Factors Influencing Infarct Size Following

Experimental Coronary Artery Occlusions

By PETER R. MAROKO, M.D., JOHN K.
KJEKSHUS, M.D., BURTON E. SOBEL, M.D.,
TAN WATANABE, M.D., JAMES W. COVELL, M.D., JoHN Ross, JR., M.D.,
AND EUGENE BRAUNWALD, M.D.

SUMMARY
The purpose of this study was the determination of whether hemodynamic and
pharmacologic factors influence the extent and severity of myocardial necrosis produced
by coronary occlusion. In 48 dogs, 10 to 14 epicardial leads were recorded on the
anterior surface of the left ventricle in the distribution and vicinity of the site of oc-
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clusion of a branch of the left anterior descending coronary artery. The average S-T
segment elevation for each animal was determined at 5-min intervals after occlusion.
This elevation was used as an index of the presence and severity of myocardial ischemic
injury. The number of sites showing this elevation provided an additional measure of
the size of the injured area. Occlusion alone raised the average S-T segment elevation
from 0.22 + 0.04 to 3.32 + 0.37 mv (SEM). Isoproterenol, ouabain, glucagon, bretylium,
and tachycardia given prior to a repeated occlusion increased the severity and extent of
ischemic injury, while propranolol decreased it. Elevation of arterial pressure with
methoxamine reduced the occlusion-induced S-T segment elevation, and lowering of
the mean arterial pressure by hemorrhage had the opposite effect. In 19 additional
experiments, propranolol, isoproterenol, and alterations in arterial pressure produced
similar alterations in S-T segment elevation when these interventions were applied
as long as 3 hr after ligation. In a third group of dogs, myocardial creatine phospho-
kinase (CPK) activity was determined 24 hr after occlusion at the same sites at which
epicardial electrocardiograms were taken. Depression of myocardial CPK activity in
injured portions of the left ventricle 24 hr after coronary artery ligation correlated
well with S-T segment elevation in the same sites 15 min after ligation. Moreover,
isoproterenol increased and propranolol decreased the area of depression of myocardial
CPK activity. We conclude that the hemodynamic status and neurohumoral back-
ground at the time of occlusion and for up to 3 hr thereafter can alter the extent and
severity of myocardial ischemic injury and myocardial necrosis.

Additional Indexing Words:

Coronary occlusion S-T segment elevation Myocardial necrosis
Epicardial electrocardiogram Myocardial oxygen consumption
Myocardial creatine phosphokinase

T HE CLASSICAL treatment of power possible therapeutic approach to this syn-

failure of the heart consequent upon drome would be an attempt to limit the size of
myocardial infarction is relatively ineffective. the infarction. Accordingly, the purpose of the
Considering that the infarct's size is an present investigation was the examination of
important determinant of power failure, a the hemodynamic conditions and pharmaco-

From the Department of Medicine, School of
Medicine, University of California, San Diego, La
Jolla, California 92037.
Supported by U. S. Public Health Service National
Institutes of Health Contract PH-43-68-1332, National
Circulation, Volume XLIII, January 1971
Institutes of Health Program Project Grant HE-12373,
and U. S. Public Health Service International
Fellowship 1 F05 TW 1428 (Dr. Kjekshus).
Received July 15, 1970; revision accepted for
publication September 8, 1970.
67
 68
logic interventions that might alter the size of
an infarct by changing the balance between
oxygen supply and demand in the area of
myocardium supplied by the occluded vessel.
Despite the important clinical implications
of limitation of infarct size, it has been
difficult to assess quantitatively the extent of
tissue damage immediately after coronary
artery occlusion. This difficulty was circum-
vented in these studies by examination of the
extent and magnitude of epicardial S-T
segment elevation in areas surrounlding the
occluded coronary artery. This technique
allowed rapid and reproducible determination
of ischemic cellular injury in the same animal,
permitting the use of each dog as its own
Downloaded from http://circ.ahajournals.org/ by guest on May 21, 2017
MAROKO ET AL.
extent of S-T segment elevation measured
with epicardial electrodes at specific myocar-
dial sites were compared with CPK activity in
myocardial specimens from these sites ob-
tained 24 hr after coronary artery occlusion.
Methods
Studies were carried out in 85 dogs weighing
between 15 and 27 kg and anesthetized with
sodium thiamylal (25 mg/kg). Respiration was
maintained with a Harvard respirator, and the
heart was exposed through a left thoracotomy and
suspended in a pericardial cradle. A branch of the
left anterior descending coronary artery, usually
the apical branch, or the main left anterior
descending coronary artery itself, was dissected
from the adjacent tissues and intermittently

occluded with two Schwartz intracranial arterial

control. However, epicardial electrocardio-
graphic changes occur very early during the
course of ischemic damage, and it has not yet
been established to what extent S-T segment
elevation presages the later development of
cellular damage. As it has been shown
recently that the reduction in myocardial
creatine phosphokinase (CPK, activity is a
quantitative indicator of the extent of cell
death 24 hr after coronary artery occlusion,' in
the present investigation the magnitude and
clamps. Arterial pressure was monitored with a
Statham pressure transducer (model P23Db). All
variables, including limb leads and the epicardial
electrocardiogram, were recorded on an oscillo-
graphic recorder.
Ten to 14 sites on the anterior surface of the
left ventricle were selected for epicardial electro-
cardiography. The limb leads were connected in
the usual fashion, and the precordial lead was
terminated in a special hollow metallic cylinder 4
mm in diameter held at a right angle to the
epicardium and connected to the standard
precordial electrode. This exploring electrode was

