Changes myocardial perfusion

Clinical Investigations

Perfusion Changesin Myocardial Emission bv Positron Abnormalities Intense AfterLong-term, Tomography RiskFactorModification BrownMDiF Patterson EdensPhD PhD:Shrley l\.4D DeanOrnsh,MDLarrySchervr'iiz, K LanceGoud. li/lDl lvlarvJaneHess,RN NizarMuian i LeonardBolomeyFrankDoblrs,PhD W iamT. Armstrong, B ings, PhD Sparler MAi James Terr Merrltt,l\4siThomasPorts MD Slephen pedusion LIPID-LOWERING tlials in patients Obiective.-To quantifychangesin sizeand severllyof myocardial (PET)ln palientswithcoronaryaF with corcna4' atheNsclerosis lale demby positronemissiontomography abnormalities onstuated no poglession or pa'tia.l relery diseaseafter5 yedrsol ris\ lacto'mooifical:on. gression of coron T artery stenosesby controlled tial.

Design.-Randomized coronan, ai'ieriography compared qnth communly setting.

Setting.--Oulpalient progression of stenosis severily in con Inlervenlion.-Randomizal on ot patientsto r sk factor modificationconssting trols trcated with standdd thempy.'" exercise, stressmanagement, and Holl'ever, these re$ession trials shar€ diei,m 1dio moderate ofverylowlatvegetarlan group,n=20)ortousualcarebytheirownphysicians, seveml comon limitations, ircluding the groupsupport(experimental principally of antianginal therapy(controlgroup,n=15). consisting follo{ins: the de$ee of rcg€ssion ll'a-s Main Oulcome Measures.--{uanlitalve coronaryarterographyand PETal :Mtomica.lly nrodesi, being 57. to 10% Automated, objecllvemeasuresof size dia.Inet€rst€nosisunih; percent diameter baselineand5 yearsatlerrandomizalion. perfusion PETimagesand of st€nosisis poorly rclated lo flow @pacity on rest-dipyridamole of abnomalities and severily ol corondf arteri€s ol coronatr).flos're_ were madeby computeralgonthrnsstenosisseverityon arteriografirs PETim- senelrni'; progression or regressior of on dipyridamole Resulls.-Slzeandseverityof perluson abnonnaliiies grcup corondt' :d'ieiy stenosesmay Deassoct ln the expeimenlal (improved) aller sk factormodificalion agesdecreased ated with conplex slape chnngesor r€ of sizeand severityin conlrols.The peF nodeling,l in which the inte$ated hemo comparedwithan increase(wolsening) abnormalilles outside2.5SDsoi lhoseof norma d).nainiceffects of!€r@nt n:u orirg, abcenlageof leftvent clepedusion PETimageot soluie altefial lumen are.r,and length e persons(basedon 20 d seasejreeindividuals) on the dlpyrdamole countsworsenedincontros (mean:!SE,+ 10.3%15,6%)andimproved not accourt€d for by my singleseomet}jc norrnalized perceniage of left dimension such a perc€nt steDosisrr;r; (moan1SE,-5.1%:!4-8%)(P=.02);the intheexpermentalgrcup dipyidamolePET ad queti$.ing single fo.dl srcnoseson vent clewithactivitylessihan607ooflhemaximumactivityonlhe lmageof normalized countsworsenedin controls(+'13.5%13.8%)andimproved corcna4. aftedograms do6 not rccomt ( 4.2"/.i.3.a"/") (P=.002);and ihe myocadialquadranton for ndtiple si€noses,ditrnse aiherosclen theexperimentalgroup expressed as a perceniageof maxi_ rosis, of the associatedvasomoinr abnoF lowest average aclivily the PET imagewiih the prcsenri'"i :rd thereinlheexpe menlal malities hequentiy andimprcved n conlrols(-8.8o/.:r2.3%) mumaciivitywoFened fore doesnot reflect the pedirsion crpa.abnormalities on ;ty of the entne int€grated coronalT group( + 4.9%a3.3%)(P=.001 ).Thesizeandseverly of perlusion groupas arterial cirunaiion afrected by ,there improvedin the experimental restingPETimageswerealsosignillcanlly ofchangesin sizeandseverityol comparedwithconirols.The relativemagnitude the magditude ol to or greateTthan was comparable PETperiusionabnormaliles Although severallipid]ox ering tdals stenosislumenarea,or stenosis have demonstrated only nodest reducchangesin percentdiameterslenosis,absoLule tion in percent dianeter narro$ins in coronaryarteriography. by quantitative ilow reservedocumented treated vs contrcl groups, these studies after risk factor ofcoronary artery slenoses regression Conclusions.-lvlodesi with decreasedslzeand severitvoi pertusionabnoF have rcported a prcpo$onaiely greater modiljcation rs associated ol coronary decrcase in cardiac elents in treate'i or regression PET mages-Progression rnalities on rest-dipyidamoe €nt widesprcad reflecting PET the gl oups.+In view of cu by dipyridamole arterydiseasecan be followednoninvasively intercst in the noninvasive management lntegratedflow capacily of the entire coronaryarte a by cholesr. ,rnurr.rs*-nou of coronary atherosclerrsis "',"r,"llk di€t, exercise, ard FrcmrheDepadmonr.r Medc ne lDrsGoud Ed6ns and Dobbsand lvl*s6 Muran and E.omo, and lhe Poslon Daqnodcand Feseaohcenier(MsHess)or rhe un ve€ iy of Tsras Medca s.h PBenfva MedcLneReseadr ndrul6 saus lo ca r t D. s Om s h S . h e M t d r r B n q s M sM e r t a id M r

494

Spa,€a Ca roma Fa.l c Medca ce lDc ons[ aid Amsrcnsl and lhelnvercryoica rori a ar SanFran.iscd(Drcomsh Enwn and Fo(S) Feprni €queds to Dv'son or Cadooqy Rfth Uiv6rsty ol TexasM6d.a sdroo ar HouslonHdu6lonrr 77030(Dlcoud)

JAMA, Sefember20, lq95 Vol z?4,\o. ll (Bepinled)

teml-lowering tuugs, behiviolal inteF entions, the potential impact ofthese tdals on clinical puctice is substantial, bul data on changes in

@'ao, Ln?rnJn \l edkd, \-.ofl n'on

\l l ri ghr\ rc .enr' l

myocadiat pefusion abnonia.lities cor rcspondingto the obseNed ateiograph ic chang€sare larking. Accordingly, we neasru€d the size and sev€dty of myocaxdial pel.frision abnormaljties by positrcn emission tonogEphy (PET) at rest and after diptridamole str6s at baseline and at an avemg€ folow-up of5 yerrs in patients with corcnary aftery dis€as€ (CAD) nndomized to the conuol group or to the expednental group undergoing intense dsk facior modifrcation.

METHODS Study Palients Patients selected for palticipation in the rhk modification progrrn were men and wonen,41 to 70 year8old, who had CAD docunented by alteriogaphy, had no recent myocadia.l infarction, were not ta.king lipid-lowering drugs, had left venidcular ejection fi'aciion gr€ater than %%, and resided in the sreater San Ira.ncisco area of Califomia. Individu a.lsin each$oup gave infonned consent a.ndwere nndomized after we obtained baseline quantitative coronary arterio$?phy but beforc other baseline meaModification of dsk facto$ has been d$cdbed Feviouslyra and consisted of a low-cholestercl (<5 mg/d), low-fat (<10% of total energy intake) vegetariar diet with t5% protein and ?5%con' plex cdbohydrate augmented with vitamin BD.r'1Patients stopped smokins, practiced stress nanagement techniques for t hour daily, a'Id participated in mild to moderate aerobic exerche 3 hours per week. Adherence to the program was quentilied by a scorc rcflecting a 3 day diet dialf,', a exercise and stress nanagenent diary, and conlinnation of smoking cessation by plasma cotinine conc€ntration. A iotal score of 1.0 indicated 100% adher€nce to the recoF mended lifestyle changes, whereas a score of zero indicated no adherence. A 8coregreater than 1.0indicated that pa tients did more than was reconn€nded.

