Mechanisms of Myocardial Ischemia Induced

by Epinephrine: Comparison with Exercise-

Induced Ischemia

BONG HEE SUNG, P H D , MICHAEL F. WILSON, MD, CASEY ROBINSON,

PHD, UDHO THADANI, MD, AND WILLIAM R. LOVALLO, P H D

The role of epinephrine in eliciting myocardial ischemia was examined in patients with cor-
onary artery disease. Objective signs of ischemia and factors increasing myocardial oxygen
consumption were compared during epinephrine infusion and supine bicycle exercise. Both
epinephrine and exercise produced myocardial ischemia as evidenced by ST segment depres-
sion and angina. However, the mechanisms of myocardial ischemia induced by epinephrine
were significantly different from those of exercise. Exercise-induced myocardial ischemia was
marked predominantly by increased heart rate and rate-pressure product with a minor contri-
bution of end-diastolic volume, while epinephrine-induced ischemia was characterized by a
marked increase in contractility and a less pronounced increase in heart rate and rate-pressure
product. These findings indicate that ischemia produced by epinephrine, as may occur during
states of emotional distress, has a mechanism distinct from that due to physical exertion.

INTRODUCTION nisms by which phychological stimuli in-

Myocardial ischemia is caused by an
imbalance between the demand for oxy-
gen by the myocardium and the ability of
the coronary circulation to supply oxygen.
This condition is usually accompanied by
angina pectoris and may be precipitated
by either physical or psychological stim-
uli. The mechanisms of myocardial is-
chemia induced by exercise have been
studied extensively, while the mecha-
From the College of Pharmacy (B.H.S., C.R.), De-
partments of Medicine (B.H.S., M.F.W., V.T.) and
Psychiatry and Behavioral Sciences (W.R.L.), Uni-
versity of Oklahoma Health Sciences Center, and the
Veterans Administration Medical Center (M.F.W.,
W.R.L.), Oklahoma City, Oklahoma.
Address reprint requests to: Bong Hee Sung, Ph.D.,
Behavioral Sciences Laboratories (151A), Veterans
Administration Medical Center, 921 N.E. 13th Street,
Oklahoma City, OK 73104.
Received for publication October 19, 1987; revi-
sion received December 23, 1987.
Psychosomatic Medicine 50:381-393 (1988)
Copyright © Bong Hee Sung
Published by Elsevier Science Publishing Co , Inc.
52 Vanderbilt Ave., New York, NY 10017
duce ischemia are poorly understood.
Psychological stimuli have been asso-
ciated with angina, along with electrocar-
diographic (ECG) and metabolic evidence
of myocardial ischemia. Ischemia has been
shown to occur during recall of emotional
events (1), while driving in traffic (2), prior
to major surgery (3), and in bank account-
ants prior to an audit (4). Moreover, ar-
rhythmias may be induced in susceptible
patients (5) and in animals (6, 7). These
observations suggest a potential role of
psychogenic stimuli in altering the bal-
ance between myocardial oxygen supply
and demand, which may be of clinical sig-
nificance in individuals with underlying
coronary heart disease.
In patients with coronary artery dis-
ease, ischemic ECG changes occur at a
significantly lower rate-pressure product
during emotional arousal than during
exercise (8, 9). The rate-pressure prod-
uct (RPP = heart rate X systolic blood
381

