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E R Bates, F M Aueron, V Legrand, M T LeFree, G B Mancini, J M Hodgson and R A Vogel

transluminal coronary angioplasty on regional coronary flow reserve.

Comparative long-term effects of coronary artery bypass graft surgery and percutaneous

Print ISSN: 0009-7322. Online ISSN: 1524-4539

Copyright © 1985 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231

Circulation

doi: 10.1161/01.CIR.72.4.833 1985;72:833-839

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SURGERY

Comparative

long-term

effects of coronary artery

bypass

graft surgery and percutaneous transluminal

coronary angioplasty on regional coronary flow

reserve

ERIC R. BATES,M.D., FRED M. AUERON, M.D., VICTORLEGRAND,M.D.,MICHAEL T. LEFREE, B.S.,

G. B. JOHN MANCINI, M.D., JOHN M. HODGSON, M.D., AND ROBERT A. VOGEL, M.D.

ABSTRACT Toevaluate the relative long-term improvement in coronary artery hemodynamics after revascularization by coronary artery bypass graft surgery (CABG) or percutaneous transluminal coro-nary angioplasty (PTCA), regional coronary flow reserve (CFR) was measured, by digital computer analysis of 35mmcine film, in 50 menundergoing cardiac catheterization. CFR (mean ± SEM) in 12 atherosclerotic arteries before revascularization was 1.02 + 0.05. Mean CFR in 29 normal arteries of men with normal coronary arteriograms was significantly higher (2.59 + 0.11) than that in 16

atheroscleroticarteries of patients revascularized by CABG (2.02 + 0. 17, p< .01) or in 14 atheroscle-rotic arteries of those revascularized by PTCA (1.97 + 0.12, p< .01). NodifferenceinCFR between the CABG and PTCA groups was found and variables known to influence CFR were similar between groups. Equivalent and significant long-term improvement in coronary artery hemodynamics is pro-vided by CABG or PTCA. We postulate that the difference in CFR in the men with normal arteries and

thosewho underwentrevascularizationwasrelatedtothe effects of thegeneralatherosclerotic process,

which remain despite successful treatment by these techniques.

Circulation 72, No. 4, 833-839, 1985.

MYOCARDIAL REVASCULARIZATION can now

beaccomplishedbyeithercoronary arterybypass graft

surgery (CABG) or percutaneous transluminal

coro-nary angioplasty (PTCA).`- Although symptomatic,

metabolic, hemodynamic, and functional

improve-ment has been demonstrated with each technique,5-'5

little data exist comparing the two. 6. 17 One difficulty

inundertakingcomparativestudies resides in the clini-cal disparities in groups ofpatients undergoing these procedures. While patients who undergo CABG are

more likely to have chronic symptoms, a history of myocardial infarction, and multivessel disease, those

treatedby PTCAcharacteristicallyhaverecentonsetof

symptoms, normal ventricular function, and

single-vessel disease. More importantly, the lack ofa

gener-ally available clinicaltestsensitive enoughtoevaluate

From the Division ofCardiology,VeteransAdministration Medical

Center, AnnArbor.

Supported in part bygrants from the VeteransAdministration, the

MerckFellowshipFoundation of the AmericanCollegeofCardiology,

andthe MichiganHeartAssociation.

Address forcorrespondence:Eric R.Bates,M.D.,Division of Cardi-ology,VeteransAdministrationMedicalCenter,AnnArbor,MI48105.

Received Feb. 7, 1985;revision acceptedJune 20, 1985

subtle regional differences in coronary blood flow or

myocardial function dueto eithertechnique has inhib-ited investigation.