DOG E7
Con Occl

Site I

Sfte 7

Figure 1
(Right panel) schematic representation of the anterior surface of the heart. The coronary
arteries and branches, and sites of the epicardial electrocardiograms are marked. LAD=
left anterior descending coronary artery; LA = left atrial appendage; LC = left circumflex
coronary artery.
(Left panel) electrocardiograms from sites 1 and 7 before and 15 min after occlusion.
Circulation, Volume XLIII, January 1971
 FACTORS INFLUENCING INFARCT SIZE
held in such a way as to minimize pressure when
it was applied to the surface of the heart. Some
studies were done with the use of a cotton wick
soaked in saline and impacted in the hollow
cylinder. Epicardial recordings were obtained at
one-tenth the normal electrocardiographic sensi-
tivity (1 mv/mm recording).
Sites for recording were selected within the
area supplied by the coronary branch that was
occluded, in areas immediately adjacent to this
zone, as well as portions of the left ventricle
remote from this area which were presumed to be
adequately perfused. Since the recordings ob-
tained from each specified epicardial site had to
be repeated several times, sites were selected near
the bifurcation of arteries or veins so that the
recording probe could be easily repositioned at
the same location. Epicardial electrocardiograms
were obtained from each site before each
Downloaded from http://circ.ahajournals.org/ by guest on May 21, 2017
69
occlusion and 5, 10, 15, and 20 min after
occlusion. In 60 of the 85 dogs the occlusion was
released afterward, and further coronary occlu-
sions were not performed until the epicardial S-T
segments had returned to normal, a period of
approximately 45 min.
The S-T segment elevation at each site was
used as an index of the severity of local
myocardial injury (fig. 1). The sites at which
myocardial ischemic injury was considered to
exist were those at which the S-T segment
elevation exceeded 2 mv when recorded 15 min
after ligation. Thus, for example, in figure 2
myocardial ischemic injury was considered to be
present at sites 6, 7, 8, and 9. In each animal, the
S-T segment elevations from all recording sites
were added; this value, YS-T, was then used as an
overall index of the intensity of myocardial injury
in any given animal. The mean S-T segment

Run Intervention

0---- / occlusion
80 - v- * 2 occi * isuprel p
O----O 3 occlusion I
/
70 - *----. 4 occi * Isuprol