Ouantilalive Coronary Arleriography Initial and follov'-up coronary afleIio$a,.ns were pedomed usingthe standdd percutaneous femo%] approach.

Detailed records of the view angles, x ray exposl]Ies, inaee intensifier, x-ray tube, patient distances, and refercnc€ catheter dnnensions were maintained.

These same characteristics vere used in follo*up artedogl?Ins to reproduce views and exposurcs as closely as possibte. Angiogrms were analyzed si ndtareoftly in pairs by a technician unawr.re of clinica.l data or g11)upassignment using autonated border recognition and stenosisanalysistechniques to avoid the potential bias, inprecision, O luu5 { m e n t d n V e d r c a lA\- o o ,r ' o n

All n g h b

ard uncertainties of visua.l interyrctation. The p ma4' stenosis dimensions lneasul€d by th€ automated zrter io$aphic pr.ogra,n previously de scribedraa ^ include proxinal diameter and cross-sectionallunen area, rnininal dimeter md area, dtuta.ldia,netel and ar€a, the exit angl€ and exit shape effects, and ca.lculatedmeasures ofsever ity, including percent diametu stenosis, percent area nanowing, integrated length-area effects, ad stenosis flow reserve. This progrm has b€en validated in three 3eparate experinental shrdie8,45 appli€d in humans,rr.?aeD ald used routinely in apploximately 5000 clinjcal artedograrns in ou labol?to4,.

The 959, confrden€einterval for stenosis flow reserve is 40.66, vith a reproducibility ofpdnaif,i dinensions of 13% PET lmaging As previoftly d€scribed,r6!3PET inaging of myocardia.l pefiusion was per foflned at rcst and efter adninistntion of dipyddamole. Fluoroscopy was used to mark the cadiac borders for patient positionins. The PET imaging was perforned usins the University of TexaF de8igled cesiun fluoride, multislice tomograph with a rcconst$cted rcso' lution of 12 lnrn tull width at half naximum (FWHM) in plane and 14 nr, FWHM analy. Transmission images were obtained to corect for photon at t€nuation using the segmented attenuarion conection method.q Emission images were obtained following intrtrvenousi4jectionof 18mci of cyclotmnFoduced nitrog€n 13 (r'N or after 40 to 50 nci of genentor produced rubidium 82, depending on avail ability of a generator (Bdstol-Myen Squibb, Princeton, NJ). The mdionuclide used at baseline was also used in the ffnal follorup PET study.

At 5 to 10 minutes after th€ firct dose of rubidium 82 or at 40 minut€s after administration of the first dose of an monia to allow for decay of the first radionuclide dose, dipridamole (0.142 mgn(g per ninute) was infused inhavenously for 4 minutes. Two ninutes after the intusion vas complete,zSE ol predetemined maxinal ha,rdgdp was h€ld by the patient with one hand for 4 ninutes. Two minutes after the strxt of the handgdp, a seconddose ofthe sa.rne amount of the same mdionuclide was inject€d intravenomly, with the handsrip continued for 2 minut€s. The PET inasins w6 then repeaied by the same protocol as for the rcsiing study.

Tra,rsnission sca,rscontained 100mil lion to 150million counts.Emission scans of ihe whole healt contained 20 million to 40 nillion comt3 for 15 to 20 lnCi of e - cn e d

intuvenous riN anrmoniaand 15 million to 25 million counts for 40 to 50 rnci of rubidium 82.

Baseline and frnal dip) damole im ases were displayed together for diect side-by{ide conpdison and were vtuualy interyrcted by thr€e independent rcaden blinded to patient identilication, quantitative data, treatment group, and a.]tclinical infomation. The image pairs werc Endomized and were independenuy read by the three blinded rcadellsasworse, bett€r, undurs€d, or showing mixed changes for differcnt directjona.lchangesin the four quadEnts and apex as dessibed below. The vhual chanse fron baseline to ffnat PET inage was 8cored aE no chanse, zero, or improved on a sca]e of + I, coiaesponding to definite but nild improvenent, to +3 for naxilnal imFovement, or -1 lor definjte but mild worsening to -3 for na,\inal wolTening. A al change cor rcsponded to a one color ditrerence (eg, r€d vs yelow, r€presenting a step in count density of 15% of rn -ximum) between baseline and final PET scans; a 12 change conesponded to a two-color ditrerence(eg, red vs green);and a r3 chanse conesponded to a thrce color ditrercnce (es, red $ blue) for a color scale as shown in Figule 1. Any change of +1 or greater was considercd in proved- Any change of -1 or less was considered volse. Any stud]' with a changein one pat of the heaft of + 1 or greater and a changein mother palt of 1or l€ss{as coNider€dto b€ a mixed change.

All measurementsofsevedty and size of pertusion delects were carried out by conputer analysis as pevioNly describ€ds s.B10 Fitho t operator interpreiation, visual drawing of boders, visua.llocaiion of defect, or any other operator interaction, backgmund sub' traction, image enhancenent, or other image nanipulation. A thee dinen sionalrestructEing algodthm generated tme shoil' and lons axG views from PET iransaxial cardiac images and three-dimensional vieivs of ihe lefi ven tricle as vieNed from ihe ght (septal), antedor, left lateral, and infedor viem, reflecting relative regional activity dis tribution at rest and aJrer diplridmole stress.Polar mapsed three dirnensiona.l views are divided into flxed sectionsconsisting ol septal, anterior, lat€Ial, and inferior quadmnts and an apical ses nent of the pold or three-dimensional display.rs'Bo The baselne PET scan was conpared with the fina.l PET scan by autonated analysis of ditrerences in sizeand sevedty ofpedrsion abnornalities, also \rithout operator judgment, selection of areas of interest, or imase

(F6pinred) JAMA, \tnnhfr

:o

positron tomogFigure1.-Top letl,Odentation of three-dimensional emission raphy(PET)images.

Topright,Example of PETatterdipyridamole at baseline (upperrow)andalter5 yearsas a controlpatient(lowerrow)in right(septal), leltlaleral,andinfe or views.Relative radionuclide uptakeis shown anterior, aclivity(100%)in whiledownin a graded-color scalerangingftommaximum wardin 57oincremenls corresponding to thesteppedcolorscalethroughred, yellow,green,blue,andblackasminimum activity, showninlhecolorbars.The withbaseline tinalstudy{lowerrow)compared {upperrow)showsworsening lo progression ot ihroughoul lhe heart,particulay inle o y, co.responding Bottom ghl,Exthree-vessel diseaseby quantitative coronary arteriography. (upperrow)andatter5 yearsof at baseline ampleof PETafterdipyridamole lifeslylechange(iowerrow)withihe samevi€wsandcolorscale.Theinferior perfusion lessseverewithbetter,moreunilormperiusion inthe delectbecomes lo reg€ssionoi three-vessel defeclanc,in the reslot the heartcorresponding diseasebi quanlilaiive coronary arle 09taph!.

