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


control. However, epicardial electrocardio- clamps. Arterial pressure was monitored with a
graphic changes occur very early during the Statham pressure transducer (model P23Db). All
course of ischemic damage, and it has not yet variables, including limb leads and the epicardial
been established to what extent S-T segment electrocardiogram, were recorded on an oscillo-
graphic recorder.
elevation presages the later development of Ten to 14 sites on the anterior surface of the
cellular damage. As it has been shown left ventricle were selected for epicardial electro-
recently that the reduction in myocardial cardiography. The limb leads were connected in
creatine phosphokinase (CPK, activity is a the usual fashion, and the precordial lead was
quantitative indicator of the extent of cell terminated in a special hollow metallic cylinder 4
mm in diameter held at a right angle to the
death 24 hr after coronary artery occlusion,' in epicardium and connected to the standard
the present investigation the magnitude and 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 69
held in such a way as to minimize pressure when occlusion and 5, 10, 15, and 20 min after
it was applied to the surface of the heart. Some occlusion. In 60 of the 85 dogs the occlusion was
studies were done with the use of a cotton wick released afterward, and further coronary occlu-
soaked in saline and impacted in the hollow sions were not performed until the epicardial S-T
cylinder. Epicardial recordings were obtained at segments had returned to normal, a period of
one-tenth the normal electrocardiographic sensi- approximately 45 min.
tivity (1 mv/mm recording). The S-T segment elevation at each site was
Sites for recording were selected within the used as an index of the severity of local
area supplied by the coronary branch that was myocardial injury (fig. 1). The sites at which
occluded, in areas immediately adjacent to this myocardial ischemic injury was considered to
zone, as well as portions of the left ventricle exist were those at which the S-T segment
remote from this area which were presumed to be elevation exceeded 2 mv when recorded 15 min
adequately perfused. Since the recordings ob- after ligation. Thus, for example, in figure 2
tained from each specified epicardial site had to myocardial ischemic injury was considered to be
be repeated several times, sites were selected near present at sites 6, 7, 8, and 9. In each animal, the
the bifurcation of arteries or veins so that the S-T segment elevations from all recording sites
recording probe could be easily repositioned at were added; this value, YS-T, was then used as an
the same location. Epicardial electrocardiograms overall index of the intensity of myocardial injury
were obtained from each site before each in any given animal. The mean S-T segment
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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 MAROKO ET AL.

elevation in any dog (S-T) was calculated as the to recover. Twenty-four hr later, another thora-
quotient of IS-T and the total number of sites, cotomy was performed, and the heart was quickly
and changes in the average S-T for a group of removed. Full wall thickness myocardial speci-
animals analyzed by the paired t-test technique mens (approximately 500 mg) were obtained as
were used to determine the effects of a variety of previously described1 from the same sites from
interventions on the severity of myocardial which epicardial recordings had been obtained 24
ischemic injury. hr previously.
The animals were divided into three groups. In In the second subgroup (12 dogs) the effect of
the first group (48 dogs), the effects of acute drug interventions was studied. A control occlusion
interventions were studied. In all groups the was performed in each animal for 20 min and
experimental protocol was similar. A control epicardial electrocardiograms were recorded. Af-
occlusion was carried out with epicardial record- ter release and return of the electrocardiogram to
ings just before, and 5, 10, 15, and 20 min after control values, a second occlusion was carried out.
occlusion. After release of the occlusion and Commencing 5 min before the second occlusion,
return of the aortic pressure, heart rate, and which was maintained for 24 hr, isoproterenol or
epicardial electrocardiogram to control values, propranolol was administered intravenously to six
one of eight interventions was employed: dogs each. The dosage regimen for isoproterenol
(1) An infusion of isoproterenol (0.25-0.50 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,
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gg/kg/min) was begun 5 min before occlusion


and maintained during the occlusion (nine followed by 0.5 mg/kg at 4-hr intervals for a total
experiments). of 12 hr. The electrocardiograms were taken in
(2) Heart rate was increased by an average of 62 the usual manner, and the chest was closed; the
beats/min by right atrial stimulation (three procedures followed were as in the first subgroup.