60 - /

EST 50-
Elevation
in mV 40 -

30 -

20 -

10 -

I
CONTROL 5 10 15 20
TIME - minutes
Figure 2
Effects of occlusion alone and occlusion after the infusion of isoproterenol (0.25 ,ug/kg/min).
(Right panel) abbreviations as in figure 1. Cross-hatched area. area of injury after 15 min
of occlusion. Stippled area: increase of area of injury when the occlusion was performed
under the influence of isoproterenol. Lined area: area that showed no ST segment elevation
under any circumstances.
(Left panel) 2ST in the same experiment after two simple occlusions and after two occlu-
sions under the influence of isoproterenol. Time = minutes after occlusion.
Circulation, Volume XLIII, January 1971
 70
elevation in any dog (S-T) was calculated as the
quotient of IS-T and the total number of sites,
and changes in the average S-T for a group of
animals analyzed by the paired t-test technique
were used to determine the effects of a variety of
interventions on the severity of myocardial
ischemic injury.
The animals were divided into three groups. In
the first group (48 dogs), the effects of acute
interventions were studied. In all groups the
experimental protocol was similar. A control
occlusion was carried out with epicardial record-
ings just before, and 5, 10, 15, and 20 min after
occlusion. After release of the occlusion and
return of the aortic pressure, heart rate, and
epicardial electrocardiogram to control values,
one of eight interventions was employed:
(1) An infusion of isoproterenol (0.25-0.50
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gg/kg/min) was begun 5 min before occlusion
and maintained during the occlusion (nine
experiments).
(2) Heart rate was increased by an average of 62
beats/min by right atrial stimulation (three
experiments).
(3) Propranolol (0.5, 1.0 or 2.0 mg/kg) was
administered intravenously 5 min before occlu-
sion (eight experiments).
(4) Methoxamine (0.01-0.05 mg/kg/min) was
infused for augmentation of the mean arterial
pressure; the infusion was begun 5 min before
occlusion and maintained during occlusion
(eight experiments).
(5) Arterial bleeding was carried out before
occlusion so that mean arterial pressure might
be reduced (six experiments).
(6) Glucagon (5-20 ,g/kg) was administered
intravenously 5 min before occlusion (four
experiments).
(7) Bretylium tosylate (5 mg/kg) was adminis-
tered intravenously 30 min before occlusion
(two experiments).
(8) Ouabain (0.03 mg/kg) was administered
intravenously 5 min before occlusion (six
experiments).
In the second group (19 dogs), coronary
occlusion was maintained for 3 hr, and the
effects of isoproterenol (two experiments), pro-
pranolol (six experiments), and methoxamine or
phenylephrine HCI (11 experiments) on the
epicardial electrocardiogram were then deter-
mined while the occlusion was maintained.
In the third group (18 dogs), the correlation
between S-T segment elevation 15 min after
occlusion and CPK depletion 24 hr later was
studied. In the first subgroup (six dogs), which
was not subjected to any pharmacologic inter-
ventions, epicardial electrocardiograms were re-
corded at 5-min intervals after coronary occlusion;
the thorax was closed and the animal was allowed
MAROKO ET AL.
to recover. Twenty-four hr later, another thora-
cotomy was performed, and the heart was quickly
removed. Full wall thickness myocardial speci-
mens (approximately 500 mg) were obtained as
previously described1 from the same sites from
which epicardial recordings had been obtained 24
hr previously.
In the second subgroup (12 dogs) the effect of
drug interventions was studied. A control occlusion
was performed in each animal for 20 min and
epicardial electrocardiograms were recorded. Af-
ter release and return of the electrocardiogram to
control values, a second occlusion was carried out.
Commencing 5 min before the second occlusion,
which was maintained for 24 hr, isoproterenol or
propranolol was administered intravenously to six
dogs each. The dosage regimen for isoproterenol
was 0.25-0.5 ,ug/kg/min for 3-5 hr. Propranolol
was given in a dose of 0.5-2.0 mg/kg initially,
followed by 0.5 mg/kg at 4-hr intervals for a total
of 12 hr. The electrocardiograms were taken in
the usual manner, and the chest was closed; the
procedures followed were as in the first subgroup.
Chemical Procedures
All chemicals were of the highest grade
commercially available, and were prepared for
use in doubly distilled deionized water. CPK
standard was obtained from Worthington Bio-
chemical Corporation. Creatine phosphate,
glucose-6-phosphate dehydrogenase, nicotine ade-
nine dinucleotide phosphate, sodium adeno-
sine diphosphate, sodium adenosine monophos-
phate, and hexokinase were obtained from
Calbiochem. Cysteine hydrochloride and bovine
serum albumin were obtained from Sigma
Chemical Company. Ventricular myocardium was
homogenized as previously described' and CPK
activity was assayed in the 16,000 x g superna-
tant fraction spectrophotometrically according to
the method described by Rosalki.2 Diluents and
assay conditions were exactly the same as those
described previously.' CPK activity was ex-
pressed as International Units (IU) (,umoles of
substrate converted per min) per mg of super-
natant fraction protein. Reaction rates were linear
for at least 15 min after an equilibration period of
5 min; activity was proportional to the quantity of
supernatant fraction protein added to the assay
system; enzyme activity was acid and heat labile;
and results of duplicate determinations of enzyme
activity agreed within 3%.
Results
The Effects of Coronary Occlusion
After coronary occlusion, an area of the left
ventricle that was cyanotic and bulged during
systole could be observed in most experiments.
Circulation, Volume XLIII, January 1971
 FACTORS INFLUENCING INFARCT SIZE
The correlation between this area and the area
of myocardial ischemic injury as reflected in
the S-T segment elevation was excellent. Also,
the interventions, which altered the area of
severe myocardial ischemic injury, affected the
area of visible cyanosis in a parallel fashion.
Figure 1 shows the results of an occlusion of
a branch of the left anterior descending
coronary artery. Site 1, which was remote
from the site of occlusion, showed no evidence
of S-T segment elevation before or during
occlusion, while site 7, well within the area of
distribution of the occluded vessel, showed a
7-mv elevation of the S-T segment 15 min
after occlusion. In the experiment illustrated
in figure 2, epicardial recordings were ob-
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tained at 14 sites. In Run no. 3 IS-T increased
from a control value of 7 mv before occlusion
to 24 mv 15 min after ligation. In the 48 dogs
studied, the average S-T segment elevation
increased from 0.22 + 0.4 mv (SEM) before
occlusion to 3.22 ± 0.37 mv (P < 0.001) 15
min after occlusion, while the average number
of sites showing S-T segment elevation exceed-
ing 2 mv rose from 0.0 to 3.6 + 0.4 (P <
0.001).
The reproducibility of the S-T segment
elevation was studied in nine experiments in
which two 20-min periods of simple occlusion
were carried out in the same dog with an
intervening period of 1 hr during which the
occlusion was released. The epicardial sites at
which ischemic injury was present 15 min
after occlusion were identical, and the average
S-T segments for the group were 4.2 + 1.0 and
3.9 ± 1.0 mv during the first and second
occlusions, respectively (P > 0.3, fig. 3). More-
over, after recovery from an intervention where
repeated "control" occlusions were performed
(fig. 2, runs 1 and 3), the magnitudes of the S-
T segment elevations were similar.
Effects of Isoproterenol
The infusion of isoproterenol (0.25-0.50
gg/kg/min) elevated heart rate from 136+7
to 179 + 12 beats/min and lowered mean
arterial pressure from 116+8 to 99±9 mm
Hg. After a stable hemodynamic state was
achieved and while the isoproterenol infusion
Circulation, Volume XLIII, January 1971
71
was continued, coronary occlusion was re-
peated. In each dog, the number of sites of
severe myocardial ischemia increased and the
extent of the S-T segment elevation at any
particular affected site was augmented. More-
over, the effects of isoproterenol were repro-
ducible, resulting in similar increases in S-T
segment elevation when separate infusions
and coronary occlusions were done (fig. 2,
runs 2 and 4). With 20-min periods of
coronary artery occlusion, isoproterenol did
not appear to produce irreversible damage;
thus, the S-T segments became isoelectric
after release of the ligation and cessation of
isoproterenol; reocclusion then produced S-T
segments similar to those during the first
control occlusion (fig. 2, runs 1 and 3).
In the 12 experiments performed in nine
animals, the average S-T 15 min after
occlusion increased from 1.6 ± 0.4 mv during
the control occlusions to 6.8 ± 1.1 mv after
ligation during isoproterenol infusion (P <
0.01) (fig. 3), and the number of sites of
ischemic injury increased from an average of
2.2+ 0.9to7.0± 1.1 mv (P<0.01).
When an infusion of isoproterenol (0.25
gg/kg/min) was begun 3 hr after coronary
occlusion, in two dogs the S-T rose from 0.4 to
3.3 mv and from 1.7 to 8.3 mv, respectively.
X OCCLUSION ALONE
* OCCLUSION + ISOPROTERENOL
i OCCLUSION .OUABAIN
E5OCCLUSION +GLUCAGON
1 2 OCCLUSION +PROPRANOLOL
O
5 OCCLUSION + HEMORRHAGE
a OCCLUSION + METHOXAMINE
8-
avg ST6
in mV
4-
2i
0
9 9 4 68 6 8
Figure 3
Summary of results. Influence of repeated occlusions
under the influence of isoproterenol, ouabain, glucagon,
propranolol, hypotension, and hypertension on the
average ST segment elevation (ST) after an occlusion.
Bars represent standard errors of the mean. Figures
below columns indicate number of experiments.
 72 MAROKO ET AL.