The end points were the severity and sizeofperfusion defectson PET images at rest and alter dipy'ridamole stress, defrned as follows: The end point loaresl qffid,rant aueragewas the average number of normalized counts for the quadrant having the lowest average activity, in which an anterior, septal,lateral, and inferior quadrant sunound a central apex area. The mean value for any given quadrant with the lowest or minimum activity was the quadrant that contained the most severe perfusion defect. This lowest quadrant average was determined for the PET image at rest after dipl..ridamole stress. This end point quantified the relative severity of the perfusion abnormality. For example,a value of 65Vowould indicate that the mean count value for the quadmnt with the lowest counts, and therefore containing the perfusion defect, would be 65Voof the normal maximum of 1007a.

The end point percenktge outside 2.5 SDs was the sizeof the pertrrsiondefect deter"rnined asthe percentageofthe cardiac image outside 2.5 SDs of that of normalindividuals(basedon 20diseasefree persons)for the PET image at rest or after dipFidamole stress. Because 2.5 SDs includes 97.670of the normal distribution, there was only a 2.4/o chance that nornal values outside 2.5 896

the gaoup.A one-tailedt test was justified on thegrounds that improvedlifestyle changeswould not be expectedto male perfusionabnormalitiesworse,as speciied at the beginningof the study.

Two-tailed I tests are also reported as more rigorous tests of significance.

Analysis of variance v/as carried out using the Bonferroni post hoc correction algorithmlH in Statview software (Abacus ConceptsInc, Berkeley, Califl. For discrete variables such as number or percentageof subjectsshowingchanges greater than 1 SD from baselinevalues, significance of differences between groupswas deter"rnined

by Fisher's exact test (one tailed).6a Samplesizewas deterrninedin initial trial design by power calculations from estimared changesexpected and variability of quantitative arteriographic end points, the primary end points as preStatistical Analysis viously reported for 1-yearfollow-up.r" Changesin perfusionabnormalities In view of previousreports on changes from the baselineto the frnal PET were in arteriographic stenosis severity in compared bet\i/een experimental and thisra and other trials,L2awe report arcontrol groupsby unpaired,one-tailed, teriographic changesonly briefly in comparison to PET results. test for continuousvariables,atu3 Data are reported as meanal SEM unless At entry into the study, four patients otherwisenoted,reflectingthe variabilhad one or more completely occluded ity of means in each group and calcu- coronary arteries with extensive collatlated as the SD divided by the square erals to viable myocardium. These paroot of z, where z is the sample size of tients demonstrated severeperdNion abSDs would be observed, The end point pelcento,gewith a ratio Lessthan 0.6was ameasureofcombined severity and sizeofper{rsion abnormalities determined as percentage of myocardiumwith activity oflessthan 607,of maximum activity (10070)on the PET giveslhe size image.This measurcment of the defect characterizedby the severity threshold ofless than 607oofthe normal maximum of 1007r,and therefore reflectsthe combinedintensity and size of the defect on the PET image.A value ofless than 0.6or lessthan 607,of maximumon the PET imageis approximately 3 SDs belowthe normal meanof 807o1-79o of maximrm activity. Because 3 SDs contain 99.77oof the normal distribution, there was less than a 0.37, chancethat normal valuesvrouldbe observedbelow 607oof maximumactivity.

20, 1995-Vol274,No. ll (Beprinted) JAMA, September

01995 American M€dical Association. All riqhts resened.

Table1.-Changesin RiskFactors* ControlGroup

ExperlmenlalGroup Risk Factor systolicbloodpressure,mm Hg Diastolicbloodpressure,mm Hg weight ,kg mmol/L(mgr'dl) Cholesterol,

+y Follow-up

Change

128x14+

-7113

77!B+ 8 3 !1 2 5 4 .5 0 1 0 .8 5 (175r33)S

-1.3010.95 (-50137)

1 3 5 :1 5 8219 91115 5 .8 0 :1 .3 5 (225a53)

mmoyL{mgr'dL) LDL choleslerol,

3.7041.30 (143t50)

2.6510.90 (103a35)S

HDL choleslerol, mmoYL(mg/dL)

1.0510.30 (40112)

0.9010.30 ( 3 st1 1 )

Tnqlyceides,mmoul (mg/dl)

2 .5 a r 1 .3 4 (228a119)

2 .7 A!1 .2 O \247!107) 1 .1 4 a 0 .2 4 5

0.6710_37

-1.05a1.03 i-41a40) -0.1510.35 (-5a13) +0.22a0.98 (+19a87) +0.55:0.29

Baseline 137:!27 81114 76118 6.4510.95 {250137) 4.35a0.78 {168:t29) 1.3510.55 (5sa22)

5-y Follov/-up 127).13

2.62!2.A4 1232!251) 0.60r0.29

Change -11!21 -5t 13 +2L5

7A !19 5.95a0.85 i230J33) 3.801090 (148135)

-O.50a1.10 ( 20143) -O 50:t1 00 (-19138)

1.3010.40 (50a16)

-0.03!0.40 (-t 115)

2.20!0.76 (194167)

4.42!2.42 {J81250) +0.0910.19

0.71!O_27

Pl

<.001 .04 13 .26

*LDL indicaleslow-density lipoprcteinNumb€rsindicatemean11 SD unlessotheMse indlcated. lipoprotein; and HDL,high-density groupvs conlrclgrcup. tPlor change,€xperim€ntal +Forbaseljnevs expe mentalpeiod, 8.03.

SForbaselinevs exps menlalpeiod, P<.001.

See lext tor erDlanation.

management pTogram are snown tn Table 1. At final follow-up there was no difference in frequency, duration, or severity of angina pectoris between experimental and control groups, most likely due to revascularization procedures performed in the control group.

Twenty patients (5770)were studied with r3N ammonia at baseline and final PET studies, and 15patients (437o)were studied with rubidium 82 at baseline and Iinal PET studies, with the same proportion in the exDerimentaland control groups. No systematic differences in the changesfrom base)ineto final study were observedbel,weenthese two perfusion radiotracers in the experimental vs the conr,rorgroup.

Figure 1, top right, shows the perfusion images in a control patient after RESULTS diplrridamole at baseline(upper row) and Ofthe 48 patientsenlolled,five (25Vo) at filal follow-up 5 years later (lower row). In this control patient, the final of 20 patients in the control group and eight t297o)of28 patientsin the experi- study in comparisonto baselineshowsa marked decreaseot activity in the inmental group dropped out or were unferior mvocardium and a definite but available for follow-up study, including less severe decreasein lateral, septal, onecontrol patient with b;pass surgery, anterior, and apicalmyocardium, reflectleaving 35 patients for analysis.Fifteen patients (12men and three women) were ing decreasedperfusioncapacitycorrespondingto progressionof three-vessel in the conhol group and 20 patients (all men) were in the experimental g:roup. diseasedocumentedby quantitative coronary arteriography. From a patient Mean age ofthe experimental gr.oupwas 5716 yearc and of the control grcoup in the experimental group (bottom right) to baseline rhe finalsLudyin eomparison 6218 years.

Time foornbaselinecontrol PET to the shows increased activity, particularly final PET study was 5.0a0.2 yeaxs in the inferior myocardium but also (meantl SEM) and was comparablefor in lateral, septal, anterior, and apical control ard experimental groups (5.1t 0.2 myocardium,reflecting increasedflow years vs 4.9:-0.2 yeax"s,respectively). capacityand regressionof three-vessel diseaseby quantitative coronary arteBaselinechaxacteristicsofthe control and experimental study groups were compa- riography. These examples illustrate characteristic changesthat occuryed in rable, as previously reporLed.' most patients.