experiments). Chemical Procedures
(3) Propranolol (0.5, 1.0 or 2.0 mg/kg) was All chemicals were of the highest grade
administered intravenously 5 min before occlu- commercially available, and were prepared for
sion (eight experiments). use in doubly distilled deionized water. CPK
(4) Methoxamine (0.01-0.05 mg/kg/min) was standard was obtained from Worthington Bio-
infused for augmentation of the mean arterial chemical Corporation. Creatine phosphate,
pressure; the infusion was begun 5 min before glucose-6-phosphate dehydrogenase, nicotine ade-
occlusion and maintained during occlusion nine dinucleotide phosphate, sodium adeno-
(eight experiments). sine diphosphate, sodium adenosine monophos-
(5) Arterial bleeding was carried out before phate, and hexokinase were obtained from
occlusion so that mean arterial pressure might Calbiochem. Cysteine hydrochloride and bovine
be reduced (six experiments). serum albumin were obtained from Sigma
(6) Glucagon (5-20 ,g/kg) was administered Chemical Company. Ventricular myocardium was
intravenously 5 min before occlusion (four homogenized as previously described' and CPK
experiments). activity was assayed in the 16,000 x g superna-
(7) Bretylium tosylate (5 mg/kg) was adminis- tant fraction spectrophotometrically according to
tered intravenously 30 min before occlusion the method described by Rosalki.2 Diluents and
(two experiments). assay conditions were exactly the same as those
(8) Ouabain (0.03 mg/kg) was administered described previously.' CPK activity was ex-
intravenously 5 min before occlusion (six pressed as International Units (IU) (,umoles of
experiments). substrate converted per min) per mg of super-
In the second group (19 dogs), coronary natant fraction protein. Reaction rates were linear
occlusion was maintained for 3 hr, and the for at least 15 min after an equilibration period of
effects of isoproterenol (two experiments), pro- 5 min; activity was proportional to the quantity of
pranolol (six experiments), and methoxamine or
phenylephrine HCI (11 experiments) on the supernatant fraction protein added to the assay
epicardial electrocardiogram were then deter- system; enzyme activity was acid and heat labile;
mined while the occlusion was maintained. and results of duplicate determinations of enzyme
In the third group (18 dogs), the correlation activity agreed within 3%.
between S-T segment elevation 15 min after
occlusion and CPK depletion 24 hr later was Results
studied. In the first subgroup (six dogs), which The Effects of Coronary Occlusion
was not subjected to any pharmacologic inter- After coronary occlusion, an area of the left
ventions, epicardial electrocardiograms were re-
corded at 5-min intervals after coronary occlusion; ventricle that was cyanotic and bulged during
the thorax was closed and the animal was allowed systole could be observed in most experiments.
Circulation, Volume XLIII, January 1971
FACTORS INFLUENCING INFARCT SIZE 71
The correlation between this area and the area was continued, coronary occlusion was re-
of myocardial ischemic injury as reflected in peated. In each dog, the number of sites of
the S-T segment elevation was excellent. Also, severe myocardial ischemia increased and the
the interventions, which altered the area of extent of the S-T segment elevation at any
severe myocardial ischemic injury, affected the particular affected site was augmented. More-
area of visible cyanosis in a parallel fashion. over, the effects of isoproterenol were repro-
Figure 1 shows the results of an occlusion of ducible, resulting in similar increases in S-T
a branch of the left anterior descending segment elevation when separate infusions
coronary artery. Site 1, which was remote and coronary occlusions were done (fig. 2,
from the site of occlusion, showed no evidence runs 2 and 4). With 20-min periods of
of S-T segment elevation before or during coronary artery occlusion, isoproterenol did
occlusion, while site 7, well within the area of not appear to produce irreversible damage;
distribution of the occluded vessel, showed a thus, the S-T segments became isoelectric
7-mv elevation of the S-T segment 15 min after release of the ligation and cessation of
after occlusion. In the experiment illustrated isoproterenol; reocclusion then produced S-T
in figure 2, epicardial recordings were ob- segments similar to those during the first
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tained at 14 sites. In Run no. 3 IS-T increased control occlusion (fig. 2, runs 1 and 3).
