Coronary Artery Reperfusion

I. EARLY EFFECTS ON LOCAL MYOCARDIAL FUNCTION

AND THE EXTENT OF MYOCARDIAL NECROSIS

P. 1{. MARIOKO, P. LIBBY, W. 1B. CINKS, C. NI. BoiOO, W. 1L. SHIEL.,B. E. SOBEr, anid J. 1()ss, Jni.

Froml the Departmenlt of Medicitne, Untive,.sity of Califo-niia, San, Dirgo,School of Medicine, La Jolla, California 920.37

A B S T R A C T The effects of coronary artery reper-fusion 3 hr after coronary occlusion on contractilefunction and the development of mvocardial damage at24 hr was studie(d experimentally. In 14 control anid 6rel)erfused dogxs relationships between epicardial STsegmiienit elevation 15 min after coronary occlusionl andmyocardial creatine phosphokinase activity ( CPK) and(Ihiistologic appearance 24 lhr later were examinied. Theelectrocardiograms were recorded from 10 to 15 siteson the left ventricular epicardiumn an(l transmuralsamples for CPK and histology were obtained from thesamiie sites wlhere epicardial electrocardiograms had beenrecordedl. AIn inverse relation existed between ST seg-mlent elevation (mxv) 15 mmin after occlusion and logCPK activity (IU/ mg of protein) 24 hr later, logCPK - 0.06ST + 1.26. In dogs subjected to coro-narv artery reperfusion, there Avas significantly lessCPK depression (log CPK =-0.01ST + 1.31, [P <0.01]) thaan that expecte(l from the control group.In the control group 97% of sl)ecimenls showiing STsegmiient elerations over 2 mv at 15 mnil showed ab-normial histology 24 hr later. In contrast, in the re-perfused group 43% of sites exhibiting elevated STsegment at 15 min showed abnormal histology 24 hrlater. In six additional dogs it was shown that theparadoxical movement of the left ventricular wall couldbe reversed within 1 hr of perfusion. Therefore, by en-

zymatic and histologic criteria, as well as by functionalassessment, coronary artery reperfusion 3 hir after oc-clusion resulted in salvage of myocardial tissue.

Received for puiblication 3 April 1972 antd it revised formii20 Jutne 1972.

INTRODUCTION

Mechanical failure of the heart mluscle currently ap-pears to be the mlaiin cause of in-hospital deatlh in pa-tients xvith acute mivocardial infarction ( 1 ). Suchcardiac failure is imiost likely the result of a largemvocar(lial infarction (2, 3), and therefore severalexperimlental apl)roaches have been exvaluated for de-creasing the size of the developing infarcts by medicaltherapy (4-l0). These approaches tend to affect favor-ably the energy balance of the heart by decreasingoxygen deman(d relative to supply or by enhancinganaerobic metabolislmi; however, a imiore direct methodof preserving myocardial cells wvould be to increaseoxygen supply by restoring blood flowv to the obstructedvessel. It is not known whether or not coronary arteryreperfusion can spare myocardial cells and restore theircontractile function. Accordingly, the present studiesundertook to examine this problem experimentally.Coronary artery reperfusion was carried out 3 hr afterocclusion. Change in left ventricular contractile functionwas assessed immediately after the reperfusion, and(alterations in the extent of damlage determiiined by myo-cardial creatine phosphokinase assay and by histologicassessment 24 hr later (4, 5). An experimental methodfor evaluating the size of the resulting myocardial in-farction at 1 wk, together with a comparison to controlanimals not subjected to reperfusion, is described inthe accompanying work ( 1).

METHODSStudies were carried out in 20 mongrel dogs anesthetizedwith sodium thiamylal. With respiration maintained mechani-

2710 The Journal of Clinical Investigation Volume 51 October 1972

cally, a lateral thoracotomy was performed through the fifthleft intercostal space and the heart suspended in a pericardialcradle. The left anterior descending coronary artery or oneof its branches was dissected free so that it could be oc-cluded. The extent and severity of myocardial ischemicinjury was assessed by an epicardial electrocardiographicmapping technique described previously (4). Briefly, themethod consists of recording electrocardiograms from 10-14anatomically recognizable sites on the anterior surface ofthe left ventricle, chosen at the onset of each experimentsuch that some would be within and others distant fromthe expected area of ischemia. Epicardial electrocardiographicmaps were obtained before and at intervals after occlusionof the coronary artery. ST segment elevation over 2 mv isconsidered abnormal (4-6), and the number of such sites(NST)1 provides an index of the exLent of ischemic injury.NST was always zero in maps obtained before occlusion.The average ST segment elevation at all sites, (ST), pro-vides an index of the severity of myocardial damage.The animals were divided into two groups: a control (14