DOG E9
A Run /nlervention HR
o-G / occlusion /70
* * 2 occl */supre/ 204
o-a 3 occl *pacing 205

40

30
EST
Elevation
in mV
20
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10

TIME-minutes
E95 * * OCCL. ALONE
B 60 -

O- ---- OCCL. + PROPRANOLOL

50 -

40-

E
I- 30-
U,4

20- --

1-0- -
-0

10-

0- g 1 1
Control 5 10 i5 20
TIME (minutes)
Figure 4
(Panel A) effects of tachycardia and isoproterenol. IST = sum of ST segment elevations.
(Panel B) effects of propranolol.

Effects of Simple Tachycardia the effects produced by this drug in three

In order to identify the specific contribution separate experiments, we elevated the heart
of the tachycardia induced by isoproterenol on rate by electrical stimulation by an average of
Circulation, Volume XLIII, January 1971
 FACTORS INFLUENCING INFARCT SIZE
62 beats/min to a level similar to that which
had been previously produced by isoprotere-
nol infusion, and the effects of coronary
occlusion were again studied. In each instance
pacing-induced tachycardia augmented the S-
T segment elevation produced by occlusion
(fig. 4A; compare runs 1 and 3), but did so to
a lesser extent than when similar levels of
heart rate had been achieved with isoprotere-
nol (fig. 4A; compare runs 2 and 3).
Effects of Ouabain
Ouabain (0.03 mg/kg) administered 5 min
before occlusion, did not alter the arterial
pressure and heart rate existing 15 min after
occlusion. Generally, ouabain depressed the S-
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T segments at sites remote from the occluded
vessel but despite this effect of the drug, the
average S-T segment elevation increased from
2.2 0.8 to 4.1 1.2 mv (P <0.01), and the
number of sites with S-T segment elevations
exceeding 2 mv increased from an average of
5.0 + 1.7 to 7.2 + 1.4 (P < 0.025) (fig. 3).
Effects of Propranolol
Propranolol (0.5-2.0 mg/kg), admini-
stered to eight animals, reduced heart rate
from an average control level of 130 + 6 to
111 + 4 beats/min; systemic arterial blood
pressure was not significantly altered. Coro-
nary occlusion carried out in the presence of
propranolol resulted in a decrease in the
average S-T segment elevation from control
levels of 3.9 0.9 mv after simple occlusion to
1.6 0.8 mv after occlusion carried out
following the administration of propranolol
(P< 0.01) (figs. 3 and 4B). The number of
sites with S-T segment elevations exceeding 2
mv declined from 5.4 + 0.6 to 1.1 0.5
(P < 0.01). In two additional experiments,
heart rate was maintained constant by electri-
cal stimulation, and propranolol was found to
reduce the S-T segment elevation 15 min after
coronary occlusion to 33% and 40% of the levels
observed after the control occlusions.
In the six experiments in which propranolol
(1.0 mg/kg) was infused 3 hr after coronary
occlusion, the average S-T segment elevation
decreased from 7.6 + 1.8 to 4.9 + 1.3 mv
(P<0.01).
Circulation, Volume XLIII, January 1971
73
Effects of Glucagon
Glucagon (5-20 ,g/kg), administered to
four animals increased IS-T segment elevation
as well as the area of ischemic injury. Fifteen
min after occlusion the average S-T segment
was increased from a control value of
3.4 + 1.8 to 8.0 + 4.1 mv (fig. 3), and the
number of sites of ischemic injury rose from
an average of 3.5 1.0 to 6.0 0.4. Moreover,
when heart rate was maintained constant by
atrial stimulation, glucagon still increased the
IS-T and the number of sites showing an S-T
segment elevation of more than 2 mv.
Effects of Bretylium
After a control occlusion in two dogs,
bretylium tosylate* (5 mg/kg) was given
slowly intravenously, and 30 min later coro-
nary occlusion was repeated. The average S-T
segment elevation increased from 1.4 to 3.0
mv, while the number of sites of myocardial
ischemic injury rose from 2.5 to 8.0.
Effects of Varying Arterial Pressure
Arterial hypertension was produced in eight
experiments by the infusion of methoxamine
(0.01-0.05 mg/kg/min) (fig. 5B and D).
Mean arterial pressure was elevated from
116 8 mm Hg during the control occlusion
to 189 6 mm Hg 15 min after coronary
occlusion during methoxamine infusion, while
the corresponding heart rate fell from 123 1
to 109 + 8 beats/min. The average S-T 15 min
after occlusion decreased from 4.9± 1.3 mv
during the control occlusion to 1.6 0.6 mv
(P < 0.01) 15 min after occlusions carried out
during methoxamine infusion (fig. 3), while
the number of epicardial sites showing severe
ischemic injury declined from 4.4 0.9 to
2.1±0.9 (P<0.025).
In six experiments arterial hypotension was
produced by acute arterial hemorrhage (fig.
SA and C). Mean arterial pressure fell from
an average of 140 + 11 to 63 + 10 mm Hg,
while heart rate decreased from an average of
146 10 to 123 + 11 beats/min. The average
*Kindly supplied by Burroughs-Wellcome Labora-
tories.
 74

Run
/---
1

*ST 50-
A
occlusion

Elevation 40-
in mV 30/
70-
60
DOG E45
InlerventionBP HR
220/140(170) /80
- @ 2 occI.*emorrhoge 15/;70(90) /40
O-o /
.
Run

SST 501
60-

Elevotion 40
in mV 301_
B
Intorvntfion
occlusion
DOG E47

*- *2 occ/.*methoxomine 250/160(200) W
70-
MAROKO ET AL.

BP HR
/15/85(95) /0

20-
10-
0 5 . a . 5
control 5 10 15 2 0
TIME - minutes TIME- minutes
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CEFFECT OF HYPOTENSION
D
EFFECT OF HYPERTENSION
100-
90-
80-
:EST 70-
Elevation :ST 60-
in mV Elevation 50-
in mV 40-
30-
20-
10-

2060
'
1oO0 140 I8o
W . . 1a

20
1
a

I do11
a

60
a
a1 11
A

140 fIS -0
. o 5
Mean Arterial Blood Pressure - mmHg Meon Arterial Blood Pressure - -mmHg
Figure 5
Influence of arterial blood pressure. (Panel A) effects of hypotension on IST segment eleva-
tion after coronary occlusion. (Panel B) effects of hypertension on YEST segment elevation
after coronary occlusion. (Panel C) summary of results in all experiments in which hypoten-
sion was induced. Each line connects two points that represent 2sST at 15 min after occlusion,
when performed before and after bleeding in the same dog. (Panel D) summary of results
in all experiments in which hypertension was induced. Each line represents the 2ST at 15
min after occlusion when performed before and after methoxamine infusion in the same dog.