from a control value of 7 mv before occlusion In the 12 experiments performed in nine
to 24 mv 15 min after ligation. In the 48 dogs animals, the average S-T 15 min after
studied, the average S-T segment elevation occlusion increased from 1.6 ± 0.4 mv during
increased from 0.22 + 0.4 mv (SEM) before the control occlusions to 6.8 ± 1.1 mv after
occlusion to 3.22 ± 0.37 mv (P < 0.001) 15
min after occlusion, while the average number ligation during isoproterenol infusion (P <
of sites showing S-T segment elevation exceed- 0.01) (fig. 3), and the number of sites of
ing 2 mv rose from 0.0 to 3.6 + 0.4 (P < ischemic injury increased from an average of
0.001). 2.2+ 0.9to7.0± 1.1 mv (P<0.01).
The reproducibility of the S-T segment When an infusion of isoproterenol (0.25
elevation was studied in nine experiments in gg/kg/min) was begun 3 hr after coronary
which two 20-min periods of simple occlusion occlusion, in two dogs the S-T rose from 0.4 to
were carried out in the same dog with an 3.3 mv and from 1.7 to 8.3 mv, respectively.
intervening period of 1 hr during which the
occlusion was released. The epicardial sites at X OCCLUSION ALONE
which ischemic injury was present 15 min * OCCLUSION + ISOPROTERENOL

after occlusion were identical, and the average i OCCLUSION .OUABAIN


E5OCCLUSION +GLUCAGON
S-T segments for the group were 4.2 + 1.0 and 1 2 OCCLUSION +PROPRANOLOL

3.9 ± 1.0 mv during the first and second O


5 OCCLUSION + HEMORRHAGE

occlusions, respectively (P > 0.3, fig. 3). More- a OCCLUSION + METHOXAMINE


8-
over, after recovery from an intervention where avg ST6
repeated "control" occlusions were performed in mV
(fig. 2, runs 1 and 3), the magnitudes of the S- 4-
T segment elevations were similar. 2i
0
Effects of Isoproterenol 9 9 4 68 6 8
The infusion of isoproterenol (0.25-0.50 Figure 3
gg/kg/min) elevated heart rate from 136+7 Summary of results. Influence of repeated occlusions
under the influence of isoproterenol, ouabain, glucagon,
to 179 + 12 beats/min and lowered mean
arterial pressure from 116+8 to 99±9 mm propranolol, hypotension, and hypertension on the
average ST segment elevation (ST) after an occlusion.
Hg. After a stable hemodynamic state was Bars represent standard errors of the mean. Figures
achieved and while the isoproterenol infusion below columns indicate number of experiments.
Circulation, Volume XLIII, January 1971
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 73
62 beats/min to a level similar to that which Effects of Glucagon
had been previously produced by isoprotere- Glucagon (5-20 ,g/kg), administered to
nol infusion, and the effects of coronary four animals increased IS-T segment elevation
occlusion were again studied. In each instance as well as the area of ischemic injury. Fifteen
pacing-induced tachycardia augmented the S- min after occlusion the average S-T segment
T segment elevation produced by occlusion was increased from a control value of
(fig. 4A; compare runs 1 and 3), but did so to 3.4 + 1.8 to 8.0 + 4.1 mv (fig. 3), and the
a lesser extent than when similar levels of number of sites of ischemic injury rose from
heart rate had been achieved with isoprotere- an average of 3.5 1.0 to 6.0 0.4. Moreover,
nol (fig. 4A; compare runs 2 and 3). when heart rate was maintained constant by
Effects of Ouabain atrial stimulation, glucagon still increased the
Ouabain (0.03 mg/kg) administered 5 min IS-T and the number of sites showing an S-T
before occlusion, did not alter the arterial segment elevation of more than 2 mv.
