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TRIGGERS AND TIMING OF CARDIAC EVENTS
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MENTAL STRESS AS A TRIGGER
OF
MYOCARDIAL ISCHEMIA AND
INFARCTION
David
S.
Krantz,
PhD,
Willem
J.
Kop,
PhD,
Helen
T.
Santiago,
MA,
and
John
S.
Gottdiener,
MD
Acute and chronic stress long have been
suspected as risk factors for coronary artery
disease morbidity and mortality. Among the
lay public, it is widely believed that acute
stress can act as a trigger for myocardial in-
farction (MI) and sudden cardiac death. Until
recently, this view was corroborated primar-
ily by anecdotal and case reports,2l some epi-
demiologic and human and animal
studies demonstrating physiologic and patho-
physiologic effects of mental stress on the
cardiovascular
46
Despite this re-
search literature, the cardiology community
has regarded the evidence for a causal link
between mental stress and the onset of acute
cardiovascular events with skepticism.',
29
Doubts about the scientific validity and clini-
cal relevance of this evidence have resulted
from difficulties in defining and measuring
stress, the multifactorial nature of coronary
disease and its onset, and the presence of
numerous confounding variables in epidemi-
Preparation of this article was assisted by a grant from
the NIH (HL47337) and USUHS grant R07233. The opin-
ions and assertions expressed herein are those of the
authors and are not to be construed as reflecting the
views of the USUHS or the US Department of Defense.
ologic studies. Moreover, although observa-
tional epidemiologic studies can point to as-
sociations between stress and coronary artery
disease events, they do not reveal mecha-
nisms by which psychosocial stress can affect
the onset and course of coronary artery dis-
ease.
Several recent developments have led to an
increased interest in the role of stress as a
trigger
of
clinical cardiovascular events. Al-
though widely debated for many years, re-
cent evidence implicates vulnerable plaque in
the onset of acute MI, and suggests that in
susceptible patients, acute events are fre-
quently triggered by activities such as physi-
cal or mental stress rather than occurring
spontane~usly.~~ In addition, studies making
use of a variety of current techniques for as-
sessing cardiac function in the laboratory and
in the field provide convincing evidence for
the pathophysiologic mechanisms and effects
of behavioral factors as triggers of myocardial
ischemia.'6*
28,
61
Although the endpoints of pri-
mary importance for the prevention of cardio-
vascular disease include MI, unstable angina,
and sudden cardiac death, research on ische-
mia has provided a pathophysiologic model
From the Department of Medical and Clinical Psychology, Uniformed Services University of the Health Sciences,
Bethesda, Maryland (DSK, WJK, HTS); and the Department of Psychiatry (DSK) and Department of Medicine,
Division of Cardiology
(JSG),
Georgetown University Medical Center, Washington, D.C.
CARDIOLOGY CLINICS
VOLUME 14
-
NUMBER
2
*
MAY
1996
271
272
KRANTZ
et
a1
for understanding mechanisms by which
mental stress may trigger clinical events. This
article reviews evidence for the pathophysio-
logic effects of acute mental stress in individ-
uals with pre-existing coronary artery disease,
recent epidemiologc research implicating psy-
chosocial stress as an acute trigger of MI in
patients with pre-existing coronary artery dis-
ease, and field and laboratory studies that
suggest important causal links between men-
tal stress and myocardial ischemia. The focus
of this review is on the acute triggering role
of mental stress for clinical events, rather than
on the chronic effects of stress on coronary
artery disease pathology.