Differencesbetween the control and Figure 2 showsthechangein severity experimental groups in the changefrom of myocardial perfusion abnormaJities baseline to average values during the follow-up period for blood pressure, after dipyridamole stress measured as the lowest quadrant activiw expressed weight, serum cholesterollevel, and adherenceto the exercise.diet. and stress as a percentageof maximumactivity in

normalities and myocaldial steal after diplaidamole stress by PET. Myocardial steal by PET after dipyridamole stress is diagnostic for substantial coronary collateralization as compared with coronary arteriography.al Areas of myocardium showing myocardial steal would not be exDectedto show decreasedsize or severity of perfusion abnormalities corresponding to stenosisregression becausethe artery is occluded and usually doesnot reopenv/ith lipid lowering. Myocardial steal and severity of perfusion defect aller dipy.ridamolestress increase with time as resting collateral supply improves to myocardium distal to the occlusion.aeAccordingly, image data were analyzed both with and without the four patients with myocaldial steal.

O1995 American Medical Association. All riqhts resewed.

the heart, The quadrantwiththe lowest activity contains the most severe perfusion abnormality of the PET image after dipyridamolestress.In the control group, this lowest activity decreasedfitrther, indicating a more severe or worsening abnormality on the final study compared with the baseline study. In the experimental group, the lowest quadmnt activity inqeased, ie, becameless severe,indicating improvement in the perfusionabnormalityon the final study compared with the baseline study. The differencesin changesbetween control and treated groups were sigdficant (P=.001for a one-tailedI test; P=.002 for a two-tailed i iest; and a power of 95Eo).

Figure 3 showsthe changein size of myocardial perfu sion abnormalities after dipl'ridamole stress expressed as percentage ofthe left ventricle (LV) outside 2.5 SDs of norrnal individuals. In the control group, the size of the myocardial perfrsion defectsincreased,rndicating a larger perfusion abnor"rnality, In the experimental group, the size of the perfusion abnormalitiesdecreased, indicatingimprovement.The difference in the changes between control and treated groups was significant (P=.02 for a one-tailedt test; P=.05 for a twotailed t test; and a power of ?07,).

Figure 4 shows the change in combined size and severity end poini expressed as percentageof the LV with activity less than 607. of maximum activity. In control patients, the percentage of the LV below 607oof maximum activity increased,indicatingworsening ofthe perfusionabnormality. In the experimentalgroup,the percentageofthe LV below 607oof maximum activity became smaller, indicating improvement in the perfusion abnormality. The differenceinthe changesbetweenthe control and experimental groups was signifrcant (P=.002for a one-tailed, test;

(Fleprinted)JAIVA, Seplember 20. 1995 Vol2?4.No. ll

997

+8

<5

d)

=:

.^

0

+12

o .r|3,

,+8

<i q= >: b8

6

o ! ?\

;.4

r9 =-b

-â&#x201A;Ź

s5

-1 0

898

E

0 -q E

-a

perfusion insizeolmyocardial 3.-Changes per- Figure inseverily of myocadial Figure 2.-Changes tomography emission afbypositron tomogra- abnormalities emission bypositron fusion abnormalities asthe slress.Sizois measured ismeasured terdipyridamolo phyafterdipyridamole Severity stress.

(LV)outside 2.5SDs oftheleflventricle quadranl (asshown l) av' percentage in Figure asthelowest insize,shown by Anincrease range. of maxi oflhonormal as percenlage expressed erageactivity a decrease in worsening:and a plussign,indicates shownbya in activily. mumactivitv.

A decreaso improvebya minus sign,indicates inac- size,indicated anincrease worsening; minus sign,indicates wiih improvemenl-ment,Thevaluesshownale meanasEM, livity, shown byaplussign,indicates andn=l5forlhecontrcl withn-16tor n=l6 fortheexperimental Thevalues shown aremean!SEIL'|. group. group. theexpemental andn=15forthecontrol P=.004for a tv/o-tailed t te6t; and power ot 95%).

Table 2 shows the changes in three PET end points, including the fow patients who, at entry, had occluded collateralized coronary arteries and myocardial steal after dip)'rddamole stress.

The values for the experimental group (n=20) and the P values compared with those for the controls (n=15) in Table 2 are somewhat different than in Figures 2 through 4. The differences in changes between the control group and the experimental group (Table 2) remain statistically signifrcant, although they were not as large due to unimproved size and severity of per.firsiondefects associated with myocardial steal in the four patients with occluded arteries at study entry. For Table 2, P values are for one-tailed t test, with the same results with two-tailed , testing.

Figure 5 showsthe percentageofpatients with signifrcant changes, either worse or better, in sizeand./orseverity of myocardial perfusion abnormalities after diplddamole stress. Sigaificant change in each of the three PET measurements ofsize and/or severity ofperfusion abnormalities was defined as a change in each PET measurement on the final PET study that was greater than 1 SD of each PET measurement on the baselinestudies of the control and expedmental groups combined.The percentageof patients showinga threshold change defined in this way was averaged for each of the tlree PET measurements, and the resulting percentage of patients is shown in Figure 5.

This analysis of patients based on a threshold chanEeshowsthat 4570ofcontrols had worsening defects,507oshowed no change,and 57oshowedimprovement.

By comparison,most of the patients in

+13.5!3.8

the experimental group showed improvement or no change.The difference in these changes between the control and experimental groups was significant (P=.03by Fisher's exact test).

As a seconda.4rend point, PET images were also visually interpreted independent of the automated quantitative analysis. Among three blinded readers there was agreement in 33 of 35 patients on whether the baseline to frnal dipyridamole images showed visual worsening, improvement, or mixed changes.In lhe l"wopatjents requiring consensusreadings, all three readets agreed that these two patients showed mixed chanEes. Visual interpretation of worsening or improvement did not agree with automated measurements indicating worsening or improvement in three patients who had mixed changes that the automated method determined as a net total change of improvement in one patient and worsening in two, a quantitative result not possibleby visual interpretation. In 31 of the 32 remaining patients, the automated measurements concurred with visual interpretation of worsening or improvement. In the one case of disagreement between automated and visual analysis, the visual interpretation was borderline improvement, whereasthe automatedmeasurements showed borderline worsening.

Analvsis of variancewith the Bonferroni post hoc correction algorithm did not chanEethese conclusions;P values for differences between the control and experimentalgroupsfor changesin size and severity of perfusionabnotmalities

by PET after dipyridarnole were as follows: for lowest quadrant average counts,P=.006;for percentageoutside 2.5SD limits, P=.04;forpercentagewith

1995-Vo1274,No. ll {Reprinted) JA[4A, September2o,

sizeandseverity Figure4.--â&#x201A;Źhangesin combined perfusion by positron abnormalitigs of myocardial stress. afler dipyridamole emissiontomography The combinedmeasureol size and seve ly is ex(LV) pressedasthe percentage ol thelettvenlricle whichis 3 withactivitylessthan60%of marimum, in An increase of 80o'o.

SDsbelowthe normalmean sizeandsevedtyis shownbya plussignindicating A decrease insizeandseveityisshown worsening.

Thevalues improvemenl. bya minussignindicaling wilh n=16for theexpe ' shownare mean=SEM. mentalandn=15for thecontrolgroup. activitv less than 607a of maximum activity on the dipl.ridamole image, P=.01.