pressure and heart rate existing 15 min after Effects of Bretylium
occlusion. Generally, ouabain depressed the S- After a control occlusion in two dogs,
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T segments at sites remote from the occluded bretylium tosylate* (5 mg/kg) was given
vessel but despite this effect of the drug, the slowly intravenously, and 30 min later coro-
average S-T segment elevation increased from nary occlusion was repeated. The average S-T
2.2 0.8 to 4.1 1.2 mv (P <0.01), and the segment elevation increased from 1.4 to 3.0
number of sites with S-T segment elevations mv, while the number of sites of myocardial
exceeding 2 mv increased from an average of ischemic injury rose from 2.5 to 8.0.
5.0 + 1.7 to 7.2 + 1.4 (P < 0.025) (fig. 3).
Effects of Varying Arterial Pressure
Effects of Propranolol
Arterial hypertension was produced in eight
Propranolol (0.5-2.0 mg/kg), admini- experiments by the infusion of methoxamine
stered to eight animals, reduced heart rate (0.01-0.05 mg/kg/min) (fig. 5B and D).
from an average control level of 130 + 6 to Mean arterial pressure was elevated from
111 + 4 beats/min; systemic arterial blood 116 8 mm Hg during the control occlusion
pressure was not significantly altered. Coro-
to 189 6 mm Hg 15 min after coronary
nary occlusion carried out in the presence of
occlusion during methoxamine infusion, while
propranolol resulted in a decrease in the the corresponding heart rate fell from 123 1
average S-T segment elevation from control
to 109 + 8 beats/min. The average S-T 15 min
levels of 3.9 0.9 mv after simple occlusion to after occlusion decreased from 4.9± 1.3 mv
1.6 0.8 mv after occlusion carried out during the control occlusion to 1.6 0.6 mv
following the administration of propranolol (P < 0.01) 15 min after occlusions carried out
(P< 0.01) (figs. 3 and 4B). The number of during methoxamine infusion (fig. 3), while
sites with S-T segment elevations exceeding 2 the number of epicardial sites showing severe
mv declined from 5.4 + 0.6 to 1.1 0.5
(P < 0.01). In two additional experiments, ischemic injury declined from 4.4 0.9 to
heart rate was maintained constant by electri- 2.1±0.9 (P<0.025).
cal stimulation, and propranolol was found to In six experiments arterial hypotension was
reduce the S-T segment elevation 15 min after produced by acute arterial hemorrhage (fig.
coronary occlusion to 33% and 40% of the levels SA and C). Mean arterial pressure fell from
observed after the control occlusions. an average of 140 + 11 to 63 + 10 mm Hg,
In the six experiments in which propranolol while heart rate decreased from an average of
(1.0 mg/kg) was infused 3 hr after coronary 146 10 to 123 + 11 beats/min. The average
occlusion, the average S-T segment elevation
decreased from 7.6 + 1.8 to 4.9 + 1.3 mv *Kindly supplied by Burroughs-Wellcome Labora-
(P<0.01). tories.