Thecoronaryreactive hyperemicresponse isan

im-portant,reproducible physiologicparameter.l' 1' Itcan

be measuredbydeterminingthe ratioof maximal coro-nary blood flow to resting flow. Increasingly

signifi-cant obstructive coronary artery disease progressively exhausts thiscoronaryflowreserve(CFR) byreducing

peak flow.202 Three techniques have recently been

developedthat allow themeasurementofregionalCFR inman. Thefirstuses apulsed Dopplercoronary artery catheter, which can measure proximal coronary flow velocity in the catheterization

laboratory.2-2

The second

uses a Doppler velocity probe, which can be applied

directlyto selected epicardial coronary arteries at the time of open heart surgery to measure the reactive hyperemic response to transient arterial occlusion.25

Thethirdisadigital radiographic techniqueperformed

during routihe cardiac catheterization that measures

the myocardial reactive hyperemic response to

intra-coronary injection of contrast medium.24 25

The presentstudy, in which we usedthethird

tech-833

at UNIV MEDECINE LEIG 228272 on May 27, 2014 http://circ.ahajournals.org/

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BATES etal.

nique,

was

designed

to evaluate the relative

improve-ment in

long-term regional

CFR after

myocardial

re-vascularization

by

CABG or PTCA.

Methods

Patientpopulation. The patient population consisted of 50 men undergoing coronary arteriography. These patients were

divided intofour groupsforanalysis. GroupIwas composedof 10

patients

withsymptomaticcoronary arterydisease(atotal of 12diseasedarteries)who subsequentlyunderwent revasculari-zation

by

CABG or PTCA. Eleven patients with 16 arteries

previously

treated byCABGformed group II, and 13 patients

with 14arteriespreviously treated byPTCAformed group III; these

patients

were studied to evaluate postrevascularization

vesselpatency. Ingroup Il patients all grafts were patent and

nonstenotic, and in those in group III there was a residual translesional pressuregradientof 20mmHgorlessatthe time of

angioplasty

and no angiographic evidence of restenosis at

follow-up.

Twenty-nine arteries in 16 patients with atypical

chest

pain

and normal coronaryarteriograms formedgroup IV and servedasthenormalcontrolgroup. Patientswereexcluded if

they

had valvular heart disease, electrocardiographic evi-denceof leftventricularhypertrophy,morethanmild

hypokine-sisdocumentedonthecontrastventriculogram,or

angiographi-cally

visible coronary collateral vessels. Data from 15% of arterial distributions were excluded from analysis because of use ofan

inadequate

contrastinjectiontechnique,motion

arti-fact, poorvisualization ofthe perfusionbed, orfailure of the

angiographer

toacquire arteriographicdatasuitable fordigital

processing.

Prescribed medicationregimenswerenotfollowedthe

morn-ing

of the cardiaccatheterization. Patientswere premedicated

with 10 mg

diazepam

and 50 mgdiphenhydramine. Thisstudy

was

approved

by the institutional committees on human

re-search andinformed consent wasobtained from eachpatient.

Arteriographic

technique. To obtain images for digital

processing,

the following arteriographic technique was used. Standard left ventriculography and multiple-view selective coronary

arteriography

were performed by the Judkins

tech-nique. Arteriography

for subsequent functional image digital

processing

was obtained in the left anteriorobliqueprojection on 35 mm cine film. Fixed parameter (kV, mA, and pulse

width)

cineradiography

at 30 frames/sec was used. Patients were

required

toceaserespirationand remainmotionlessduring

filming.

Veingrafts and coronary arterieswereopacifiedby a

fixed dose of 5to8 mlof sodiummegluminediatrizoate

(Reno-grafin-76)

injected by an electrocardiographically triggered

power

injector

gated to the R wave of theelectrocardiogram.

Refluxofcontrastmedium intotheaorta wasconsideredproof thatamaximal bolus ofcontrastwasdeliveredtothearteryand

that thecatheterwasnotimpedingcoronary blood flow. Base-line studies were performed at least 3 min after the previous

injection

ofcontrast. Studies underhyperemicconditions were

performed

10 sec afterintracoronary injection ofan identical dose ofcontrastmedium. Cineradiographywasinitiatedatleast onefull cardiaccyclebeforeinjectionofcontrast.Adensitystep

wedge

was imaged and checked densitometrically after film

processing

toensure that the film gray scale waskeptconstant on a

day-to-day

basis.