pressure) is a reliable indicator of myo-
cardial oxygen consumption (10). The
reason for this discrepancy in the isch-
emic rate-pressure product with that
found in exercise remains unknown, al-
though various explanations have been
proposed. Schiffer and colleagues (8)
have suggested that emotional arousal
may somehow decrease myocardial oxy-
gen delivery, perhaps via coronary ar-
tery vasoconstriction, and therefore lower
the threshold for myocardial ischemia.
On the other hand, Specchia and co-
workers (11) proposed that "mental
stress" may cause a disproportionate in-
crease in oxygen demand in susceptible
patients.
Stimulation of the sympathoadrenal
system normally occurs during physical
exertion, psychological stimulation, and
other situations in which the organism is
challenged to mobilize energy resources.
However, sympathoadrenal activity is not
uniform to all such stimuli. The cardio-
vascular response to exercise involves
stimulation of the sympathetic nervous
system, inhibition of vagal activity, utili-
zation of the Frank-Starling mechanism,
and metabolic vasodilation in the exercis-
ing muscles. Emotional arousal appears to
influence cardiovascular activity by en-
hancement of sympathoadrenal activity,
particularly involving beta-adrenergic
stimulation (12, 13), even though vasodi-
lating metabolites from exercising skeletal
muscles are lacking. Frankenhaeuser (14)
has suggested that epinephrine levels may
increase under circumstances of distress
associated with novelty, anticipation, un-
predictability, and general emotional
arousal, whereas norepinephrine levels
increase preferentially during physical ac-
tivity or during work on tasks that are not
associated with distress (15). Several other
investigators have reported elevated plasma
382
B. H. SUNG e t a l .
epinephrine levels during various mental
stressors with proportionally smaller
changes in norepinephrine levels (16, 17).
Furthermore, epinephrine, but not nor-
epinephrine, infusion causes emotional and
physical signs of restlessness, apprehen-
sion, and anxiety (18).
The purpose of the present study was
to elucidate the possible role of circulating
epinephrine in induction of myocardial is-
chemia such as may accompany psycho-
logical events. Accordingly, we examined
the mechanisms by which epinephrine may
induce ischemia in patients with docu-
mented coronary artery disease and how
the effects of epinephrine infusion on
myocardial function differ from those of
exercise.
METHODS
Patients
Twenty-two male patients, mean age of 56 ± 8
(SD) years, were studied. All had been previously
diagnosed as having coronary artery disease (CAD)
documented by the presence of greater than 75%
luminal stenosis of at least one large coronary ar-
tery by selective angiography. Three had one-vessel
disease, four had two-vessel disease, and 15 had
three-vessel disease. All had a clinical history of
exertional angina, and 10 patients had a history of
documented but not recent (within 6 weeks) myo-
cardial infarction. All study patients were taking
short-acting nitrates for occasional angina pectoris.
Eight patients were receiving additional medica-
tions; four patients were taking thiazide diuretics,
two patients were taking aminophylline, one pa-
tient was taking digoxin and furosemide, and one
patient was treated with propranolol 40 mg twice a
day. All medication was stopped at least 72 hours
before the study. All patients were informed of the
investigational nature of the study and had signed
written consent forms.
Study Protocol
Each session consisted of the following: instru-
mentation of the patient, 30 minutes of supine rest
Psychosomatic Medicine 50:381-393 (1988)
EPINEPHRINE-INDUCED ISCHEMIA
during labelling of red blood cells with 25 mCi of 99
m Technetium (Tc-99m) and reinjection of labelled
cells, baseline measurement (3 minutes), epineph-
rine infusion (3 minutes at each dose rate), recovery
period (1 hour), pre-exercise baseline (3 minutes),
and graded supine bicycle exercise (3 minutes at each
stage). The full protocol usually required 2£-3 hours.
All patients were tested in the morning following an
overnight fast.
Instrumentation. An intravenous line was estab-
lished by inserting a 19-gauge indwelling angio-
catheter into the left antecubital vein. The line was
connected to a calibrated infusion pump (Sage In-
struments, Cambridge, MA model 350). Blood pres-