Myocardial perfu sion abnormalities by PET at resting conditions prior to dipy'ridamole stress also improved but not to the same degree as after dipyridamole because resting myoca.rdial perfu-

sion is less affected by coronary a,rtery stenosesthan is maximum perfusion capacity after pharmacologicarteriolar vasodilation.2p The changesin size and severity of perfusion abnormalities on resting PET imageswere improved or better in the experimental group ascompaxed with controls, with P values as iollows: for the myocardial quadrant with the lowest average activity, P=.02 by one-tailedt test and P=.04by two-tailed , test;for percentageofLV activity with lessthan 607oof the maximum activity on the resting PET image, P=.01 bY one-tailed,test and P=.02by two-tailed , test; for percentage of LV outside 2.5 SDs ofnormalizedcounts,P=.06by onetailed , test and P=.11 by two-tailed t test.

Figure 6 compares lhe changes in these three primary PE T measurements with the changesin minimum lumen diameter,percent diameter stenosis,and stenosis flow reserve documentedby quantitative coronary arteriographic analysis.Sincethe uni|s of these six arteriographicand PET measurements are different, the absolutedifferencein changesbetween the control and experimental grfoupswas expressedas a percentage of the mean of each measurement at baseline for all patients without the minus or plus sign for direction ofchange. For quantitative coronary aneriography. the difference in chanEesbetween the control ard ex-

@1995 American Medical Association. All rishts reserved.

(PET)* Tomography Abnomalities

by PositronEmission Table2.-Changesin Perfusion PET End Poini

ControlGroup

ExperimenlalGroup

Lowesl quadrantavâ&#x201A;Źragâ&#x201A;Ź counts,% ol marimum % ol LV outside2.5 SDs

+ 1 0 .3 a 5 .6

-1.9!4.2

<60% of maximum

+ 1 3 .5 1 3 .4

-1.4!3.7

control 155% -----

+1.613.1

|

45"/" I

*Final PET-basâ&#x201A;ŹlinePET. Includespatientswith lolal coronaryarleryocclusionsat entry.Lv indicaieslefl vsnt cle- Numbercare meantsD unlessolhe ise indicaled,

and severity of perfusionabnormalities by diplridamole-PET may be improved endothelial-mediated coronary a.r'tery and arteriolar vasomotor function crccurring within weeks to months after vigorous cholesterollowering but before anatomicregressionoccurs.r6 COMMENT Both coronary atherosclerosisand This study demonstratesthat the size hypercholesterolemia impair endothelial-mediated vasodilation of epicardial and severity of myocardial perfusion abcoronary conduit arteries.ts Dietar:y fat nomalities documentedby PET at rest and after dipyridamole stress decrease restriction, lipid reduction by drugs, or both restore this endothelial-mediated or improve in patients undergoing intense risk factor modification in com- epicardial artery vasodilation in expenparisonto an increaseor worseningin mental animalss565eebefore anatomic patients Changesin regressionofCAD is seen.6e perfusion abnormalities in the coronary microcirculation may play treated with standard therapy. a role in the observedimprovement in AlthouEh it is used as a measureof perdrsion defects. Atherosclerosis of changingitenosis severity in lipidJowproximal, conduit, and epicardial coroering trials, percent diameter narrowinE or absolutelumen size documented nary alteries impairs endothelial-mediated vasodilationofthe distal microcirby coronary arteriography does not acTherefore, the coronar'lr culation,tF,se,@s count for complexshapechangesof steflow responseinducedby the direct efnoses.4Percent stenosisis also poorly fect of diplridamole on arteriolar vasorelated to flow capacity or coronary flow dilation may be augmented by an imreserye2sir?and fails to account for diffuse diseasepresent in most patients oroved flow-mediated. endothelial-dewith localized coronary artery na.r"row- oendent.fufther arteriolar vasodilation in responseto the initial inqeased flow ing.s$ The degreeof improvementin inducedby the effect of dipyridamoie. percent stenosisin regressiontrials is quite modest, ranging up lo 1VodiamSince coronary artery stenosesaffect maximum flow capacity much more than eter stenosisunits for all stenosesand resting flow, the improvement in restup to 107oofdiameter stenosisfor more These modest ing perfusion abnorualities suggestsdifs6vere stenoses.t2a,6o,51 anatomicchangesrcpoded in recent cho- fuse improvement in vasomotor funclesterol-loweringtrials raise quesiions tion throughout the coronarlr arterial and arteriolar circulation in the expenabout their functional significance.In this study,the substantialimprovement mental group compared with conhols.

These results also provide a mechain perfusionabnormalitiesmeasuredby PET images documentsthe functional nism explaining the substantial decrease sigdfrcance of relatively small changes in anginapectoris reported to occur early in lipidJowering trials,fa Becausemyoin the atherosclerotic corona.ry artedal circulation associatedwith this modest cardial perfusion reflects the integrated effects of single or multiple stenoses, extent of arteriographic regression in difflrse atherosclerosis, and vasomotor long-term cholesterol-loweringtrials.

The improvementin sizeand Eeverity dysfunction on coronarlr flo\ry,quantitaof myocardial perfusion abnormaliries tive PET perfusion imaging provides at resting conditionsand after dipyri- inforrnationon severity ofCAD beyond damolestressin comparisonto worsen- a single dimensionof a single localized coronary artery narrowing asmeasured ing in controlsmost likely involvestwo The first is partial anaLomic on an arteriogram. Furtherrnore, bemechanisms. cause perfusion is related to lumen raregr.ession of localized coronary artery 2e stenosisas demonstratedby quantita- dius raised to the fourth power,s small lumen diamchanges in arteriographic tive coronary ar"leriography.which improves maximurn flow capacity and deeter that are difficult to measure on the creasessize and severity of peffirsion arteriogram produce proportionately greater changes in perfusion that are abnormalities after dipl.ridamole stress, A secondmechanismfor decreasedsrze apoarent on PET scan.

perimenial groups ranged from 187, to SlVo of lhe mean baseline value. For PET the differencein changesbetween control and experimental gr.oupsranged fuom 22Eato 96qoof the mean baseline value.

@1995 Amedcan Medical Association. All riqhts reserved.

ol patienls wilhsigniticanl Figure s.-Percentage greater change, asdechanges thana threshold pe. finedbelouinsizeandsevetyol myocardial tomogralusion abnormalities byposilron emission phy(PET)afterdipyridamole stress.Significant of ineachofthethreePETmeasuremenls change was abnormalities sizeandseveityol perfusion on defined asa change ineachPETmeasurement thanI SDof thelinalPETsludythaiwasgrealer on lhebaseline eachol lhe PETmeasurements studiesof the control(n=15)andexpemental groupscombined. (n=16) valuesof eachol lhe wereaverthreePETendooinlslor eachoatienl fortheexperimental andcontrol agedseparalely groupsUsing endpoint measurementsof stenosisseverity,arteriographicregression trials have comparedaveragechangein stenosisseverity between control and experimental groups or have compared the percentage of patients showing a change in severity g"eater than some thresholdvalue,reflectinginherent varjability of the measurement technique.

In this study we analyzedthe PET data using both ofthese approachesand found concurring results.

Lipidlowedng trials have also characteristically categorizedpatients or stenosesasshowingregression or no change as opposedto progressionin severity.

The reasonis that progressionis associated with high dsk of future coronary events,such as death, myoeardialinfarction, bypass surgery, or balloon angioplasty, whereas partial regression or stability of coronary artery stenoses is associatedwith low risk of coronary events.2J550J0 Accordingly,in our analysis based on theshold change in the PET images(Figure 5), we categorized patients as showing improvement or no change vs progressrontn srze ano severity of per{usion abnormalities due to theseobservedprognosticimplications.

In view of several previous trials demonstrating modest arteriographic regressionofsingle,locatzedcoronaryartery stenoses,thecurrent study reports unique, long-term follow-up data on the functionaland mechanisticcor'telatesof these arteriographic changesseen alter a variety of lipid-loweringinter"ventions.