Digital

processingof thefunctionalimage. Digital image

processing

wasperformed by a technique similarto that

pre-viously

described.2 27 Threegeneral operationswererequired:

digitization,

mask-mode substraction, and functional image

generation. Arteriogramsweredisplayedon acine film

projec-tor

(Vanguard

Corporation, XR-35) equipped with aprimary beam splittercoupledtoafixed-gainvideo camera and a video

analog-to-digital converter. Five toseven end-diastolic frames from consecutive cardiac cycles were chosen, with use ofthe criterion of closest duplication of arterial position, beginning

with the end-diastolic frame just before injection of contrast

medium. Theseframes were digitized into 512 x 512 x 8-bit matrixes. Video-amplified gain andprojector light levels were

adjusted to provide a linearcorrespondence between contrast x-ray absorption and digital scale. The digital images were stored in the disk memory of a digital radiographic computer (DPS-4100C. ADAC Labs, Edenvale, CA) for subsequent

processing.

Imageenhancement was performed bystandard mask-mode subtraction with useof theend-diastolic frame beforeinjection ofcontrastasthemask. Asingle contrastintensityand

appear-ancetime-modulated functional imagewasthengeneratedfrom eachsetofenhancedframes(figure 1).25Theintensityvalueof each pixel corresponded to the maximum contrast density

reachedduringeach acquisition, while theappearance time of

contrastin thepixelwascolormodulated, withadifferentcolor assigned to eachpostinjection cardiac cycle (redfor the first cycle,yellowfor thesecond, etc.).Only pixelswithanintensity aboveapresetthresholdappearedonthe finalfunctionalimage. This thresholdwasmanuallysetatalevel that excludedmostof the background noise intensity. Acquisition and processing

wereidentical for each pairofbasal and hyperemicimages so that eachset was technically comparable.

Analysis offunctional images. Mean myocardial contrast

density and appearance were determined by a computer

pro-gramthataveragedpixelvalues inaregionofinterest definedby

the operator in the basal images and in the same area of the hyperemicimages(figure 1). Large epicardialcoronaryarteries andareasthat overlapped with the aortic root, diaphragm, or

coronary sinus were excluded from analysis. Since contrast

density is directlyrelatedto thevolume ofdistribution in the myocardiumand flow isinverselyrelatedtomyocardialcontrast

appearancetime,digitalestimation ofcoronaryblood flowwas

calculated as

Q Xcvolume/time xCD/AT

whereQ =meanregionalcornaryflow;CD =meanmaximal

contrast density; and AT = mean contrast appearance time.

CFR,the ratio ofhyperemic(H)flowtobasal(B) flow,

correct-ed for heart rate (HR), was calculatedas

CFR= QH/QB = CDH/CDB X ATB/ATH x HRH/HRB

Studies indogshavedemonstratedanexcellent correlation

be-tween CFRmeasured by electromagnetic flow probe and the ratioCD/AT measuredby digital subtractionangiography(r = .92).Thedigitalmeasurementswereaccurate(regressionslope

=.90),reproducible(+-13%),andhad low interobserver(r .99) and intraobserver(r = .98)variability.25

Dataanalysis.Dataareexpressedas mean + SEM.

Statisti-cal comparisons between groups wereobtained withthe

two-tailed, unpaired t test. Significant differences were assumed when confidence limits exceeded 95% (p < .05).