sures were measured from the right arm using a cuff
sphygmomanometer. A standard 12-lead ECG was
recorded with a Siemens-Elma Mingograph 62. Left
ventricular function was determined by gated ra-
dionuclide ventriculography using ECG-synchro-
nized blood pool scintigraphy as previously de-
scribed (19, 20). Cardiac images were acquired in
the left anterior oblique view, which offered the best
separation of the left ventricle from other chambers
of the heart, using a mobile gamma camera equipped
with a low-energy, all-purpose parallel-hole colli-
mator interfaced to a commercial system for com-
puter acquisition and analysis (Medical Data Sys-
tems, Ann Arbor, MI). A Quinton bicycle ergometer
was used for supine exercise testing.
Epinephrine infusion test. One ampule of epi-
nephrine HC1 (Parke-Davis, Adrenalin chloride so-
lution, 1000 M-g/ml) was diluted to 250 ml with nor-
mal saline solution. The diluted epinephrine solution
(4 M-g/m') w a s infused in graded dose rates of 0.06,
0.12, 0.18, and 0.24 jig/kg/min for 3 minutes at each
dose rate while the patient rested in a supine posi-
tion. ECG, heart rate, and blood pressure were mea-
sured each minute before the infusion for 3 minutes,
every minute during the infusion, and each minute
after termination of the infusion until the heart rate
and blood pressure returned to baseline. Cardiac im-
ages were acquired for 2 minutes at baseline and
during the final 2 minutes of each dose rate of the
infusion. The end point of the infusion was either
moderate angina, significant ventricular arrhyth-
mias, or completion of the maximum dose rate,
whichever came first.
Supine bicycle exercise. After the completion of
the epinephrine infusion, the patient rested in the
same position for 1 hour allowing the cardiovascular
parameters to return to baseline. The patient then
assumed the exercise position with his feet on the
ergometer pedals which were above horizontal.
Preexercise baseline ECG, heart rate, and blood
Psychosomatic Medicine 50:381-393 (1988)
pressure were recorded each minute for 3 minutes
along with gated radionuclide ventriculography,
which was performed for the final 2 minutes. The
patient then started pedaling the ergometer at a work-
load of 200 kg meter/minute (KPM) at a speed of 50-
60 revolutions per minute. The workload was in-
creased in 200 KPM increments at 3-minute intervals
until the patient experienced moderate angina, sig-
nificant ventricular arrhythmias, or severe fatigue.
ECG, heart rate, systolic and diastolic blood pres-
sures were recorded each minute during exercise and
after termination of the exercise until these param-
eters returned to baseline. Cardiac images were ac-
quired for the last 2 minutes of each exercise stage.
At the end of the study, a 10-ml blood sample was
drawn from the patient for calibration of radioactiv-
ity from Tc-99m labelled red cells for determination
of left ventricular volumes.
Data anaiysis. Gated radionuclide ventriculogra-
phy images obtained during the study were analyzed
as previously described (21). Background-corrected,
time-activity curve data were used for determination
of end-diastolic and end-systolic images. End-dia-
stolic and end-systolic volumes were determined by
the attenuation corrected, geometry-independent
volume method (22), which has been validated against
the thermodilution method in our laboratory. Cardiac
parameters were determined as follows:
Stroke volume = (end-diastolic volume) - (end-
systolic volume)
Ejection fraction = stroke volume/end-diastolic
volume
Cardiac output = stroke volume x heart rate
Mean blood pressure was calculated as the sum of
the diastolic blood pressure plus one-third of the
pulse pressure. Total peripheral resistance (ex-
pressed in dynes.s.cm""5) was computed by dividing
the mean blood pressure by the cardiac output and
multiplying by 80. Myocardial contractility index was
calculated as the ratio of systolic blood pressure to
end-systolic volume. This index has been reported
to be a more sensitive indication of the contractile
state of the heart than left ventricular ejection frac-
tion (23, 24).
Statistical Analysis
Cardiovascular effects of epinephrine infusion and
supine bicycle exercise were assessed relative to
baseline in all study patients by analysis of vari-
ance with repeated measures. Hemodynamic and left
383
 B. H. SUNG e t a l .