Circulation, Volume XLIII, January 1971
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 four levels of arterial pressure on the IS-T 15
from 2.8 + 1.2 mv during the control occlusion min after coronary ligation were examined. An
to 9.0 + 3.4 mv during hemorrhagic hypoten- inverse relation between the arterial pressure
sion (P<0.01) (fig. 3), and the number of and YS-T segment elevation was noted in each
sites exhibiting ischemic injury increased from experiment (fig. 6A). The regression equation
1.8+ 0.7to6.3± 1.1 (P<0.01). for all of the experiments in which arterial
In four experiments the effects of three or 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

_12 en
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 SITE OF SPECIMEN
mm Hg by methoxamine or phenylephrine Figure 7
HC1 3 hr after coronary ligation, the average The correlation between epicardial ST segment ele-
S-T decreased from 4.3 + 0.4 to 2.2 ± 0.5 mv vation and subsequent CPK depression in correspond-
ing samples from a representative dog subjected to
(P<0.01) (fig. 6B). coronary artery occlusion. Epicardial ST segment ele-
Correlation of Epicardial S-T Segment vation (o) was measured 15 min after coronary artery
Elevations and Myocardial occlusion, and the per cent myocardial CPK depres-
CPK Depletion sion (c) based on myocardial CPK activity in normal
In the normal animal, the variation of CPK tissue from the same animal was determined 24 hr
activity in multiple transmural specimens from later. Actual values for myocardial CPK activity from
each site are indicated in the open circles at the top
divergent sites in the same heart averaged 6%. of the figure. The sample site represented on the
CPK activity was measured in samples from abscissa is indicated on the diagram at the top of the
the myocardial wall, divided into an inner figure.
Circulation, Volume XLIII, January 1971
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 an exponential activity in nonischemic tissue from dogs with
curve: coronary artery occlusion. Activity in samples
log CPK = 1.27-0.065 S-T of nonischemic tissue from six animals treated
(r =-0.87; P < 0.01) (fig. 8A). In myo- with isoproterenol averaged 19.4 + 0.5 IU/mg
cardium clearly not supplied by the (N = 25 samples), compared to 18.2 0.5
ligated coronary artery, S-T segment elevation IU/mg (N = 27 samples) in nonischemic
was consistently less than 2 mv, and CPK tissue from six animals receiving no drug (fig.
activity in corresponding sites measured in six 9). A representative experiment demonstrat-
dogs was 18.2 0.5 IU/mg protein (N = 27), ing the effects of isoproterenol is illustrated in
not differing significantly from that in myocar- figure 1OA. In several sites with an S-T
dium from four unoperated control animals segment elevation of less than 2 mv during
(18.2 + 0.9 IU/mg protein; N = 20). control occlusion, as indicated by the asterisks
The Influence of Isoproterenol and in figure IOA, there was a marked increase in
Propranolol on CPK Depression S-T segment elevation during isoproterenol
Administration of isoproterenol (0.25-0.5 infusion. The increase in S-T segment eleva-
,ug/kg/min for 5 hr) did not lead to tion associated with administration of isopro-
subsequent depression of myocardial CPK terenol over and above that produced by
Circulation, Volume XLIII, January 1971
FACTORS INFLUENCING INFARCT SIZE 77

24 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-
C-) sion of myocardial CPK activity was signifi-
cantly less than that anticipated from the
:x-)
-J
ca magnitude of S-T segment elevation produced
Z7
E. by coronary artery occlusion alone (fig. 8B).
C- P The regression line relating CPK depression to
C)X ?5 S-T segment elevation in control animals
c:r
C> 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
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0 5

ST-SEGMENT ELEVATION ( mV) administration of propranolol was reduced


Figure 9 compared to that anticipated from the S-T
segment elevation after the control occlusion.
Augmentation of the area of epicardial ST segment
elevation and myocardial CPK depression after coro- Discussion
nary artery occlusion accompanied by isoproterenol.
Values represented are means + SEM. (e) = values in There is some evidence to suggest that
nonischemic tissue from six dogs receiving no iso- factors that influence myocardial oxygen
proterenol. (o) = values from sites without ST seg- demands may aggravate or alleviate symp-
ment elevation in animals subjected to coronary artery toms of myocardial ischemia.3 For example, in
occlusion and given isoproterenol. (A) = values in the patients with angina and hyperthyroidism
same animals from sites with no ST segment eleva-
tion after coronary artery occlusion alone but with ST treatment of the hypermetabolic state, and the
segment elevation after occlusion plus isoproterenol associated reduction of myocardial oxygen
administration. The results demonstrate that myo- needs, is often associated with relief of
cardial CPK depression occurred in these sites within angina.4 Also, the reduction of myocardial
24 hr.