S-T 15 min after coronary occlusion increased
from 2.8 + 1.2 mv during the control occlusion
to 9.0 + 3.4 mv during hemorrhagic hypoten-
sion (P<0.01) (fig. 3), and the number of
sites exhibiting ischemic injury increased from
1.8+ 0.7to6.3± 1.1 (P<0.01).
In four experiments the effects of three or
four levels of arterial pressure on the IS-T 15
min after coronary ligation were examined. An
inverse relation between the arterial pressure
and YS-T segment elevation was noted in each
experiment (fig. 6A). The regression equation
for all of the experiments in which arterial
pressure was altered was
Circulation, Volume XLIII, January 1971
 FACTORS INFLUENCING INFARCT SIZE 75

A EFFECT OF ARTERIAL BLOOD PRESSURE portion and a corresponding outer portion.

Values obtained were similar: 20.1 ± 1.8 and
19.7 + 1.4 lU/mg, respectively (mean + SEM;
N =8; samples from eight separate dogs).
A representative experiment demonstrating
SST
Elevation
the correlation between S-T segment ele-
in mV vation and myocardial CPK activity de-
pression is illustrated in figure 7. Near
the border of the infarcted area, both S-T
segment elevation and CPK depression 24 hr
later were smaller than those in the center of
the infarcted area, where S-T segment eleva-
Et 0z 30
tion and CPK activity were maximally altered.
0
The relationship between the increase in S-T
w 2 segment elevation 15 min after ligation and
the decrease in myocardial CPK activity 24 hr
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later was studied in multiple corresponding

_i
J i - specimens from six dogs. S-T segment eleva-
tions greater than 2 mv were invariably
Kt associated with a decrease in myocardial CPK
zo
activity 24 hr later. The inverse relationship
C I30-
LLC
_i
CO 60 120 180 240 30
TIME (minutes)
Figure 6
(Panel A) relationship between arterial pressure and
myocardial injury. mST 15 min after an occlusion at .10 .5
three to four different levels of mean arterial ptres- 100I
sure. Each line represents one animal.
It
be
CL. 8.=
(Panel B) influence on myocardial injury of methox-
amine administered 3 hr after occlusion. Black bar ;o t 6 _2"W 0

represents infusion of methoxamine (0.015 mg/kg).

cm 1 -4 al,
W
cn
ES-T (mv) = 0.36 MAP + 75.4 LL

where MAP = mean arterial pressure in mm
Hg (r = 0.69; P < 0.01).
In 11 experiments in which arterial blood
pressure was elevated from 112 ± 4 to 168 ± 5
mm Hg by methoxamine or phenylephrine
HC1 3 hr after coronary ligation, the average
S-T decreased from 4.3 + 0.4 to 2.2 ± 0.5 mv
(P<0.01) (fig. 6B).
Correlation of Epicardial S-T Segment
Elevations and Myocardial
CPK Depletion
In the normal animal, the variation of CPK
activity in multiple transmural specimens from
divergent sites in the same heart averaged 6%.
CPK activity was measured in samples from
the myocardial wall, divided into an inner
Circulation, Volume XLIII, January 1971
_12 en
SITE OF SPECIMEN
Figure 7
The correlation between epicardial ST segment ele-
vation and subsequent CPK depression in correspond-
ing samples from a representative dog subjected to
coronary artery occlusion. Epicardial ST segment ele-
vation (o) was measured 15 min after coronary artery
occlusion, and the per cent myocardial CPK depres-
sion (c) based on myocardial CPK activity in normal
tissue from the same animal was determined 24 hr
later. Actual values for myocardial CPK activity from
each site are indicated in the open circles at the top
of the figure. The sample site represented on the
abscissa is indicated on the diagram at the top of the
figure.
 76 MAROKO ET AL.
A B
30

20 20

1 0N
1F0 8

8 6N

6 c

-Z log CPK 1.27 -0.065 STA

2 r =-0.87

0 24 6 810 1214 0 4 8 12 16

ST-SEGMENT ELEVATION (mV) ST-SEGMENT ELEVATION (MV)

Figure 8
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(Panel A) depression of myocardial CPK activity and epicardial ST segment elevation. Epi-
cardial recordings were obtained 15 min after coronary artery occlusion from readily identi-
fiable sites. CPK activity was measured in homogenates from full wall specimens obtained
from the same sites 24 hr later, and is expressed on a logarithmic scale. Multiple samples
were obtained from six dogs. Corresponding symbols represent samples from the same dog.
(Panel B) depression of myocardial CPK activity after administration of isoproterenol and
propranolol in animals with coronary artery occlusion. Data from multiple samples from six
animals given isoproterenol and from six animals given propranolol. Line A: regression line
for control study (see panel A), (log CPK = 1.269 0.065 ST; r -0.87). Line B: regression
-

line relating ST segment elevation after coronary artery occlusion before isoproterenol was
given, and log CPK from myocardial sites that showed increased ST segment elevation dur-
ing isoproterenol infusion (log CPK = 1.080-0.076 ST; r=-0.80). Thus, in animals that
had received isoproterenol, depression of myocardial CPK activity was greater than that
which would be expected from ST segment elevation occurring prior to isoproterenol in-
fusion. Line C: regression line for ST segment elevation after coronary artery occlusion be-
fore the propranolol was given and log CPK from corresponding sites 24 hr later (log CPK =
1.302 0.035 ST; r =-0.53). Thus, in animals that had received propranolol, depression of
-

myocardial CPK activity was less than that which would be expected from ST segment ele-
vation occurring prior to drug administration.