Results

Clinicalcharacteristics.Theclinicalcharacteristicsof

the patients groups are listed in table 1. Nine of 11

patients ingroup II(CABG) had triple-vesseldisease,

while nine of 13 patients in group III (PTCA) had

single-vessel disease. Forty-two of the 48 diseased

arteries in group IIand IIIpatients were successfully

revascularized. Two patientseachin groups II andIII

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FIGURE 1.Conit-astmiiediuILIm appearancepictLrCes fanaolt malrigehtcaot00dB atter inthleii ititeitol- obiiuLeCprojectionls at

baselinle(/efit and Linidet l\peIci-ciz tJi conditions. CFR was calculated tobe2.49 in the ecionlat interest.

still had exertional chest pain; the others were pain

free. The hemiioglobin averaged 14.9 + 0.7 gldl in

group II and 15.0 + 0.3 g/dl in group III and the

interval between revascularization and catheterization inthese two groups was 15.4 ± 2.0 and 32.6 ± 4.2 weeks, respectively.

Cardiac

catheteri7zationi.

Data obtained at cardiac catheterization for the fourpatientgroups arelisted in table2. There were nosigniificant dilferences in heart rate, mean aortic pressure, or pressure-rate product between groups.

Althougrh

group Ill patients had a

significantly lower left ventricular ejection fraction than the men with normal arteries (group IV) (p <

.01), the value was not statisticallydifferentfromthat in group 11, and was well within normal physiologic limits. No difference in left ventricular end-diastolic

pressuresexisted. Percent luminal stenosis of arteries

was 80 + 4% in group I and 17 ± 3% in group Ill.

CFR. Individual values for CFRfor each group are

plotted in figure 2. CER in five patients who

subse-Vol. 72, No. 4. OctobeI 1985

quently underwent CABG and in five patients who subsequentlyunderwent PTCAaregroupedtogether in

group I becausetheywereequivalent(l.

1u

± 0.05 vs

0.95 + 0.06). Mean values for CFR for grcoups 1,11, Ill, and IV were 1.02 ± 0.05, 2.02 + 0.17, 1.97 +

0.12, and 2.59 ± 0.11, respectively. While CFR in

patients withatheroscleriotic arteriesrevascularized by

CABGorPTCA was significantlyhigherthan in those with arteries not revascularized (p < .0001), it was

significantlylower thanCFRin men withnormal

arter-ies (p< .(01). NodifferenceinCFRingroupsII and III

was found. Discussion

Autoregulatory changes maintain basal coronary

blood flow in arteries with flow-limiting stenoses by

decreasing distal coronary resistance, but this limits

potential further increases in flow. In arteries with

high-grade stenoses suitable for revascularization by

CABGorPTCA, CFR isexhausted. An improvement

835

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BATESetal.

TABLE 1

Characteristics of the 50studypatients

Group I Group II Group III Group IV (n = 10) (n = 11) (n = 13) (n = 16)

Age(yr)A 56+3 57+2 55+3 48+2

No. of diseased vessels 19 31 17 0

No. ofvessels revascularized 18 27 15 0

No. of vessels studied 12 16 14 29

LAD 7 5 6 9

Diagonalbranch 0 3 0 0

Leftcircumflex 2 6 2 8

RCA 3 2 6 12

Medications beforetesting

Nitrates 10 3 3 10

,f-blockers 2 9 0 11

Ca+ +-blockers 6 2 9 3

LAD = left anteriordescendingartery;RCA AMean ± SEM.

rightcoronary artery.

inindividual arterial CFR several months after CABG andimmediatelyafterPTCA,asmeasuredbycoronary

radiography, has been demonstrated previously.26 27 Wehave since modifiedour image analysis algorithm

andusecontrastdensityinformationtoreflectregional vascular volume and the CD/AT ratio to more

accu-rately estimatecoronary blood flow.25 While the CFR

values found for vessels without severeobstructionare

higher when CD/AT ratios than when AT ratios are

used,2 27findingswithbothmethodsindicatethatCFR is absent in vessels with high-grade stenoses suitable forrevascularization. In this report, the long-term ef-fects ofrevascularization as determined bythese two

techniques werecompared with this refined image

al-gorithm. Equivalent and significant long-term

im-provements in regional CFR were found in arteries

revascularized byeither CABG orPTCA.