oxygen needs produced by beta-adrenergic
coronary artery ligation alone, is reflected by
blockade5 or carotid sinus nerve stimulation6
reduces symptoms of myocardial ischemia.
corresponding changes in myocardial CPK Conversely, treatment of hypothyroidism or
activity. It can be seen that CPK depression the development of tachycardia, influences
after administration of isoproterenol was that increase myocardial oxygen needs, in-
significantly greater (P < 0.05) than that creases the frequency and severity of
which would have been expected on the basis myocardial ischemia in patients with coronary
of S-T segment elevation after coronary artery
ligation but before isoproterenol administra- artery disease. The importance of the de-
tion (fig. 8B). This point is demonstrated also creased availability of oxygen is apparent in
by data represented in figure 9. Specimens cases where arterial hypotension and acute
from portions of the myocardium with normal anemia may cause infarction in the absence of
S-T segments after coronary artery occlusion coronary occlusion.7 These clinical observa-
before isoproterenol was administered, but tions suggested to us that hemodynamic and
with elevated S-T segments during administra- pharmacologic stimuli might alter the extent
tion of the drug, clearly demonstrated a of myocardial ischemic injury and infarction
depression of CPK activity 24 hr later after coronary occlusion, and the present
(P <0.001). investigation was designed for exploration of
Administration of propranolol after coro- this possibility.
Circulation, Volume XLIII, January 1971
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
epicardial S-T segment has been demonstrat-
r_
20 2
4
X
'a
-
ed.10 Sayen and his collaborators" -'4 found a
0
.>
poor correlation between S-T segment eleva-
tion and intramyocardial P02 immediately
SITE OF SPECIMEN
after coronary occlusion, but reported that 5
Figure 10 min after occlusion the sites at which S-T
segment elevation occurred correlated well
(Panel A) correlation between epicardial ST segment with those at which PO, were reduced.12
elevation after coronary artery occlusion before (A) Scheuer and Brachfeld's reported a close
and during (A) isoproterenol infusion and subsequent
CPK depression. CPK activity was measured in cor- correlation between S-T segment elevation
responding specimens 24 hr later (-), and is expressed and the development of anaerobic metabolism
as per cent of activity in nonischemic tissue from the when coronary blood flow was reduced.
same animal. Actual values for myocardial CPK ac- Results obtained in this investigation dem-
tivity from each site are shown in the open circles at onstrate a close correlation between the extent
the top of the figure. Depression of CPK activity and magnitude of early elevation of S-T
correlates more closely with the pattern of epicardial
ST segment elevation after isoproterenol infusion than
with that seen prior to drug administration. Asterisks subsequent CPK depression. (-) = same as in panel A.
indicate points exhibiting no ST segment elevation Depression of CPK activity correlates more closely
before administration of isoproterenol, but definite ST with the pattern of epicardial ST segment elevation
segment elevation during drug administration. CPK after propranolol administration than with that seen
activity was depressed in these regions, indicating ad- after coronary artery occlusion alone. Asterisks indi-
ditional tissue damage associated with isoproterenol cate points with striking ST segment elevation before
administration. propranolol was given, but marked reduction of ST
(Panel B) correlation between epicardial ST seg- segment elevation during administration of the drug.
ment elevation after coronary artery occlusion before CPK activity in corresponding specimens was normal,
(A) and during (A) propranolol administration and indicating a protective effect produced by propranolol.