ventricular function effects of epinephrine infusion

Comparison of Epinephrine Infusion
and supine bicycle exercise were compared to each
and Supine Bicycle Exercise
other for all 22 patients by Wilcoxon's matched
Since all 22 patients1 received epineph-
signed rank test at baseline, maximal stress, and for
percent change from baseline. Factors increasing
rine infusion before supine bicycle exer-
myocardial oxygen consumption were examined in
cise, we examined any possible residual
those 13 patients who developed ischemia during
effects of epinephrine infusion on cardio-
both epinephrine infusion and exercise. This com-
vascular parameters at preexercise base-
parison was made at the point at which equivalent
ST segment changes occurred. Significance of the
line by Wilcoxon's matched signed rank
difference in objective signs of myocardial is-
test. No significant differences were found
chemia between epinephrine infusion and supine
between the preepinephrine and preex-
bicycle exercise was determined by chi-square tests.
ercise baseline values for any cardiovas-
All values are expressed as mean ± SEM, unless
cular parameter, indicating no residual ef-
noted otherwise. A p value of less than 0.05 was
considered significant. fects of epinephrine infusion at the onset
of exercise.
The duration of epinephrine infusion and
RESULTS supine exercise varied widely from pa-
Effects of Epinephrine Infusion and tient to patient. All 22 patients received
Supine Bicycle Exercise 0.06 |x/kg/min of epinephrine; 21 had 0.06
and 0.12 jji/kg/min; 18 had 0.06, 0.12, and
Epinephrine infusion and exercise both 0.18 ^g/kg/min; and 16 patients received
significantly increased heart rate and all four dose rates of epinephrine. All six
systolic blood pressure, and thus rate- patients who had to stop the epinephrine
pressure product (p < 0.0001). Diastolic infusion did so due to moderate chest pain.
blood pressure was significantly in- All 22 patients performed exercise at 200
creased during supine bicycle exercise KPM, 13 patients exercised at 200 and 400
(p < 0.05) but did not change during KPM, and two at 200, 400, and 600 KPM
epinephrine infusion (NS). Both chal- ergometer workloads. Angina pectoris was
lenges led to significantly decreased total the limiting factor for eight patients, and
peripheral resistance and increased car- the other 14 stopped because of fatigue.
diac output (p < 0.001). Left ventricular Average exercise time was 5.3 minutes.
ejection fraction and myocardial contrac- Because of the variation in stress levels
tility index were significantly increased among the study patients, the maximal
during epinephrine infusion (p < 0.001), stress point for each challenge and percent
while there was either no significant change from baseline to maximal stress
change or a slight decrease in these pa-
rameters during supine bicycle exercise
(NS). The left ventricular volume re-
sponses to epinephrine infusion and su- 'One patient was on propranolol 40 mg twice a
pine bicycle exercise were different. Ex- day and stopped taking the drug 72 hours before the
ercise increased end-diastolic, end- test. He did not show supersensitivity to epinephrine
infusion. His heart rate was increased 21% compared
systolic, and stroke volumes (p < 0.001), to the group mean (±SEM) of 26 ± 5%, systolic
while epinephrine infusion did not blood pressure rose 16% compared to the group mean
change end-diastolic volume (NS), de- (±SEM) of 31 ± 4%, and diastolic blood pressure
creased end-systolic volume, and in- did not change compared to the group mean (± SEM)
of — 1 ± 4%. Thus, this patient was included in the
creased stroke volume (p < 0.001). data analysis.