Additional-ly, eventhough revascularization wasquitesuccessful in each artery, normal CFR was not restored.

Clinicalimplications.CABGhas been themost

popu-larmeansofrestoring regional myocardialblood flow

to perfusion beds distal to coronary stenoses for 15

years. More recently, PTCA has emerged as an

alter-native revascularizationtreatmentfor single-vessel ob-structive coronary artery disease. It has clearly been demonstrated that successful revascularization by CABG or PTCA produces symptomatic, metabolic,

hemodynamic, and functional improvement.'-" The

current investigation is the firstto suggestthat

equiv-alentimprovementinindividualcoronaryartery

hemo-dynamicsisachievedbythetwotechniquesandfurther justifies the use of revascularization by CABG or

PTCA in properly selected patients.

Theoreticalimplications.The failure of successful

re-vascularizationto restorenormalCFRto

atherosclerot-ic coronary arteries is probably the most interesting findingofthis study andoneforwhich anexplanation

isnotreadilyapparent.Thepatients in eachgrouphad

equivalent basal oxygen demands, as estimated by

pressure-rateproduct, and normal global left

ventricu-larfunction. Patientswith severeregionalwall motion

abnormalities, collateral blood flow,orleft ventricular

hypertrophy were excluded becausethese factors can

haveaneffecton CFR independentof that ofcoronary

TABLE 2

Cardiac catheterization data

GroupI GroupII Group III Group IV (n = 10) (n = 11) (n = 13) (n = 16)

Heart rate(beats/min) 75+2 75+3 74+3 71 3

Mean aortic pressure (mmHg) 92 3 95 4 97 3 93 3

Pressure-rateproduct (x10 ') 99 + 4 96+ 5 98 ± 5 90+ 6 Left ventricularejection fraction (%) 65 ± 4 67+ 3 59 + 3A 73 ± 3 Left ventricular end-diastolic pressure (mm Hg) 13 ± 2 10+2 14 ± 2 13+1

Data expressed as mean + SEM.

Ap< .01,ascompared with the control group(group IV).

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4.0 - 35-0 H 3.0 Cc W G 2.5-W U) W cc 200 LAL >- 1.5 z 0 g 1.0o o5 p<O.OOO1 I p<O.01 N.S. 0 0 0 0 0 a a GROUP CAD n:12 GROUP II CABG n 16 0 a to GROUPIlIl PTCA nfl 14 0 0

L

GROUPIV NORMAL n:29

FIGURE 2. Long-term CFRvalues for thepatientgroupsasdetermined

by digitalcoronary radiography. CAD = coronaryartery disease.

stenoses.28-31 By using contrast medium as a direct

vasodilator stimulus, ratherthan depending onthe

is-chemic stimulation ofvessel occlusion often used in

the operating room, we avoided measurement ofany

influence dualblood supply mayhave hadon

determi-nations of graft CFR. Also, the arteries subjected to

PTCA had very mild residual luminal stenoses and

wouldthusnotbe expectedtobeassociated with limi-tations of peak coronary blood flow.20 21 In the early postrevascularization period patients were receiving

antianginal medications prescribed by their referring physicians for prophylactic reasons, not because of persistentischemia;nonereceivedantianginal

medica-tions on the day of the catheterization.

Itisunlikelythatuseofasaphenousveingraftasthe

proximal conduit for coronary blood flow influences coronary artery hemodynamics. No change in timing

ofthe resting pulse wave, pressure contour, or distal

blood flow was found by Kakos et al.32 in bypassed

normal canine coronary arteries. Others have shown

graft CFR to be normal in the canine model.`

Like-wise, Brandtet al.34 have demonstrated restoration of

normal CFRbyCABG ina nonatherosclerotic human

right coronaryartery originating fromthe left sinus of Valsalva.