between the two approximated
curve:
log CPK = 1.27-0.065 S-T
(r =-0.87; P < 0.01) (fig. 8A). In myo-
cardium clearly not supplied by the
ligated coronary artery, S-T segment elevation
was consistently less than 2 mv, and CPK
activity in corresponding sites measured in six
dogs was 18.2 0.5 IU/mg protein (N = 27),
not differing significantly from that in myocar-
dium from four unoperated control animals
(18.2 + 0.9 IU/mg protein; N = 20).
The Influence of Isoproterenol and
Propranolol on CPK Depression
Administration of isoproterenol (0.25-0.5
,ug/kg/min for 5 hr) did not lead to
subsequent depression of myocardial CPK
an exponential activity in nonischemic tissue from dogs with
coronary artery occlusion. Activity in samples
of nonischemic tissue from six animals treated
with isoproterenol averaged 19.4 + 0.5 IU/mg
(N = 25 samples), compared to 18.2 0.5
IU/mg (N = 27 samples) in nonischemic
tissue from six animals receiving no drug (fig.
9). A representative experiment demonstrat-
ing the effects of isoproterenol is illustrated in
figure 1OA. In several sites with an S-T
segment elevation of less than 2 mv during
control occlusion, as indicated by the asterisks
in figure IOA, there was a marked increase in
S-T segment elevation during isoproterenol
infusion. The increase in S-T segment eleva-
tion associated with administration of isopro-
terenol over and above that produced by
Circulation, Volume XLIII, January 1971
 FACTORS INFLUENCING INFARCT SIZE
24
C-)
:x-)
-J
ca
Z7
E.
C- P The regression line relating CPK depression to
C)X ?5
c:r
C>
Downloaded from http://circ.ahajournals.org/ by guest on May 21, 2017
0 5
ST-SEGMENT ELEVATION ( mV)
Figure 9
Augmentation of the area of epicardial ST segment
elevation and myocardial CPK depression after coro-
nary artery occlusion accompanied by isoproterenol.
Values represented are means + SEM. (e) = values in
nonischemic tissue from six dogs receiving no iso-
proterenol. (o) = values from sites without ST seg-
ment elevation in animals subjected to coronary artery
occlusion and given isoproterenol. (A) = values in the
same animals from sites with no ST segment eleva-
tion after coronary artery occlusion alone but with ST
segment elevation after occlusion plus isoproterenol
administration. The results demonstrate that myo-
cardial CPK depression occurred in these sites within
24 hr.
coronary artery ligation alone, is reflected by
corresponding changes in myocardial CPK
activity. It can be seen that CPK depression
after administration of isoproterenol was
significantly greater (P < 0.05) than that
which would have been expected on the basis
of S-T segment elevation after coronary artery
ligation but before isoproterenol administra-
tion (fig. 8B). This point is demonstrated also
by data represented in figure 9. Specimens
from portions of the myocardium with normal
S-T segments after coronary artery occlusion
before isoproterenol was administered, but
with elevated S-T segments during administra-
tion of the drug, clearly demonstrated a
depression of CPK activity 24 hr later
(P <0.001).
Administration of propranolol after coro-
Circulation, Volume XLIII, January 1971
77
nary artery occlusion led to a marked
reduction in the extent and magnitude of S-T
segment elevation compared with that result-
ing from coronary artery occlusion alone and
to lesser depression of CPK activity (fig.
LOB). With propranolol the extent of depres-
sion of myocardial CPK activity was signifi-
cantly less than that anticipated from the
magnitude of S-T segment elevation produced
by coronary artery occlusion alone (fig. 8B).
S-T segment elevation in control animals
differed significantly (P<0.05) from that
relating CPK depression after propranolol to
S-T segment elevation before administration
of the drug. Thus, tissue damage after
administration of propranolol was reduced
compared to that anticipated from the S-T
segment elevation after the control occlusion.
Discussion
There is some evidence to suggest that
factors that influence myocardial oxygen
demands may aggravate or alleviate symp-
toms of myocardial ischemia.3 For example, in
patients with angina and hyperthyroidism
treatment of the hypermetabolic state, and the
associated reduction of myocardial oxygen
needs, is often associated with relief of
angina.4 Also, the reduction of myocardial
oxygen needs produced by beta-adrenergic
blockade5 or carotid sinus nerve stimulation6
reduces symptoms of myocardial ischemia.
Conversely, treatment of hypothyroidism or
the development of tachycardia, influences
that increase myocardial oxygen needs, in-
creases the frequency and severity of
myocardial ischemia in patients with coronary
artery disease. The importance of the de-
creased availability of oxygen is apparent in
cases where arterial hypotension and acute
anemia may cause infarction in the absence of
coronary occlusion.7 These clinical observa-
tions suggested to us that hemodynamic and
pharmacologic stimuli might alter the extent
of myocardial ischemic injury and infarction
after coronary occlusion, and the present
investigation was designed for exploration of
this possibility.
 78 MAROKO ET AL.
The epicardial electrocardiographic tech-
A nique utilized in this study overcomes several
difficulties inherent in other methods8 for
study of this problem. Since observations are
carried out in the same heart and at the same
ou
S.' 100 20 o; epicardial sites, the influence of variations of
_ CO
>. 0.6 coronary arterial distribution among different
0~ 80 16 E ° animals is eliminated, and each dog can serve
f- Z t as its own control. The constant number of
60 12 c> 4
C)
sites showing elevations of the S-T segment
I-
40 8 W and the small variations in the magnitude of
S-T segment elevation during repetitive occlu-
20 4 a ° sions attest to the reproducibility of this
C.
UJ

c0
'n g-
C>
method.
0
1 There is considerable evidence that the
epicardial S-T segment elevation directly
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reflects myocardial cellular injury. Wegria and