384 Psychosomatic Medicine 50:381-393 (1988)

EPINEPHRINE-INDUCED ISCHEMIA
point were used to compare epinephrine
infusion and supine bicycle exercise.
Epinephrine increased the mean heart
rate from 74 ± 4 beats/min to 91 ± 3
beats/min, while exercise increased mean
heart rate significantly more (p < 0.005)
from 74 ± 3 beats/min to 125 ± 4
beats/min. The percent increase in systolic
blood pressure was similar between ex-
ercise (31%) and epinephrine infusion
(26%). Exercise produced a significantly
greater maximum rate-pressure product
than epinephrine infusion (213 ± 18 x io 2
versus 158 ± 18 x 102, p < 0.005). Car-
diac output increased significantly more
during exercise than epinephrine infusion
(10.8 ± 0.9 1/min versus 8.9 ± 0.7 1/min,
p < 0.05), while the percent decrease in
total peripheral resistance was similar be-
tween exercise and epinephrine infusion
(-30 ± 60% and -29 ± 7% respec-
tively, NS).
Left ventricular ejection fraction and
contractility index responses to exercise
and epinephrine infusion are shown in
Figure 1. Exercise decreased mean left
ventricular ejection fraction from 52 ± 3%
to 47 ± 3% compared to an epinephrine-
induced increase in ejection fraction of
51 ± 3% to 64 ± 4%, resulting in a sig-
nificant difference (p < 0.005) in re-
sponses to exercise and epinephrine in-
fusion. The contractility index increased
from 2.3 ± 0.4 mmHg/ml to 4.2 ± 0.7
mmHg/ml (p < 0.005) during epinephrine
infusion but did not change significantly
during exercise (2.4 ± 0.4 mmHg/ml to
2.1 ± 0.2 mmHg/ml, NS).
The left ventricular volume response to
exercise and epinephrine infusion is given
in Figure 2. Exercise increased end-dia-
stolic volume significantly more than did
epinephrine infusion (24 ± 6% versus
7 ± 4%, p < 0.01). Mean end-systolic vol-
ume increased during exercise (50 ± 16%
Psychosomatic Medicine 50:381-393 (1988)
but decreased with epinephrine infusion
(-23 ± 6%). Mean stroke volume in-
creased significantly more during epi-
nephrine infusion (27 ± 6%) than during
exercise (8 ± 6%).
Comparison of Myocardial Ischemia
Induced by Epinephrine Infusion and
Supine Bicycle Exercise
In this study, myocardial ischemia to
either challenge was defined as greater than
1 mm of horizontal or downsloping ST
segment depression from baseline at 0.08
seconds after the J point of the ECG and/or
less than 5% increase from baseline in left
ventricular ejection fraction. Episodes of
angina pectoris and ventricular arrhyth-
mias were also recorded.
Sixteen of the 22 CAD patients (73%)
developed ischemic ST segment depres-
sions during either epinephrine infusion
or exercise; 13 of these patients (59%) de-
veloped ST segment changes during both
exercise and epinephrine infusion. Figure
3 illustrates ECG records of three patients
who had equivalent ST segment changes
along with angina pectoris during both
conditions. Epinephrine infusion clearly
induced equivalent ST segment changes
at a lower rate-pressure product than ex-
ercise, as can be seen in the rate-pressure
products shown below each tracing. A
comparison of mean (± SD) rate-pressure
products obtained at equivalent ST seg-
ment changes during exercise and epi-
nephrine infusion for these 13 patients
showed that exercise-induced equivalent
ST segment changes at rate-pressure prod-
uct of 191 ± 3 6 x 102 compared to
132 ± 29 x 102 for epinephrine infusion
(p < 0.005).
The primary determinants of myocar-
dial oxygen consumption are heart rate,
myocardial wall tension, and the contrac-
385
 B. H. SUNCetal.

100-1 • EPINEPHRINE 50
r
• EXERCISE
*

NS r^
50-

--50
control maximum change

LEFT VENTRICULAR EJECTION FRACTION

(mmHg/ml)
9.0-1 r-150

6.0- -100

3.0- NS -50

control maximum change

CONTRACTILITY INDEX
Fig. 1. Left ventricular ejection fraction and contractility index expressed as ratio of peak systolic blood
pressure to end-systolic volume responses to epinephrine infusion and exercise in 22 patients with
coronary artery disease. Comparison was made between epinephrine infusion and exercise at control,
maximum stress, and percent change from the control. *p < 0.005; NS, not significant

tile state of the heart (25). In considering
factors that increase myocardial oxygen
demand during epinephrine infusion and
exercise, we examined the following pa-
rameters: heart rate, wall tension indi-
cated by systolic blood pressure, rate-pres-
sure product, end-diastolic volume, and
contractility indicated by left ventricular
ejection fraction and myocardial contrac-
tility index. Figure 4 illustrates the percent
changes in these parameters. We noted a
significantly greater increase in heart rate,
rate-pressure product, and end-diastolic
volume during exercise-induced ischemia
than epinephrine-induced ischemia.
Changes in left ventricular ejection frac-
tion and myocardial contractility index
were significantly greater during epineph-
rine-induced ischemia than exercise-in-
duced ischemia. The change in systolic
blood pressure was similar between the
two tests. On the balance, exercise-in-