The greater changesin size and severity of perfusion abnormalities obiained noninvasivelyin lhis study may be interpreted as being functional consequences of or correlates with the mod-

(Reprinted)JA[.{A,Seplenber20, 1995-Vo1274,No. 1]

899

967.

Eq .

Sisg

I QuantitativeCoronaryArteiography Tomography Emission E Positron

and Robeto Robeti, MD, of Beth Israet PET C€nter, Ne!,/ York, NY, for paticipating in blinded reathngs of PET images.

Beietences

1, Onish DM. Brcwn SE, Scherwitz LW, et al. Can lifestyle €hanges reveNe athemsclerosis? ran.d. *99+ 199q$6:129-133. d.E;6 2. Bm{'r G, Albers JJ, Fisher LD, et al. Reg"eso E g, l i sion of coronary arier:y disease as a r4ult of intensive lipidlowering therapy in men with high levAlsof apoLipoproteinB. N EnQt J Metl 1990: 0 E 323:1 9-1298. i5, ! -, : 1 3. Kare JP, Malloy MJ, Pots TA, Phillips NR, Low Quad [.,linDia o/.DS Di€hl JC, Havel RJ. Regession of comnary athercsclerosis durinE treatment of familial hwercholesterolemia with combined drug regirnens. J.4"L4.

1990:2€'4:3007€012. quanlitalive coronary ar(PET) and positron tomography emission o, changesby Fiourc6.--4omDanson quadrantwiththe lowestaverageac1v1y(Low 4. Gould (L. Omish D, Kbkeeide R, et al Imt il"i"ii6"lCidif. irr" pEt mZasureiweremyocardial l€ssthan provedstenosisgeomel-ryby quantitati!e comnary ol LV actrvity andpercentage (LV)oulsidei SDsof normals. r"nventdcte ij""ji. ili"J"rioJ arteriograply afl.er vigorous risk rador modLn'a' per(lllin Dia); diameler lumen absolule "r minimum wer€ by ocA 6b:i? !'"-iiirJi"ti"itv. veasurements Lion. Arn J Cardiol. \952:,69tu5'853. of abeftects inlegraled lrom lhe (sFF) ved de flow reserve DS) and stenosls 5. lvatts GF, Lewis B, Bnrnt JN, et al Effects on all as pre"i""itii"'ez" lengthetfeclsbasedon lluiddynamicequatonsr """iii"-"i"i 7oDS,andcumulative lumendiameter, soluie comnary artery diseaseof lipid lowering diet or expe menial controtand the behveen in changes ditference Theabsolute ,eported.r-7 uioriivu"iia"t"o dier plus cholestlramine. in Lhe St Thomas' Ath percentageolthe mean asa was expressed "no plus ofchange) signlordiisclion i.i,-"! i*itn"irlir'" ti"Lor ercflerosis RegressionStudy TSTARS) Ld,'Pl patients for all at baseline 6t .d"h measurement 1992439:563-669.

6. S;hubr G, Hambrecht R, Schlief G, et a.l.Mvocadial Derfusion and reqression of coronary artery est anatomic chanEesin stenosis seYer- load due to changing anginal thresholds diseaselnoatipnlson a Fqimen of int€nsi\ e phvsr stimulus at il-y measuredby invasiveart eriography. that alter the vasodilatory cal exerciseard low fat dier. J An CoU Co nl 'The follow-up studies compared with baseDrinciDallimitation ofthe current 79g2il9:u-42. line. Whether changesin myocardial per7. SchulerG,HarnbrechlR, SchuerfC.er al.Reg!study is the relatively small number of lar Dhvsical exercise and low-fat diet: effects on up followed by be reliably can fusion in PET subiects. However, differences prolression of coronary axtery disease. C cutaboth is unor stress, SPECT, exercise imaeesbetween control and experimention. 1992;86:l-11.

8. Buchwald H. Vaxco RL. Matts JP, €t al. Effect tal groupswere statistically significant. clear. EiEht recent studies of a total of al,tenuation arLhat 4064casessuqgest of pallial ileal b)Tass surgery on nortalilv and Ouring ltre 5-year follow-up period of morbiditJ from coronary hear disease in patjents SPECTq'z of accuracy the palimit tifacts 20 control this study, frve l25Vo)of with blTercholesterolemla"N En41 J Med lgmi and sensitivity reported and reduce its tients and eight (2970)of 28 patients in 323:94&956. specifrcityto 8670andM7r. respectively, 9. Blanlrcnhorn DH, Nessim SA, Johnson RL, San_ the experimentalgroup dropped out of g57afor PET marco ME, Azen SP, Cashin-Henphi L. Benefithe sl,udvor were unavailablefor follow- compuredwith 95qoand cial effects ofcombined colestipol-niacin the€py on In nine reporls.Tr in cases on 855 based malcomputer lost bY up, or d;ta $ere coronaxy atheroscleroBis and comnaxy venous byfirrther ranlimitations, view oftechnical function. The dropo\l rale a\Ieraged Dasssmfts. "I.4-rl4A 19U'P573243 5240. domized studies v/ould be necessary to per vear. comparableto that in other 'Eo i0. Cashin-HemohnIL.l,[a.ckwJ, PogodatlM San narco ME. A7,€nSP. Blankenlorn DH. Beneffcial document the validity of SPE CT for this irlats. and wai comparablein control on comnary arheroscleeffectsoI colestipol-njacin afld exDerimentalgroups without iden- application in comparisonwith coronary rosis:a4vearfouow-up.J Al A lg9ft2 t301}3017 f.ifiablebias in the results. While some artenograpny. rr, Hask; wL. Aldcrman EL, FairJM. et al EfIn conclusion, the modest regression fects of int€nsive multiple dsk lactor rcduction on unrecosnizedbias from dropouts,small of coronary artery stenosisin patients coronafl athemsclerosis and dinical cardiac events samplJsize, or patient selectionmight in men ard q'omen with comna.ry axtery disease. with corona4yatherosclerosisafter inthe effects generalizability of limii the Circula,tioiL. l9g4ia9:n &W. is associmodifrcation tense risk factor of the lifestyle intervention, it would 12. Expert Panel on Detection, Evaluation and size decreased 'heetment of Hich Blood Cholestercl in Adults significantly with ated of size results not be expecied Loaffect (Adult Tleatment Panel II) S€cond report of the and severity of per{usion abnormalities and severity of perfusion abnormalities perfusion imixDert Panel on Detection, Eva.luation, and Treat' PET by resl-dip1'ridamole meafunctional bv PET. Noninvasive meit of Hich Blood Cholesterol in Adulh (Adult of with worsening sures of disease severity were compa- aqins as compared Tleatment ?arcl II), National Cholesterol Edu@ r6rfrision in control patients treatpd with t;\on P]{,cram. Circulqtian 1994;89:132S1445 rable to or, in somerespects, better thar 1S. Blankenlom DH. Aryioglaphic tdals testing standard antianginal therapy at 5-year invasive corona4/ arteriography perthe efflcacy of cholesterol lowedng in r€ducing prlo_ regression of or Progression follow-up. patients. formed in the same or inducing rPgression of comnary athCAD cair be I'ollowedup noninvasively F€ssion The total cost of diagnosis and followerosclercsis.Corff Arl"ru Dt6. 1991;2:87t879. by objective automatedquanLilationor up by noninvasive PET at $2200 Per r4. Singh RB. Rastogi SS, Vena R. et al. Randomjsedmn|.Iouedtrial ofcadioprotPcLivediet in costsis compa- qualilative visuai interpretation ol perstudv for all componenl" patients with rccent acute myocadial infarction. b-y rest-dipyridatusion abnormalities for of $2500 costs rable to typical t-otal AMJ. 1992;304:1016-1019. sinqle-photonemissioncomputedtomog- mole PET perfusion imaging.