B associates9 reported that the degree of S-T
segment elevation is dependent on the severity
P- of experimentally produced coronary constric-
Q-
C.>
100 tion, thus indicating that this electrocardio-
Za graphic finding reflects myocardial injury. A
:W
80 8 o= C>
., CL- correlation between the magnitude of ische-
60 6 __,. mic alteration of myocardial cellular mem-
40
Co

4 W
o brane potentials and the height of the
.-
n
r_
20 2
4
X
'a
-
0
.>
SITE OF SPECIMEN
Figure 10
(Panel A) correlation between epicardial ST segment
elevation after coronary artery occlusion before (A)
and during (A) isoproterenol infusion and subsequent
CPK depression. CPK activity was measured in cor-
responding specimens 24 hr later (-), and is expressed
as per cent of activity in nonischemic tissue from the
same animal. Actual values for myocardial CPK ac-
tivity from each site are shown in the open circles at
the top of the figure. Depression of CPK activity
correlates more closely with the pattern of epicardial
ST segment elevation after isoproterenol infusion than
with that seen prior to drug administration. Asterisks
indicate points exhibiting no ST segment elevation
before administration of isoproterenol, but definite ST
segment elevation during drug administration. CPK
activity was depressed in these regions, indicating ad-
ditional tissue damage associated with isoproterenol
administration.
(Panel B) correlation between epicardial ST seg-
ment elevation after coronary artery occlusion before
(A) and during (A) propranolol administration and
epicardial S-T segment has been demonstrat-
ed.10 Sayen and his collaborators" -'4 found a
poor correlation between S-T segment eleva-
tion and intramyocardial P02 immediately
after coronary occlusion, but reported that 5
min after occlusion the sites at which S-T
segment elevation occurred correlated well
with those at which PO, were reduced.12
Scheuer and Brachfeld's reported a close
correlation between S-T segment elevation
and the development of anaerobic metabolism
when coronary blood flow was reduced.
Results obtained in this investigation dem-
onstrate a close correlation between the extent
and magnitude of early elevation of S-T
subsequent CPK depression. (-) = same as in panel A.
Depression of CPK activity correlates more closely
with the pattern of epicardial ST segment elevation
after propranolol administration than with that seen
after coronary artery occlusion alone. Asterisks indi-
cate points with striking ST segment elevation before
propranolol was given, but marked reduction of ST
segment elevation during administration of the drug.
CPK activity in corresponding specimens was normal,
indicating a protective effect produced by propranolol.
Circulation, Volume XLIII, January 1971
 FACTORS INFLUENCING INFARCT SIZE
segments in epicardial recordings after acute
coronary artery occlusion and the later devel-
opment of cellular damage, as evidenced by
depression of myocardial CPK activity in
specimens from the same sites. In contrast to
many enzymes, CPK activity is found predom-
inantly in skeletal and cardiac muscle cells.
Accordingly, the activity of this enzyme in
infarcted heart muscle is less likely to be
influenced by other cellular components par-
ticipating in the inflammatory reaction after
coronary artery occlusion. This is supported
by recent evidence showing that decrease of
myocardial CPK activity correlates closely
with the amount of cell death in rabbits
subjected to coronary artery occlusion.' All of
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these considerations, taken together, suggest
strongly that epicardial S-T segment elevation
is the result of ischemic cellular injury and
that its persistence presages the ultimate
development of myocardial necrosis.
There is substantial evidence, based on
histological, electron microscopic, and histo-
chemical studies, that irreversible injury does
not occur within 20 min of coronary
occlusion,1621 and the total disappearance of
epicardial S-T segment elevation after release
of the occlusion in the present studies is
consistent with these findings. Therefore, it
was possible to compare the effects of several
different interventions on the severity and
extent of ischemic injury after repetitive
occlusion of the same coronary artery.
A number of stimuli,22 not necessarily
associated with myocardial ischemic injury,
such as changes in the ionic milieu of the
myocardium23' 24 and stimulation of specific
areas within the central nervous system25 and
of the stellate ganglia,26 have been shown to
produce alterations of the S-T segment.
However, the S-T segment elevations pro-
duced in this study by inotropic drugs and
hypotension were not of the nonischemic type,
since they were not observed in portions of
the left ventricle remote from that perfused by
the occluded artery.
The present investigation indicates that
factors that influence the balance between
myocardial oxygen supply and demand can
Circulation, Volume XLIII, January 1971
79
substantially alter the extent of myocardial
ischemic injury when a coronary vessel is
occluded. Myocardial oxygen consumption
was increased by augmentation of cardiac
contractility27 by the use of several stimuli,
including the administration of isoproterenol,
glucagon, bretylium, and ouabain, and the in-
duction of tachycardia. All of these influences
increased the area of ischemic injury and the
magnitude of S-T segment elevation. In
contrast, an intervention that lowered myocar-
dial oxygen consumption (i.e., the administra-
tion of propranolol ) 28 decreased the extent
and magnitude of S-T segment elevation after
coronary occlusion. Since these various inter-
ventions alter myocardial contractility by a
variety of mechanisms," it is very likely that
it is the change in oxygen consumption per se,
rather than the specific interventions, that
were responsible for the corresponding
changes in the magnitude and extent of
ischemic injury.
Isoproterenol in doses higher than those
used in this study has been shown to produce
myocardial necrosis directly,30 and the possi-
bility must be considered that this agent might
have produced electrocardiographic changes
even in the absence of coronary occlusion.
However, with the concentrations of isoprote-
renol employed, epicardial sites remote from
those supplied by the occluded coronary
artery did not show changes in the epicardial
S-T segment, indicating that isoproterenol did
not produce ischemic injury in normal tissue.
Also, the studies of Raab et al.,3 31 in which
catecholamine stimulation in the presence of a
constant coronary flow produced epicardial S-
T segment elevations, are consistent with our
findings. Moreover, the dose of isoproterenol
used in the present study did not influence
CPK activity in nonischemic myocardium,
although doses in this range do lead to