386 Psychosomatic Medicine 50:381-393 (1988)

EPINEPHRINE-INDUCED ISCHEMIA

duced ischemia was associated with heart

rate and wall tension, whereas epineph-
rine infusion affected contractility in pro-
ducing ischemia with a lesser contribution
from increased heart rate and wall tension.
Objective signs of myocardial ischemia
induced by epinephrine infusion and ex-
ercise were compared in Table I. Twenty
control maximum change of 22 patients (91%) with CAD had a re-
END-DIASTOLIC VOLUME
duced ejection fraction response during
(ml)
exercise, while only one patient (5%) had
reduced ejection fraction response during
120-1 rlOO epinephrine infusion. Thus, significantly
more (p < 0.001) contractile abnormali-
ties occurred in patients with CAD during
80- *± -50 exercise than epinephrine infusion. Twelve
of 22 patients (55%) had occasional pre-
mature ventricular contractions; among
40- these, four showed couplets, four showed
bigeminy, and one showed transient ven-
tricular tachycardia during epinephrine
infusion. Eight of 22 patients (36%) had
control maximum change
occasional premature ventricular contrac-
END-SYSTOLIC VOLUME tions during exercise; in addition, two
showed couplets and one showed bige-
miny. Hence, epinephrine infusion in-
duced more frequent ventricular arrhyth-
mias than exercise, but this difference was
not significant. Eleven of 22 patients (50%)
-100
experienced chest pain during either epi-
nephrine infusion or exercise, even though
they were not identical patients. In addi-
-50 tion to chest pain, the symptoms of leg
fatigue and shortness of breath were the
main limiting factors during exercise, while
control maximum change
symptoms of emotional distress such as
anxiety, nervousness, and tremor were fre-
STROKE VOLUME
quently mentioned during epinephrine in-
Fig. 2. Left ventricular volume response to epi- fusion.
nephrine infusion and exercise in 22 pa-
tients with coronary artery disease. Com-
parison was made between epinephrine
infusion and exercise at control, maximum DISCUSSION
stress, and percent change from the control.
*p < 0.05; NS, not significant. The dose ranges of epinephrine infu-
sion chosen in this study have been re-

Psychosomatic Medicine 50:381-393 (1988) 387


CASE NO. CONTROL
JN 6*75
/x—JUv_JU
RPP - 92 X 1(T
CE 6*51
>—y—\fy^-
RPP - 93 X 1OZ
RPP - 100 * 10
Fig. 3. Examples of ischemic ST segment depression ( I ) in the V5 lead of the ECG obtained from three
patients during epinephrine infusion and exercise (No. 2 CE shown V4 and V5). Rate-pressure
products (RPP) obtained at equivalent ST segment depression are shown below each ECG tracing.
ported to induce myocardial ischemia in
patients with CAD (26). A previous report
by our group (27) showed that 0.06 and
0.12 fjig/kg/min of epinephrine infusion
produced plasma epinephrine levels anal-
ogous to the physiological levels of en-
dogenous epinephrine reportedly seen
during "mental stress" (17) and public
speaking (16). Therefore, the ranges used
here may be taken to represent physiolog-
ical levels of epinephrine occurring dur-
ing mild to moderate emotional arousal.
The cardiovascular response to exercise
involves stimulation of the sympathoad-
renal system. During vigorous exercise,
norepinephrine and epinephrine both in-
crease, while the change in epinephrine is
small during mild exercise (28). Other
studies (15, 29, 30) also confirm that there
is a sharp increase in norepinephrine but
no significant increase in epinephrine at
388
B. H. SUNG etal.
EPINEPHRINE EXERCISE
/ J
RPP - 162 x 10 RPP - 219 x 10
RPP - 156 X 1OZ RPP -
RPP - 171 X 10 RPP - 217 x 10
workloads of 200-600 KPM during supine
bicycle exercise. The average exercise time
for our study patients was 5.3 minutes,
and they developed ischemic ST changes
at or below the 400 KPM ergometer work-
load. Thus, norepinephrine, but not epi-
nephrine, may be the major component of
the plasma catecholamine response dur-
ing exercise in this study, ruling out any
major confounding influence due to epi-
nephrine accompanying the exercise stud-
ied here.
The present study clearly demonstrates
that the cardiovascular response to epi-
nephrine infusion is significantly different
from that of exercise. Exercise produced a
greater heart rate response compared to
epinephrine infusion, possibly due to in-
hibition of the parasympathetic nervous
system in addition to activation of the
sympathetic nervous system. The systolic
Psychosomatic Medicine 50:381-393 (1988)
EPINEPHRINE-INDUCED ISCHEMIA