15. Buchwa.ldH, MattsJP, Fitch LL, et al. Changes per{rsion imag(SpgCTt slress raphv in sequential comnaxyartedogmm8 and suhequent coronarv events. J-4-114. 19s2;268:1429-1433. in; and is lessthan $8000to $10000for Thjs study was supporledin parl bv grants Rol 16. Gould I(L, Matucci JP, Goldberg DI, €t alH L 26882,H L 26885,HL 42554.and HL 2r$56 from all costsofcoronary arteriography.?lThis Short-tem chol€st€rol lowering decleasessiz€ and of Health,Bet hesda,[l d; bv I nst itutes l-he N ational study focused on changesin myocardial se\ erity ofperfusion abnormalitiesby posrlnonemsthe Houston Endowment Foundation, the Enron perfusion using the most quantitative. Comolation. Gerald D. Hin€s lnt€rests, Henry J. sion uomographyafter dipl'ridamole in palients wir h potentiai norunvtqvp comnan arJerv disease----a accurate imaging curently available, I<aiaer Family Foundation, Fetzer Institute, Concorcnary;ndothelium. Cimidot heaLlng Foundation' narkpr Cummings Nathar Ailines, tinental to attenuation which PET nrovidesdue iron. 1994i89:1530-1538 Bucksbaum Foundation, Pritzker Foundation, correction and uniform, depth-indepenu. Scandinavian Simvastatin SDrvival Studv Gmss Fourdation, ard Moldaw Foundatio& and aB Pharmacologic dent hieh resolution.

GmuD. Randomised tlia.l of cholesterol loweing in a ioint collaboEtive project with the Cla)'ton 4444 patients with coronary h€art disease ro'"?t' stress iJaho readily standardizeddeFoundation for Reseafth, Houston, Tex. 1994;344:1383-1389. ia MD, to Dal Garza, axe indebted The authors workexercise maximal

9ts g

E,fE=

spite charging 900

20. 1995-Vo1274,No. lt (R6pfinted) JAMA, SeDtember

@1995 American Medical Association. All nghts reserved'

18. delogeril M, Renaud S, Manelle N, et al. Meditenarean alpha-linolenic acid-rich diet in secondary pr€vention of comnaxy heatt dieeaee.Lancet 1994;343i149-1459.

19. Furberg CD, Adans HP, Applegate WB, et aI. EffecLoflovaslatjnon early carotidatherosclerosis and cadiovascular eve ts. Circulatian. 1994;901 1679'168?.

20. Wat€rs D, Higginson L, Gladstone P, et al Effects of monotherupy with a.nHMGCoA r€ductase inlibitor on the Fogre$ion of corona.4t atherosclerosis aB assessedby seda.l quantitative axteli.o..Iaphy. CinuLation 1991;89:959-968.

21. Bla*enlorn DH. Az€n S, Kramsch DM, et al, and the MARS ResearchCroup. CoronarJ angiographc charges with lovastatin theEpy. An?t I'ttem Med,. 1993].119:969-974.

22, Pitt B. Mancini J, E[is SG, Rosman HS, McGovem ME. havastin limitation of athemsclerosis in the coronary ateries (PLAC I). J Am C'LL Car' diol. 1994;23:1314.Abstract.

23. MAAS Investigators. Effect of simvastatin on coronary athemma. razc€r. 1994;344:633-638. %. Zhao XQ, Gmwn BG, Hillger L, et al. Eff€cts of int€nsive lipid-lowedng thempy on the coronary arteries of aspnptomati€ subjects with elevated apolipopmtein B. Circrldti,vr. 7ffi3t8at27U-27 53 25. Go\nd KL. Corowry Artzry Stan$6: A Te'rt' book of Corcndxu Pathophasiologa, @tnntitatbe Coronura Arteriographa, P EaI Pafu sion htvtgirl4 ann nnersal of CorcnnrA Artery Diaease. New York, NY: Etsevier SciencePublishing Co lnc; 1991.

26. Gould KL, Ke ey KO. Experimental validation of quantitative coronary alterioglaphy for deteF mining plessure-flow chamcteristic of comnary stenoses. dircu la irr. 1982;66:93G93?.

27. Ifilkeeide RL, Gould KL, Paxsel L. Assessment of coronarlr stenoses by myoca.tdial irnaging during comnaIxiva€odilation,VlIi validation ofcoronary flow resewe as a single integrated measue of stenosis seveity accounting for all its geometric dimenFjons.J Am C,LI Cdldiol- 1986;?:108-113.

28, Gould KL, Kirkeeide RL, Buchi M. Comnaxy flow rcs€Ive as a physiologic measure of stenoeis qe\erirJ, part l:relariveand absolutemronary no$ resen e during changingaonic pressureand cardiac worldoad; parl II: deternination from art€riographic stenosis dimensionsunderstandadized aonditio s. J Atn Col,LCard,iol. 79mi15t459-474.

29. Gould KL. Identifuing and mea$ring sevedty of coronaryaltery stenosis {uantitative coronary a.rteriography a.ndpositrcn emission tomography.

Cir cukLtion. 7988;74t237-245.

30. Marcus ML, Haxrison DG, White CW, McPherson DD. Wilson RF, Kerber KE. Assessingthe in physiologicsigni6canceof coronaryobBt11)crions Datients: importance of diffuse undetected ath€roiclerosis. Piog Cardio&sc Ds. 1988;31:39-56.

31. white CW, Wright CB, Doty DB, et al Does visual interpretation of the corcnary arteaogran predict the physiologic importar€e of a corcnary sienosiEl N EngI J Med. 1984;310:81$8%.

32. Marcus ML, Skorton DI, Jolmson MR, Coling SM, Hardson DG, Ke$er RE. Visua.l $timates of abaueredgold Dercenldiametercoronarystfnosis: irandad.. J Aa Cott .ardiot. l988iIl:882485.

33. Seiier C. Ki*eeid€ RL, Gould KL. Basi€ structure-function rclations of the epicaxdial comna.ry vascutax trce-the basis of quantitative comnaxy arteriogaphy for diftuse coronaxy artery disease.

CircutakatL. 1992i.85:1987 -2003.

34. Seiler C. Kirkeeide RL, Gould KL M€asur€ment from axteriograms ofrcgional myocaxdial bed size distat to ary point in the corcnarT arJeria] trce

for assessing anatomic area at Iisk. J Am C1II Car dio I. 199321:7S3-797.

35. Hodgson JM, Reddy KG, Suneia R, Nair RN, Lesnefsky EJ, She€har HW. Intracoronary ultlasound imaging: conelation of plaque morphology with angiography, clinical s}rdrcme and procedural rcsultsin parientsunde"goingcoronarya.ngiopla8ty.

J Am CoU,Cd,rdial. l993i2t35'M. 86. Gould KL, Goldstein RA, Mulani N, et al Non invasive assessmentof €ortonaxystenoses by myocardirl inaging during phamaxologic coronaxy vasodilation, VIII: feasibility of 3D caidiac poeitron imaging without a cyclotron using generator prod\ced Rb32. J Am CoU CdrdioL 198S;71775'792.

3?. Demer LL, Gould l(L, Golfttein RA, Kirk€eide RL. DiagnosisoI coronaryanery diseaspby pn"itron emissiontomography t' i tr u|atior1 1989179l.

825€35.