Circulation, Volume XLIII, January 1971
FACTORS INFLUENCING INFARCT SIZE 79
segments in epicardial recordings after acute substantially alter the extent of myocardial
coronary artery occlusion and the later devel- ischemic injury when a coronary vessel is
opment of cellular damage, as evidenced by occluded. Myocardial oxygen consumption
depression of myocardial CPK activity in was increased by augmentation of cardiac
specimens from the same sites. In contrast to contractility27 by the use of several stimuli,
many enzymes, CPK activity is found predom- including the administration of isoproterenol,
inantly in skeletal and cardiac muscle cells. glucagon, bretylium, and ouabain, and the in-
Accordingly, the activity of this enzyme in duction of tachycardia. All of these influences
infarcted heart muscle is less likely to be increased the area of ischemic injury and the
influenced by other cellular components par- magnitude of S-T segment elevation. In
ticipating in the inflammatory reaction after contrast, an intervention that lowered myocar-
coronary artery occlusion. This is supported dial oxygen consumption (i.e., the administra-
by recent evidence showing that decrease of tion of propranolol ) 28 decreased the extent
myocardial CPK activity correlates closely and magnitude of S-T segment elevation after
with the amount of cell death in rabbits coronary occlusion. Since these various inter-
subjected to coronary artery occlusion.' All of ventions alter myocardial contractility by a
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these considerations, taken together, suggest variety of mechanisms," it is very likely that
strongly that epicardial S-T segment elevation it is the change in oxygen consumption per se,
is the result of ischemic cellular injury and rather than the specific interventions, that
that its persistence presages the ultimate were responsible for the corresponding
development of myocardial necrosis. changes in the magnitude and extent of
There is substantial evidence, based on ischemic injury.
histological, electron microscopic, and histo- Isoproterenol in doses higher than those
chemical studies, that irreversible injury does used in this study has been shown to produce
not occur within 20 min of coronary myocardial necrosis directly,30 and the possi-
occlusion,1621 and the total disappearance of bility must be considered that this agent might
epicardial S-T segment elevation after release have produced electrocardiographic changes
of the occlusion in the present studies is even in the absence of coronary occlusion.
consistent with these findings. Therefore, it However, with the concentrations of isoprote-
was possible to compare the effects of several renol employed, epicardial sites remote from
different interventions on the severity and those supplied by the occluded coronary
extent of ischemic injury after repetitive artery did not show changes in the epicardial
occlusion of the same coronary artery. S-T segment, indicating that isoproterenol did
A number of stimuli,22 not necessarily not produce ischemic injury in normal tissue.
associated with myocardial ischemic injury, Also, the studies of Raab et al.,3 31 in which
such as changes in the ionic milieu of the catecholamine stimulation in the presence of a
myocardium23' 24 and stimulation of specific constant coronary flow produced epicardial S-
areas within the central nervous system25 and T segment elevations, are consistent with our
of the stellate ganglia,26 have been shown to findings. Moreover, the dose of isoproterenol
produce alterations of the S-T segment. used in the present study did not influence
However, the S-T segment elevations pro- CPK activity in nonischemic myocardium,
duced in this study by inotropic drugs and although doses in this range do lead to
hypotension were not of the nonischemic type, increased lactate production in experimental
since they were not observed in portions of infarction produced by microspheres.32
the left ventricle remote from that perfused by Findings in the present study demonstrate
the occluded artery. further that the augmentation of S-T segment
The present investigation indicates that elevation following isoproterenol infusion af-
factors that influence the balance between ter coronary artery ligation is associated with
myocardial oxygen supply and demand can a more profound depression of myocardial
Circulation, Volume XLIII, January 1971
so MAROKO ET AL.