It is postulated that the difference in CFR in men

with normal arteries and those who underwent

revas-cularization is related to the atherosclerotic disease process. First, although obstructive coronary artery

disease, as defined by the coronary arteriogram, is

Vol. 72, 4,

often detected as discrete proximal luminal stenoses

treatable by CABG or PTCA, anatomic descriptions have repeatedly demonstrated the diffuse nature of atherosclerotic plaque in diseased epicardial coronary

arteries.5"- Secondly, local vasomotorreactivity may notbe normal in atherosclerotic arteries. Neovascular-ization in theregion of atherosclerotic plaque has been visualized by cinematography after silicone polymer injections into the arteries ofisolated human hearts.38 These transmural vascular networks potentially pro-vide higher concentrations of vasoconstrictor sub-stances and theproliferation of autonomic nerve termi-nals known to accompany neovascularization may enhance localcatecholaminelevels.38 Also, endotheli-al damage due to mechanical injury oratherogenesis

hasbeenshown to inhibit arterial smoothmuscle relax-ation.39 40 Finally, vascular reactivity at the arteriolar level may be affected by the atherosclerotic disease

process through intimal thickening and fibrosis,41

al-tered a-adrenergic tone,42 or chronic

microemboliza-tion of platelet aggregates.43

The effect of experimental atherosclerosis on CFR hasbeen studied in thecynomolgus monkey.44 Afteran

atherogenicdiet wasgiventoinducelesionsproducing

anaverageof60% luminal stenosis,anormal diet was

givenfor aregression period of 18months. Whilethe

degreeof stenosis wasreducedto25%,intimal fibrosis was increased and CFR was only partially restored.

The authors concluded thatintimal fibrosis substantial-ly limited arterial hemodynamic improvement.

Studylimitations.Thelimitations of the digital radio-graphictechnique we used have been previously sum-marized and include those relatedtospecific hardware requirements, motion artifact, use of contrast medium

as the hyperemic stimulus, and the mathematic as-sumptions necessary for calculation of blood flow.2-27 45 Despite these difficulties, a good correla-tion between electromagnetic flowmeter and digital

radiographic determinations of relative regional CFR has been demonstrated.29 Also ofconcern is the fact that aboutaquarterof the normal CFR valueswereless than 2. We have recently shown that patients with

chest pain, normal coronary arteriograms, and low regional CFR frequently have associated regional ab-normalities onradionuclide exercise tests.46 These pa-tients probably have ischemic heart disease without

epicardial coronary stenoses.47 48 Since this normal

group was defined only by the arteriogram, without radionuclide exercise test data, it is likely that the

difference in CFR in the group with normal arteries

and the group undergoing revascularization is larger than stated.49 The widerange ofCFR values found in at UNIV MEDECINE LEIG 228272 on May 27, 2014

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BATES etal.

eachpatient group probablyreflects the multiplicity of factors that can influence arterial CFR.49 5

In summary, revascularization by CABG or PTCA

restores equivalent CFR to individual coronary

arter-ies. Although normal CFR is not

achieved,

this im-provementincoronary arterialhemodynamics is suffi-cient to reverse clinically detectable myocardial ischemia. The difference in CFRin normal and

revas-cularized arteries requires further evaluation. Confir-mation that physiologic perturbations accompany the

previously documented anatomic changes caused by the presence of coronary atherosclerosis, despite suc-cessful revascularization of angiographically visible

proximal

stenoses, would be of importance in

under-standing the pathophysiology of obstructive coronary

disease.

We areindebted toMr. GlennBeauman for technical assis-tance and to Ms. Diane Bauer forassistance in preparing the manuscript.

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Figure

FIGURE 1. Conit -ast miiediuILIm appearance pictLrCes fa naolt mal rigeht c aot 00dB atter in thle ii ititeitol- obiiuLeC pr ojectionls at baselinle (/efit and Linidet l\peIci-ciz tJi conditions

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