38. Gould I{L. PET pertusion imaging and nuclear caxdiology. J Nucl Med. 7991;32:579-606 39. Could KL. Clinical cardjacpositrcn emission tomog! apt'y. Circulation. 1991;P'4(8uppl):l-22I-36.

40. Hicks K, Ganti G, Mu[ani N, Gould KL. Automated quantitation of 3D cadiac PET for routine c\ini,cal\se. J Nual Med. 1989;30:1787-1797 41. Demer LL. Gould KL. Goldsteh RA, Kilkeeide RL. Noninvasive assessmentof coronary collater als in mar by PET pertusiol]'imaa)ng. J Nucl Med'.

1990;31:25S270.

42. Mulani NA, Goldstein RA, Gould KL, Fisher DI, Maranj SK, O Brien HA. Mlocardial pprfrl8ion with rubidium-82,l: measuFmentofext ra.tjon &ai'tion and flow srith external delectolF. J NucI Med 1983:24:898-906.

43. Goldstein RA, Mdlani NA, Fisher D, Ma.r?niS, Gould KL, O'Bien HA. Myocadial pefusion with mbidium-82, II: the etrects of metabolic and pharmacologic interventions. .I NucI Med..198324:907915.

4,1, Xu EZ. Mullani NA, Gould KL, AndeEon WL A segmented attenuation corection for PET. J Nltcl Mad,. 1*71321161-1.65.

45. Snedecor GW, Coc}Ilal:.wc. Stdtistical Meth' o&. 8th ed. Am€s: lowa State University Pr€ss; 1989.

46. G\arltz SA. Pritvr of Biostat*tics. New York, NYi McGEw-Hili International Book Co; 198?.

47. SDatz C. Johnston JD. Bosic Sralisti6. 3rd ed.

Monter€y, Calif: Bmoks/Cole Pubtishing Co; 1984.

48. Stal Viab. Berkeley, Calif: Abacus Conc€ptE Inc; 1992.

49. Den€r L, Gould KL, Ki*eeide R Asseseing stenosis severity: corona4' flow resere, collateral artcriography.posi_ funclion,quanlirative cor.onary ilon inaging, and digiial subtraction angioglaphy.

Proo Cord.iol,asc Dis. 1988:30307-322.

50. Brown BG, Zhao XQ, SaccoDE, Aibers JJ. Lipid loweringandplaquergression: new in'ights inro prevention of plaque disruprion and clinjcal €vents in coronary aitery disease.Circulation- 1993l' 8?:l?81-1?91.

51. Fuster V, Badirnon L, Badinon JJ, Chesebm JH. The pathogenesis of coronary aftery disease and t]1e acute coronaxy s),ndrcmes. N Engl J Med 1W23261242-250.

52, CohenRA, Zitnay KM, HaudenschiidCC, Cunnincham LD. Loss of selective €ndothelial cell vasoaitive ftinctionscausedby hwercholestProlemia in pig corcnaryanenes. Ctr. R€s.1988:63:903-910 It. Shimoka$aH.VanhouttePM Dieralvcodliter nesponses rn oil inproves endotheliurn.dependenl hlTeriholesterolemicand arheroscleroLicporsine .oronN afteries. d.trc?rlation. t9aA:;74:l4Zt_748O. fl. Sell(e Fw, Armstrong ML, Haxrison DG. En-

@1995 Amedcan Medical Association. All riShts resered

dothelium-dependent vascularrclaxationisabnor_ mal in the comnary miffoc culation ofathemsclerotic Drimates.Cirdldiio,?. 1990i81158G1593.

55. C-hiliar WM, Dellsperyer KC, Laj'ne SM, et al.

Effects of atherosclercsis on the comnary micrG cir(juIation, Am J Phasiol. lw0;25a(2, pl 2)iH529' H539.

56. Tomita T, Ezaki M, Miwa M, Ns.kamura K, Inou€ Y. Rapid and r€veNible inlibition by lowdensity lipoFotein of th€ endothelium'dependent relaration to hemostatlc substaftes in porcine coronarv arteries. Circ Ees. 1990i66:18-27.

5?. Ta}ahashi M, Yui Y, Yasumoto H, et al. LrpoDroteins arc in]libitols of endothelium-dependent ielaxation of mbbit aorta . Arn J PlLusi.ol.19B0i2F$l H1-H8.

58. Andrews HE, Bmckdofer KR, Dunn RC, Jacob M. Low-densiw lipopmt€ins inlibit endoth€lium-dependent rel&\ation in rabbit aorla. Nailr,"r.

1987i327t237-239.

59. Hanison DG, Armstrong ML, Freinan PC, Heistad DD. R€storation of endotheliumdependent relaxation by dieta.ry trcatnent of atheroscleroeis.

J Ctin Inaest. 198?;80:1801-1811.

60. Verbeuren TJ, Jodaens FH, Zonnekeyn LL, Van Hove CE. Coene MC, H€nnar AG. Effect of hlTercholesterolemia on vascular reactivity in the rabbit. Circ rRe6.1986;58:552-564.

61, Tarner FC, NoI G, Boulanger CM, Luescher TF. Ondized low density lipoFoteiN inhibit re' la,xstionsof porcine cotonary axtnries Circulation 1991:83:2012-2020.

62. Kuo L, Davis MJ, CannonS, Chilian WM. Pathoe{ipnd physiologicalconseqenres ofat herosclerosis inro the comnafl mictt.irulation. air. R?s. 1992; 701465476.

63. Godon JB. Garz P. Nab€i EG. et al. Athero sclemsisinlluencesihp vasomolorresponseofepicadia.l coronary arteri€s t o exetctse. J Clin Iraest.

198$83:1946-1952.

64. Z€iher AM, Drexler It, wolschlager H, Just H Endothelial dysfunction of the coronarf, microvasculature is associatedwith impaired coronary blood flow regulation in patients with ea y atheroscle_ tosls. Circulat rn. 1991;8II!9U-1W2.

65, Zeiher AM, Drexler H, Wotlschlager H, Jusi H. Modulation of coronary vasomotor tone Circ?rlofior. 1991;83:391-401.

66. Ludmer PL, Selwlal AP, Shook TL, et 4.1.Paradoncal vasoconstiction induced by acetylcholine in atherosderctic corcnary ar1,el'es.N EngI J Med. 1986;315:1046-1051.

67. HodgsonJM. MaFhall JJ. DirPct vaso.onsLri.tion and endotheliumdependent vasodilation. Circulation. 1989i7911043-l05l.

68. Uren NG, Manaccini P, Gistri R, desih'a R, Carnici PG. Altered coronary vasodilator rcserve and metabolism in myocaxdium subtended by nor_ mal axteri€s h patients with comnaxy artery dis_ ease.J Am C1LI Cadto\ l993;22i650-658 69. Benzuly KH, Padgett RC, Kaul S, Piegors DJ, ArmstronE ML. Heistad DD. Functional improv€ment prec;des structural rcgression of athemscle_ rosis. Cir@loliotx-1994i89:181G1818.

70. Waten D, Craven TE, Lesperance J. Progrostic sigificanc€ of pm9ession of coronrxy athemsclerosis. Cirflrlatton. 1993;8?:1067-10?5. ?1. Gould l{L. Beversal of comnaxy atherosclem sis: cLjnicalpromiseas rhc basis for the non_inv2sive management of corcnaxy artery diBease.Ci|1. rul&tion. 1994190t155*15'7 ?2. Wackers FJ. Artifacts in planar and SPECT myocardial peIfiEion imagir,g. Am J Card lnng' iw.1992;6.4248.

(Reprinled)JAIVA,Septenber20. 1995-Vol274,No. ll

901