CPK activity. In specimens from myocardial than do the changes in myocardial oxygen
sites that had normal S-T segments after consumption resulting from the arterial pres-
simple ligation but that exhibited S-T segment sure change. This finding is not surprising
elevations after isoproterenol administration, since, in studies on the effects of alterations in
the CPK activity was only two-thirds of that arterial pressure on the relation between
found in corresponding marginal sites in myocardial oxygen consumption and coronary
animals with coronary artery occlusion alone blood flow, it was shown that elevation of
(fig. 9). Thus, it is apparent that under these arterial pressure increases coronary flow pro-
conditions, infusion of isoproterenol not only portionately more than myocardial oxygen
alters the epicardial electrocardiogram but consumption.34 The latter observation, as well
also results in an increment of cell death, as the dependence of the collateral flow upon
evidenced by myocardial CPK depression. coronary perfusion pressure,35 could explain
It might be argued that myocardial CPK the decrease in ischemic injury when arterial
depression after isoproterenol infusion may pressure was elevated in the presence of
reflect increased washout of the enzyme. coronary occlusion. Conversely, coronary
However, this is unlikely since virtually no blood flow is known to fall abruptly when
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further depletion of CPK takes place after 24 perfusion pressures decline below 60-70 mm
hr. Although CPK depletion may be flow Hg,36 and the fact that this decline is
dependent soon after coronary occlusion,38 proportionately greater than the accompany-
the linear relationship obtained between ing reduction in myocardial oxygen consump-
relative regional perfusion and CPK depletion tion could explain the observed extension of
24 hr after coronary artery ligation' suggests the area of ischemic injury associated with
that washout is not a major factor influencing hypotension. Moreover, Corday et al.37' 38
myocardial CPK levels after 24 hr. showed that elevation of arterial pressure in
Digitalis glycosides ordinarily depress the S- hemorrhagic hypotension in dogs augmented
T segment, and indeed in this study, such both anterograde and collateral coronary flow.
changes were generally induced by ouabain in These observations led to the treatment of
areas of the myocardium supplied by unoc- cardiogenic shock in man with vasoconstrictor
cluded vessels. In spite of this effect of the drugs.
glycoside, it produced a significant increase in Some comment concerning the extrapola-
the area of ischemic injury and in the tion of the results of these studies to acute
magnitude of the S-T segment elevation after coronary occlusion in man are warranted.
coronary occlusion. Since glycosides normally Obviously, the fact that in these experiments
tend to depress the S-T segment, the intensifi- one coronary vessel is occluded while the
cation of ischemic injury produced by the remaining vessels are entirely normal differs
ouabain may actually have been underesti- from the clinical situation in which coronary
mated by the technique employed in this vascular involvement is usually more exten-
study. sive. While in the normal dog the number and
In contrast to the influence of positive size of coronary collateral vessels greatly
inotropic agents, increase of arterial pressure, exceed those occurring in normal man, the
which also augments myocardial oxygen con- relatively abundant collateral vessels in the
sumption, was found to decrease the extent of dog do resemble those occurring in patients
ischemic injury while arterial hypotension, with coronary artery disease, and in this
which reduces the heart's oxygen needs, had respect the experimental observation on the
the opposite effect. From these observations it effects of various stimuli on the extent of
appears that, in the presence of coronary myocardial ischemic injury may have consid-
occlusion, the changes of coronary perfusion erable clinical relevance.
pressure exert a greater and opposing influ- The present studies suggest that tachycardia
ence on the extent of myocardial ischemia and/or hypotension occurring in a patient
Circulation, Volume XLIII, January 1971
FACTORS INFLUENCING INFARCT SIZE 81
with acute coronary occlusion might extend 4. SOMMERVILLE W, LEVINE SA: Angina pectoris
the size of an ischemic zone and thereby and thyrotoxicosis. Brit Heart J 12: 245,
further impair left ventricular function and 1950
5. WOLFSON S, HEINLE RA, HERMAN MV, ET AL:
result in a vicious cycle. These observations Propranolol and angina pectoris. Amer J
also point to the potentially deleterious effects Cardiol 18: 345, 1966
of administration of positive inotropic agents 6. BRAUNWALD E, EPSTEIN SE, GLIcK G, ET AL:
such as isoproterenol, digitalis glycosides, or Relief of angina pectoris by electrical stimula-
glucagon to patients with acute myocardial tion of the carotid sinus nerves. New Eng J
Med 277: 1278, 1967
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that these agents augment myocardial oxygen infarction not due to coronary artery occlu-
demands in the nonfailing heart but do not sions. JAMA 112: 1675, 1939
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coronary artery ligation. J Thorac Cardiovasc
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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
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX
75231
Copyright © 1971 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539

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