150 ezzza Exercise

i i Eplnephrlne
• p < 0.05
100

50

HR SBP RPP EDV

1

Rate Wall Tension Contractility

FACTORS INCREASING MYOCARDIAL OXYGEN CONSUMPTION
-50

Fig. 4. Comparison of factors increasing myocardial oxygen consumption during epinephrine infusion
versus supine bicycle exercise in 13 patients with coronary artery disease. Percent change of heart
rate (HR), systolic blood pressure (SBP), rate-pressure product (RPP), end-diastolic volume (EDV),
left ventricular ejection fraction (LVEF), and contractility index (MCI) were each compared between
epinephrine infusion and exercise.

blood pressure response was similar dur-
ing exercise and epinephrine infusion.
Thus, the rate-pressure product obtained
during exercise was greater than during
epinephrine infusion. Exercise also in-
creased end-diastolic volume significantly
more than epinephrine infusion did. These
results suggest that the increase in myo-
cardial oxygen demand due to heart rate
and myocardial wall tension was greater
during exercise than during epinephrine
infusion.
Our study demonstrates that left ven-
tricular ejection fraction and contractil-
ity index were increased during epi-
nephrine infusion in patients with CAD
in contrast to findings of a decrease or no
change in these parameters during exer-
cise. Contractility has been shown to be
equally as potent in increasing myocar-
dial oxygen consumption as are pressure
or heart rate (31, 32]. However, left ven-
tricular volumes and contractility are
difficult to measure and therefore have

TABLE 1. Comparison of Objective Signs of Myocardial Ischemia Induced by Supine Bicycle Exercise
(Exer) Versus Epinephrine Infusion (Epi)
ST segment Abnormal LVEF Chest Ventricular
depression response pain arrhythmias
Exer 73% (16/22) 91 % (20/22) 50% (11/22) 36% (8/22)
Epi 73% (16/22) 5% (1/22) 50% (11/12) 55% (12/22)
LVEF = left ventricular ejection fraction.
*p < 0.001.

