ardial coronary (EC) constnction, it is not known whether conslnct~on plays a role in D-induced ¢schem,& We hypothesized that the dispanty is due partly m the lack ot EC conslnclion during D stress. EC diameter were measured m response to exercise and D in 10 pts wdh CAD. D was gnmn intracorenary tic) (10 to 80 .ojmm) and mtrevenously (iv) (5 to 40 pg/Kg/mm) unld ether peak dose, or myocardial =schem~a. or the -ate-pressure product a c h ~ d during exercise was reached. Finally. 100 ~g K: nltroglycenn (NTG) was g~ven. The rate-pressure product dunng ex..rctse and D was slmdar (P = NS). Exercise produced no overall change *o, EC diameter, whereas at the peak doses of D. there was significant vaso~dateon compared to baseline (5 ± 1% and 7 ~ 1%. ic and iv, both P ,: 0.02). Even segments that censtncted ~th exermse ( - 5 : 2==) ddated wi~ *c and N O (7 =: 2% and g ~ 2=~, P < 0.01 respectively). NTG dilated all EC segments (11 ~: 2=0, P < 001) The data suggests that with equivalent myocardial streSs, D causes dflabon. whereas exercise can ohe,, ~u~uit in constnctmn of EC segments m CAD. tod*catmg fundamental pathophysiolog~c d~fferences between mechamsms underlying myocardial ,schemia produced by physiologic and pharmocotog~c slressors. Thus. D stress may not be adequate for diagnosing mild CAD, and for evaluating the effects ot tremment on ischemia

Mortality Predictom in Percutaneous Interventions

Umv., Oumam, NC. USA ~ brFew clinicat models e~mt that can accurately predqct mortalrty to,lowing percutaneous coronary ,nten~ent~n (PTCA) Mettles." We developed a PTCA mortality nsk prediction mode! hem the Natmnal Cardiovascular NetwOrk Database |n = 58,714 procedures per. formed at 19 U.S. centers between 1F34Snd 1197) which used only oblactn~e climcal vanables. Resu/~s: Overall in-,bethel moflality rate was 12%. The maan ag~ was 62.7 yrS. 32% were female. 24% had d ~ e s The significant mulhvanable p~ors of in-hospital ~ i t y am displayed below: RLSkFactOr" Pre-~t~-'edtJreCan3K~gen~:F~t~ck LVEF (per 10% Oecline| Pahent Age (pet 10~11~o~Oerl Primary Ang~plaslyfo~rAcute Mt BSA lO 1 dc~cl~'~em meter?| Renal O~ase Pncr ~¢cn=try |niefv~t~Ja Dtabet~ ~ I ] ~

8:30 An Analysisof PercutaneousTransluminal Coronary Angioplasty Performed in California in 1995

D.L. Brown. Umve~s~/ of California. San Diego Medical Center, San Diego

CA. USA Background. The use of percutaneous transluminal coronary angioplasty (PTCA) continues to expand. ApDroxtmatoly one-third of all PTCA procedures in the United States are pedormed in Califon da. This study descnbes the 1995 California in-hospital expenence with PTCA using a statewide administrative data base. Methods: Discharge abstracts for all patients undergoing PTCA at non-Federal hospitals in California in 1995 were analyzed. Results: 154,193 PTCAs were pedormed. Mean age was 64.7 years and 66.2% were male. Acute myOCardial infarction (MI) was the admitting diagnosis in 32.6% of patients. Twenty-two percent of patients were diabetics, 10.7% had pdor MI, 12.5% had congestive heart failure (CHF), 13.6% had prior PTCA and 9.8% had previous CABG. PTC,~ was of a single vessel without intracoronaP/thmmbolysis in 82.8% of patients, of a single vessel with intracoronary thombolysis in 4.0% and was of multiple vessels in 11.7%. The average length of stay was 5.3 days and the average charge was

OR 125 t5 16 27 12 23 06

11

13

9 6 6 5

13 16 I3 13

Mutl~ves,~elCofona~/O~sease PTe-PTCAIABP Proximal LAD De--ease A ~ s ~ o n MI (w/oPmnaP/PTCA)

05% Ct 8l-la 5 1 4--1 fi 1 5--I 7 2 3-2 9 I 1-1 2 ! 8-2 it 0 4-0 8 1 1-1 4 I 2-1 S 1 1-2 0 I I-I 5 I 1-1 6

The rnoders overall dlscnn~nat/on abdity was excellent C-mdex = 0 813 We internally validated the model usmg a bootstrap method tadjusted C-~ndex = 0 815). The model was also well cahbrated for prtidic1irlg outcomes in lowmoderate- and htgh-nsk paSent groups Conc/usmn. This model repmseflts an accurate, oblectwe PTCA mortality r~k prediction ~ 1 which is useful for estimating patient outcomes and for ~lng phys~ans wffh nsk-a~usted mortality results.

9:00 Proteinuriain Diabetics is a PowerfulPredictorof Death FollowingPercutaneousCoronary

~'~

Tuesday, March 31, 1998, 8:30 a.m.-lO:00 a.m. Georgia World Congress Center, Lecture Hall 1 [-~

Ch* Sq 337 194 t34 75 53 26 23

Revascularization

S.P Marne. S.G. Elhs. R.E. Raymond, I. France, I~L. Whitlow, E.M. Tuzcu. E.J Topoi. C/e~etand Clinic Foundation, C/eve/arc/, Ohio, USA Background: Diabetics have a higher modality after percutaneous transcoronaty revasculanzation (PTCR) than non-diabetics, but the etiology for this is poorly understood. We hypothesized if,at diabetics with proteinuna would have higher mortality than diabehcs w~thout proteinuna foll0~vin PTCR. owing to an association of proteinuna and aCvanced atheroSctEmsis. MetMods: A total of =.537consecutive diabebcs with unnalysis (UA) uncle=went PTCR between 1/93 and 12/95 were d=vlded into preteinuna (pit), (n = 217) and non-preteinuna (non-pret) (n = 320) groups The prot group was fudher prospactwely d~nded into tow concentration (trace. 1+. 2+) and 100

non- pmtmnuna

,oo 40 ~

0

6

12 18 Time (Ma~ths)

24

0

h~ghconcentra~on

6

12' 18 T rr~ (Months)

24