dogs) and a reperfused group (6 dogs). In the control groupthe coronary artery was permanently occluded with a liga-ture and epicardial ST segment maps obtained before andup to 3i hr after the occlusion. The chest was then closedin layers and drained by an underwater self-retainingcatheter. The dogs were extubated and allowed to recoverbut were maintained under sedation by additional smalldoses of sodium thiamylal. Electrocardiograms (lead aVF)and arterial pressure (obtained from an aortic catheter in-serted through the left common carotid artery) were moni-tored throughout the experiment. All dogs received 40 cc/kgper 24 hr of normal saline through a catheter in the leftjugular vein. 24 hr after occlusion the animals were againanesthetized and placed on artificial respiration. The chestincision was then reopened and the heart excised.Transmural specimens from the same sites where the

epicardial electrocardiograms had been previously recordedwere immediately obtained and prepared for creatine phos-phokinase (CPK) determinations. These specimens, weigh-ing approximately 0.4 g, were submitted to homogenizationand differential centrifugation and assayed as previouslydescribed (4, 12). CPK specific activity was expressed ininternational enzyme units per milligram of protein in the31,000 g supernatant fraction. Reaction rates were linearfor at least 15 min after a 5 min equilibration period. En-zyme activity was proportional to the amount of supernatantfraction protein added to the assay system, was acid andheat labile, and duplicate determinations agreed within 3%.At the time of sacrifice transmural specimens for histologicexamination were also obtained from sites at which electro-cardiograms had been recorded. These specimens were fixedin 10%o formaldehyde solution stained with hematoxylin-eosin, coded, and graded for presence or absence or early

lAbbrevLiations used in this paper: CPK, creatine phospho-kinase; EDD, end-diastolic distance; ESD, end-systolic dis-tance; NST, number of sites exhibiting ST segment eleva-tion over 2 mv; ST, average ST segment elevation at allsites.

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FIGURE 1 The relationship of ST segment elevation 15 minafter occlusion to CPK activity and histologic structure 24hr later in an experiment in the control group. Left panel:Schematic representation of the anterior surface of theheart and it's arteries. LA, left atrial appendage; LAD,left anterior descending coronary artery. The shaded arearepresents the area of ST segment elevation 15 min afterocclusion. The circles represent sites where biopsies weretaken. Right panel: Comparison between ST segment eleva-tion and CPK and histologic analysis 24 hr later.

signs of necrosis by an independent observer as previouslydescribed (5).The reperfused group was subjected to an identical pro-

tocol except that the coronary artery was occluded tem-porarily with one or two Schwartz intracranial arterialclamps (Pilling Surgical Instruments, Fort Washington,Pa.) and the occlusion was released after 3 hr. In bothgroups, additional electrocardiographic maps were recordedat i, 1, 2, 3, and 31 hr after occlusion. At postmortemexamination, the coronary arteries were carefully openedand examined for the presence of thrombi with particularattention to the site of occlusion. Neither group receivedanticoagulant therapy. There was no evidence of a differencein the incidence of the ventricular tachyarrhythmias commonin dogs commencing 4-6 hr after coronary artery occlusion(5, 13), and neither group received antiarrhythmic therapysince these arrhythmias were well tolerated hemodynami-cally.The development of myocardial necrosis was estimated by

comparing the ST segment elevation 15 min after occlusionsat each site to the CPK activity and histologic appearanccin transmural specimens obtained from the same site 24 hrlater. This procedure was based on previous studies in whichit was established that ST segment elevation at 15 minwas inversely proportional to log CPK and therefore canbe used to reliably predict expected CPK depletion 24 hrafter occlusion (4). In a similar fashion, ST segment ele-vation 15 min postocclusion predicts with reasonable accu-racy the histologic appearance at the same site 24 hr later(i.e. a site without ST segment elevation shows normalhistology and sites with ST segment elevation of morethan 2 mv show signs of necrosis). Therefore, these ap-proaches permitted evaluation of the effects of reperfusionby observing possible deviations from the expected rela-tionships in the treated group.

Coronary Artery Reperfusion. 1 2711

FIGURE 2 An example of a reperfused dog showing theeffects of coronary artery reperfusion 3 hr after occlusionon the relationship of ST segment (at 15 min after occlu-sionl) to CPK and( histologic structure 24 hr later. Leftp(anfcl: ScheImiatic representation of the anterior surface ofthe heart and its arteries. LA, left atrial appendage; LAD,left anterior descending coronary artery; shaded area, area

of ST segment elevation 15 min after coronary occlusion(before reperfusion) ; circles, biopsy sites. Right panel:Comparison between ST segment elevation 15 min afterocclusion, i.e., before reperfusion, and CPK activity andhistologic structure 24 hr later.