increased lactate production in experimental
infarction produced by microspheres.32
Findings in the present study demonstrate
further that the augmentation of S-T segment
elevation following isoproterenol infusion af-
ter coronary artery ligation is associated with
a more profound depression of myocardial
 so
CPK activity. In specimens from myocardial
sites that had normal S-T segments after
simple ligation but that exhibited S-T segment
elevations after isoproterenol administration,
the CPK activity was only two-thirds of that
found in corresponding marginal sites in
animals with coronary artery occlusion alone
(fig. 9). Thus, it is apparent that under these
conditions, infusion of isoproterenol not only
alters the epicardial electrocardiogram but
also results in an increment of cell death,
evidenced by myocardial CPK depression.
It might be argued that myocardial CPK
depression after isoproterenol infusion may
reflect increased washout of the enzyme.
However, this is unlikely since virtually no
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further depletion of CPK takes place after 24
hr. Although CPK depletion may be flow
dependent soon after coronary occlusion,38
the linear relationship obtained between
relative regional perfusion and CPK depletion
24 hr after coronary artery ligation' suggests
that washout is not a major factor influencing
myocardial CPK levels after 24 hr.
Digitalis glycosides ordinarily depress the S-
T segment, and indeed in this study, such
changes were generally induced by ouabain in
areas of the myocardium supplied by unoc-
cluded vessels. In spite of this effect of the
glycoside, it produced a significant increase in
the area of ischemic injury and in the
magnitude of the S-T segment elevation after
coronary occlusion. Since glycosides normally
tend to depress the S-T segment, the intensifi-
cation of ischemic injury produced by the
ouabain may actually have been underesti-
mated by the technique employed in this
study.
In contrast to the influence of positive
inotropic agents, increase of arterial pressure,
which also augments myocardial oxygen con-
sumption, was found to decrease the extent of
ischemic injury while arterial hypotension,
which reduces the heart's oxygen needs, had
the opposite effect. From these observations it
appears that, in the presence of coronary
occlusion, the changes of coronary perfusion
pressure exert a greater and opposing influ-
ence on the extent of myocardial ischemia
MAROKO ET AL.
than do the changes in myocardial oxygen
consumption resulting from the arterial pres-
sure change. This finding is not surprising
since, in studies on the effects of alterations in
arterial pressure on the relation between
myocardial oxygen consumption and coronary
blood flow, it was shown that elevation of
arterial pressure increases coronary flow pro-
portionately more than myocardial oxygen
consumption.34 The latter observation, as well
as the dependence of the collateral flow upon
coronary perfusion pressure,35 could explain
the decrease in ischemic injury when arterial
pressure was elevated in the presence of
coronary occlusion. Conversely, coronary
blood flow is known to fall abruptly when
perfusion pressures decline below 60-70 mm
Hg,36 and the fact that this decline is
proportionately greater than the accompany-
ing reduction in myocardial oxygen consump-
tion could explain the observed extension of
the area of ischemic injury associated with
hypotension. Moreover, Corday et al.37' 38
showed that elevation of arterial pressure in
hemorrhagic hypotension in dogs augmented
both anterograde and collateral coronary flow.
These observations led to the treatment of
cardiogenic shock in man with vasoconstrictor
drugs.
Some comment concerning the extrapola-
tion of the results of these studies to acute
coronary occlusion in man are warranted.
Obviously, the fact that in these experiments
one coronary vessel is occluded while the
remaining vessels are entirely normal differs
from the clinical situation in which coronary
vascular involvement is usually more exten-
sive. While in the normal dog the number and
size of coronary collateral vessels greatly
exceed those occurring in normal man, the
relatively abundant collateral vessels in the
dog do resemble those occurring in patients
with coronary artery disease, and in this
respect the experimental observation on the
effects of various stimuli on the extent of
myocardial ischemic injury may have consid-
erable clinical relevance.
The present studies suggest that tachycardia
and/or hypotension occurring in a patient
Circulation, Volume XLIII, January 1971
 FACTORS INFLUENCING INFARCT SIZE
with acute coronary occlusion might extend
the size of an ischemic zone and thereby
further impair left ventricular function and
result in a vicious cycle. These observations
also point to the potentially deleterious effects
of administration of positive inotropic agents
such as isoproterenol, digitalis glycosides, or
glucagon to patients with acute myocardial
infarction. However, it is important to stress
that these agents augment myocardial oxygen
demands in the nonfailing heart but do not
necessarily exert such an effect when adminis-
tered to a patient with an enlarged, failing
heart.39 Bretylium tosylate has recently been
shown to be an effective antiarrhythmic agent,
and its use in the treatment of patients with
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acute myocardial infarction has been suggest-
ed,40 since it also possesses positive inotropic
properties. It should be pointed out, however,
that under the conditions of these experiments
this drug also increased the magnitude of
ischemic injury in the presence of coronary
occlusion.
Of greatest interest, from the clinical point
of view, is the finding that the severity and
extent of myocardial ischemic injury resulting
from coronary occlusion could be radically
altered not only by pretreatment of the animal
but also by an appropriate intervention as late
as 3 hr after the coronary occlusion. This
suggests that measures designed for reduction
of myocardial oxygen demands and improve-
ment of coronary perfusion, when effected
promptly after a patient has been brought to a
hospital, might potentially reduce the ultimate
size of the infarction.
Acknowledgment
The authors acknowledge the skill and technical
assistance of Mr. Frank Trousdale.
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Circulation, Volume XLIII, January 1971
 Factors Influencing Infarct Size Following Experimental Coronary Artery
Occlusions
PETER R. MAROKO, JOHN K. KJEKSHUS, BURTON E. SOBEL, TAN
WATANABE, JAMES W. COVELL, JOHN ROSS, JR. and EUGENE
BRAUNWALD
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Circulation. 1971;43:67-82
doi: 10.1161/01.CIR.43.1.67
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