Psychosomatic Medicine 50:381-393 (1988) 389


not been systematically examined as
contributors to myocardial oxygen de-
mand, while heart rate and systolic blood
pressure are easily measured parameters.
There is also an excellent correlation be-
tween myocardial oxygen consumption
and rate-pressure product during exer-
cise in patients with angina (10) as well
as in normal young men (33). Robinson
(34) reported that angina occurred when
a critical rate-pressure product was ex-
ceeded regardless of the type of provo-
cation. One of his patients developed
chest pain during mental arithmetic and
exercise when a critical rate-pressure
product was exceeded. Since that report,
investigators have tried to define the
mechanisms of psychologically-induced
myocardial ischemia on the basis of rate-
pressure product as the sole indicator of
myocardial oxygen consumption. For ex-
ample, Schiffer and colleagues (9) stud-
ied 12 executives with angina and com-
pared the mean rate-pressure product at
the time of equivalent ST segment
depression in response to a stressful quiz
and to exercise. They reported that the
rate-pressure product at ischemic thresh-
old obtained during the quiz was signif-
icantly lower than that obtained during
exercise, (181 ± 64 X 102 vs
2
225 ± 54 x 10 , respectively). They did
not measure ventricular volume and
contractility, but speculated that "emo-
tional stress" may reduce myocardial ox-
ygen supply possibly as a result of coro-
nary vasospasms.
Other work argues against a supply
deficit as the primary cause of ischemia
during emotional arousal. Specchia and
coworkers (11) studied 122 patients
undergoing coronary angiography and
found a group of 20 patients who had ST
segment changes during "mental stress"
as well as supine bicycle exercise. They
390
B. H. SUNG e t a l .
measured great cardiac vein flow in four
patients who showed ST segment changes
in anterior leads and reported that flow
increased and coronary resistance de-
creased in three patients during this
"stress." Only one patient with variant
angina had increased coronary resis-
tance. These data suggest that the blood
supply to the myocardium can and does
increase during psychological stimula-
tion. Therefore, ischemia thus induced is
not usually due to coronary vasocon-
striction, even though it may occur in
patients with variant angina. Specchia et
al. did not measure ventricular volumes
or contractility either, but the rate-pres-
sure product that they obtained during
exercise (185 ± 50 x 102) was again
higher than that during mental stress
(160 ± 33 x 10z) (11). These authors
concluded that a disproportionate in-
crease in myocardial oxygen consump-
tion during mental stress in susceptible
patients may be responsible for is-
chemia.
In the present study, we measured
ventricular volumes and contractility in
addition to heart rate and blood pressure
during two different adrenergic stimuli to
more accurately compare factors increas-
ing myocardial oxygen consumption
during myocardial ischemia. Both epi-
nephrine infusion and supine bicycle ex-
ercise induced myocardial ischemia as
evidenced by ST segment depression in
patients with CAD.
However, the factors increasing myo-
cardial oxygen consumption during the two
conditions were significantly different in
patients with proven coronary disease.
Epinephrine infusion induced myocardial
ischemia at a lower rate-pressure product
than during exercise, because in the for-
mer case an increase in contractility con-
tributed to an increased myocardial oxy-
Psychosomatic Medicine 50:381-393 (1988)
EPINEPHRINE-INDUCED ISCHEMIA
gen consumption sufficiently to induce
ischemia. Ourfindingsof a lower ischemic
rate-pressure product during epinephrine
infusion parallel those of studies contrast-
ing psychological arousal with exercise.
Together, these results suggest that the rate-
pressure product may be a reliable index
of myocardial oxygen consumption during
exercise, but is less so during stressors that
preferentially elevate adrenomedullary
activity. In such cases, contractility may
play a major role in increasing oxygen de-
mand of the heart.
The hemodynamic response to epi-
nephrine infusion in our study strikingly
resembled the cardiovascular response to
mental stress reported by Hjemdahl et al.
(35) and Atterhog et al. (36). Anxiety and
other centrally mediated symptoms, and
the arrhythmogenic response seen dur-
ing epinephrine infusion, also indicate
that epinephrine may play a major role
in mediating cardiovascular responses to
psychological stimuli. Therefore, we pro-
pose that such stimuli may induce myo-
cardial ischemia at a lower rate-pressure
product than exercise by increasing con-
tractility, via elevated adrenomedullary
activity, in addition to increasing the rate-
pressure product. Studies of direct mea-
surements of ventricular volumes and
contractility, and catecholamine levels,
during psychological stimulation in pa-
tients with CAD, are needed to confirm
this hypothesis.
SUMMARY
Epinephrine-induced myocardial is-
chemia was compared with that due to ex-
ercise in 22 patients with angiographically
proven coronary artery disease in order to
elucidate the mechanisms of ischemia in-
duced by other stressors having a signifi-
Psychosomatic Medicine 50:381-393 (1988)
cant adrenal medullary component. Left
ventricular volumes and contractility were
measured in addition to hemodynamics to
evaluate the factors determining myocar-
dial oxygen consumption more com-
pletely. Heart rate increased significantly
more during exercise (p < 0.005], while
the systolic blood pressure response was
similar during exercise and epinephrine
infusion; thus, the rate-pressure product
obtained at the time of ischemia was sig-
nificantly higher during exercise than dur-
ing epinephrine infusion (p < 0.005). End-
diastolic volume increased more during
exercise than during epinephrine infusion
(24% versus 6%) and ischemia limited the
myocardial contractility response during
exercise, but not during epinephrine in-
fusion. These results indicate that al-
though the rate-pressure product may re-
flect myocardial oxygen consumption
during exercise, this product does not ac-
curately portray the cardiac workload sec-
ondary to stressors having a major effect
on the rate of adrenal medullary secretion.
Exercise-induced ischemia was due pre-
dominantly to an increase in heart rate and
rate-pressure product with a minor con-
tribution of end-diastolic volume, while
epinephrine-induced ischemia was brought
about by a marked increase in contractility
of the heart with a smaller increase in heart
rate and rate-pressure product.
This research was supported by funds
from the Medical Research Service of the
Veterans Administration.
The authors gratefully acknowledge the
technical assistance of Ronald Lee for ra-
dionucJide ventriculography, and the sec-
retarial assistance ofRathene Bronson for
typing the manuscript. We also thank Dr.
Donald E. Parker for his assistance in sta-
tistical analysis of the data.
391
 B. H. SUNG etal.

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PLAN TO ATTEND

46th ANNUAL MEETING

AMERICAN PSYCHOSOMATIC SOCIETY

MARCH 9-11, 1989

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Psychosomatic Medicine 50:381-393 (1988) 393