In six additional dogs, the effects of acute coronary arteryocclusion and reperfusion on local myocardial contractilefunction were assessed. The dogs were anesthesized, the

heart exposed, and the coronary artery isolated as describedabove. Three or four intramyocardial radiopaque metal beads

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FIGURE 3 Relationship between epicardial ST segment ele-vation 15 min after occlusion and myocardial CPK activity24 hr later in the same sites. In the control group (solidline) log CPK = - 0.06 ST + 1.26 (r = 0.79, n = 102 speci-mens, 14 dogs). In the reperfused group (dotted line) logCPK =-0.01 ST + 1.31 (r = 0.7, 48 specimens, 6 dogs).95% confidence limits are marked; difference in slopes P<0.01.

were then inserted to lie in the left ventricular wall ap-

proximately 2 mm from the endocardium (14, 15); at leastone bead was outside the zone subserved hy the coronary

artery to be occluded, and the rest within that area. The

distance between the beads and their position in the ven-

tricular wall were verified in the excised heart at post-mortem examination. Before, and at intervals (luring and(after release of a 3 hr period of coronary artery occlusioni,biplane cineradiographs were recorded with a 16 m

Philips biplane cine system (Philips Medical Systems Inc.,Shelton, Conn.) at 200 frames per sec, the dog beingmaintained in an identical positioni throughout the perio(lof study. At the end of each experiment a 1-cm grid

was filmed in the same position occupied by the heart topermit calibration and correction for X-ray distortion. Thefilms were analyzed by identifying pairs of beads whiclhexhibited paradoxical systolic excursion during the periodof coronary occlusion, and documenting any changes thatoccurred up to 1 hr after the reperfusion. The change illthe excursion (SD), that is, the difference between theend-diastolic distance (EDD) and the end-systolic distance(ESD) between paired beads was determined. A positivedifference indicates normal ventricular motion, andl a nega-

tive difference documents paradoxical movemenit.

RESULTS

Effects of reperfusion on the development of myo-cardial necrosis

CPK activity. In the conitrol group, sl)ecimeinsfrom sites with normiial ST segments had normiialCPK activity, whereas specimens from sites withpathologic ST segment elevation always ha(l depressedICPK (Fig. 1). In the group subjected to coro-

nary artery reperfusion, sites with no abnormal STsegment elevation (0-2 myiv) showed myocardial CPKactivity at 24 hr within the normal range, as shown

in the example in Fig. 2, but sites with abnormal STsegment elevation also showed CPK activities witlinthe normal range (norimial, 18.145.2, 2 SD).

In the 14 control dogs the regression equation relat-ing ST segment elevation 15I min after occlusion toCPK 24 hr later was log CPK =- 0.06 ST + 1.26

(14 dogs, n= 102 specimens, r = 0.79, Fig. 3). In thesix reperfused dogs, ST segment elevations at each

site were comlpared to log CPK 24 hr later, and a sig-

nificantly lowNer (P < 0.01) slope was found (logCPK 0.01 ST + 1.31, r= 0.7, six dogs, 48 speci-

mens, Fig. 3). This difference in slope indicated thatreperfusion lprevente(l cells froml un(dergoing CPK de-

plletion.In all experimental animals subjected to rep)erfusioll.

when average CPK activity in all sites wvith no STsegment elevation at 15 min was compared to average

CPK in all sites which ST segment elevation at 15min, the latter mean value was 15% lower (20.8±0.5and 16.6±0.7 IU/mg of protein, respectively, P < 0.01).Therefore, despite CPK values within the normal range

in the reperfused area, there were small but significant

2712 Maroko, Libby, Ginks, Bloor, Shell, Sobel, and Ross

SITE ST CPK HISTOLOGY(mv) U mg prot

. 0 214 NORMAL

Q 0 19.9 NORMAL

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Coronary Artery Reperfusion. I 2713

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FIGURE 5 The effect of reperfusion at 3 hr on left ven-tricular wall motion. AD = EDD - ESD where EDD =

distance between beads at end diastole and ESD = distancebetween beads at end systole. Before (opeIn symbols): 3 hrafter occlusion and just before reperfusion. After (closedsymbols): 30 min after reperfusion. Squares and bars indi-cate means and SEMT.

differences between these andl control sites, values in theischemiiic zone being slightly lower after the temporaryligation.

Histologic stuidies. In 81 sites from dogs in thecontrol group examined histologicall., 27 of 28 sites(96%,> with no ST segnment elevation (< 2 mv) werenormal, while 51 of 53 (97%) of sites with abnormalST segmlent elevations showed pathologic features com-patible w-ith early myocardial infarction (Figs. 1 and4) . In the 48 specimens obtained from the reperfusedgroup, 19 of 20 (995%) of sites without ST segmentelevation showed normal histology as in the controlgroup. However, of 28 sites with abnormally elevatedST segments, only 12 sites (43%, P < 0.005) showedablnormiial histologic features (Figs. 2 and 4). Thisfinding indicates that structural integrity tended to bepreserved at 24 hr as a consequence of coronary reper-fusion at many sites otherwise destined to undergonecrosis.

Changes in ST segments after reperfusionThe epicardial ST segment elevation remained in four

dogs during the 3 hr period of coronary occlusion and de-creased greatly within 30 min after coronary reper-fusion. In the reperfused animals, average ST segmentelevation (ST) decreased from 3.6±1.0 to 0.7±0.2 myand NST from 5.5±1.7 to 1.0±0.4 within 30 min after

reperfusiOn. In oIne instan1ce a small, nonoccludin1gantemortem throimibus wvas present near the site ofprevious occlusioIn. This dog exhibited the lowest CPKvalues in the group and wN-as the only dog in whichall sites predicted to show histologic clhaniges did so.

Effect of reperfusion on myocardial contractilefunctionIn the six dogs studied cineradiographically, at

least one pIair of intranvocardial beads exhibited para-(loxical systolic excursion after 3 hr of occlusion. (Inone animal, two pairs of beads were analyzed). In each,p)aradoxical motion w\as evidenced by an average ADof - 1.7±0.7 mm (Fig. 5). Within 1 hr after reper-fusiOI significant rev-ersal of abnormal wall motion wasobserved in each instance, the average AD increasingto 4.9±-1.1 mm (P <0.01') (Fig. 5).

DISCUSSION

Recent experimental studies suggest that the amount ofacute tissue damage and consequentlynmvocardial infarctsize may be decreasedI by several interventions wlhiclfavorably chainge the oxygen requirements of the imyo-cardlium (4-10). However, measures designed to mini-mize tissue damiiage after coronary occlusion so farhave not been applied or critically evaluated clinicallv.Previous experimental studies aimed at increasing theoxygen supply to ischemic tissue by reopening an ob-structe(l coronary arterv were disappointing in pre-venting the occurrence of subsequent mvocardial infarc-tionl, as discussed in (letail in the accompanying report( 11). How-ever, the technique of aortocoronary bypass-ein grafting has proved promising clinically (16-20),and the question has again arisen as to the maximumtimle interval durinig wliclh mivocardial cells distal to acoronary occlusion can resist ischemia and whether ornot restoration of function can be accomplished. 'More-over, the question of wvhether or not the extent of(lam1iage can be mo(lifiedl by reperfusion after more than45 mnm of occlusion (21-25) has not been critically-examined.The (lexelopmiient of mietlhods for prediction of the size

of a nmvocardial infarction 24 hr after the initial occlu-sion (4 has allowed a reinvestigation of these ques-tions. The approach emiiployed predicts myocardial CPKactivity, as wvell as histological, histochemical, andultrastl-uctural changes at 24 hr (4, 5. 9), and an ex-cellent correlation has been demonstrated between in-farct size by gross anatomic measurement and myo-car(lial CPK activity ( 12). The present study indicatesthat dogs in which reperfusion was effected at 3 hr ex-hibit much less CPK depletion at 24 hr than wouldhave been predicte(l. These results are similar to previ-otis findinlgs showing that the infusion of glucose-in-

2714 Maroko, Libby, Ginks, Bloor, Shell, Sobel, and Ross

sulin-potassium solution, and propranolol, started 3 hrafter coronary occlusion limits the extent of infarction(5), althouglh to a lesser degree than reperfusion. Re-duction in epicardial ST segment elevation for up to3 hr after occlusion (4) and acute diminution in pre-cordial ST segment elevation up to 6 hr after occlusion(7) by administration of propranolol, methoxamine, ornlorepinephrine also support the contention that myo-cardial damage can be limited by intervention severallhours after occlusion. Whether or not significant differ-ences betwveen such effects, observed in the presentstudv aind these earlier investigations, will exist insp)ecies other than the dog remains to be establishedl.

It was also considered important to determine whetheror Inot reperfusion cani restore impaired myocardialfuniction. It was shown that paradoxical systolic motioncould be reversed soon after reperfusion, demonstratinga clearcut functional benefit. Reversal of dyskinesia ofthe left ventricular wall after brief periodls of inducedangiina pectoris has been reported using angiography(26) as well as apex cardiography (27). However,immiiediate improvement of function after prolongedl)eriods of ischemiiia previously has not been shown tooccur. Preliminary evidence obtained at postoperativecardiac catheterizationi studies (28) suggests that chron-icallv impaired wall motioin also may- be at least par-tiallv restored in patients who have undergone saphen-ous v-eini bypass grafting procedures.

ACGKNLEDGNIENTSThis work was supported by the National Heart and( LungInstitute, Myocardial Infarctioni Research Unit ContractNo. PH-43-68-1332.

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9716 Maroko, Libby, Ginks. Bloor. Slecll, Sobel, and Ross