THE PHYSIOLOGIC RESPONSE TO
STRESS
Possible Influences on Triggering
The foundation for the extensive body of
research on the pathophysiologic conse-
quences of stress was provided by the emi-
nent physiologist Walter Cannon, who ob-
served that behavioral states such as fear and
anger elicited a massive sympathetic "fight-
or-flight" response marked by increases in
circulating
cat echo la mine^.^
Later, Selyeffl de-
scribed a generalized physiologic stress re-
sponse to a variety of noxious stimuli,
marked by activation of the pituitary-adrenal
cortical axis. Contemporary stress research
emphasizes the crucial role of interpretation
or appraisal of events or stimuli for the per-
ception of stress and the elicitation of physio-
logic responses.43,
47
Accordingly, stress can be
broadly defined as a negative internal state
of the individual that is dependent on inter-
pretation or appraisal of threat, harm, or
demand. The stress response most often
includes release of catecholamines and corti-
costeroids, with concomitant increases in
heart rate, contractility, cardiac output, and
blood pressure.4o Recent research also
sug-
gests that acute stress also can affect pro-
cesses that are relevant to hemostasis and
thrombosis. For example, acute mental stress
results in increased platelet activation, in-
creased blood viscosity, and acute decreases
in
circulating plasma volume.52*
59,
70
Pathophysiologic Model
of
the
Effects of Stress on Cardiovascular
Pathology
Current models of the effects of mental and
physical stress on cardiac pathophy~iology~~,
54
suggest that behaviorally induced auto-
nomic nervous system activation might pre-
dispose to clinical cardiovascular events at
several levels:
1)
by promoting atherosclerosis
or coronary endothelial dysfunction,
2)
by
in-
fluencing intermediate pathologic and patho-
physiologic processes that occur in the presence
of atherosclerosis and increase vulnerability to
clinical events (e.g., myocardial ischemia, coro-
nary thrombosis, plaque rupture); and
3)
by
directly triggering lethal arrhythmias through
alterations of neural transmission to the
heart.35,
52
Pathophysiologic pathways linking
acute mental stress to myocardial ischemia
and acute cardiac events in vulnerable indi-
viduals with coronary artery disease are pre-
sented in Figure
1.
These pathways are pre-
sumed to operate among individuals who are
predisposed to clinical events by virtue of
pre-existing atherosclerosis or coronary endo-
thelial dysfunction, prior MI, or poor left ven-
tricular function.
Evidence suggests several specific compo-
nents of the physiologic responses to stress
that may promote coronary vasoconstriction,
platelet aggregation, or plaque rupture. For
example, mental stress can produce arterial
pressure surges, often comparable to those
elicited by acute exercise.61 In patients with
vulnerable plaque this surge may cause a
plaque rupture and lead to occlusive or non-
occlusive coronary thrombo~is.~~ In the pres-
ence of atherosclerosis, stress-induced in-
creases in blood pressure, heart rate, and
catecholamines lead to increases in myocar-
dial oxygen demand that can result in acute
myocardial ischemia. Furthermore, if mental
stress has induced coronary vasoconstriction
or a state of hypercoagulation, then a small
thrombus may trigger a blood clotting cas-
cade resulting in acute coronary occlusion
and subsequent MI, ischemia, or vulnerability
to arrhythmias or sudden death. Recent evi-
dence also suggests that mental stress can
lead to arterial vasoconstriction in diseased
coronary vessels with damaged coronary en-
MENTAL STRESS AS A TRIGGER
OF
MYOCARDIAL ISCHEMIA AND INFARCTION
273
?
Electrical
Instability
t
Catecholamines
+
......................
?
Heart Rate
T
Blood
Pressure
-
?Demand
......................
...............................
1
Plasma volume
T
Coronary
-
1
Supply
Constriction
...............................
Physiological Cardiac Pathological Cardiac
Responses Effects Result Event
Sudden
-
Cardiac
Death
VFNT
......................
--b
-
Ischemia
+
+
......................
Myocardial
-
Infarction
*
Plaque
4-b
Rupture
......................
.Coronary
--b
?
Platelet Activity
I
I
Thrombosis
Figure
1.
Pathophysiologic model
of
the actions
of
acute stress as a trigger of myocardial infarction
and sudden death in vulnerable individuals. Via its actions on the central and autonomic nervous
system, in patients with coronary artery disease stress can produce a cascade of physiologic
responses that may lead to myocardial ischemia, ventricular
fibrillation/tachycardia
(VFNT), plaque
rupture, or coronary thrombosis.
(MI
=
myocardial infarction; LV
=
left-ventricular.)
d0the1ium.I~ Yeung et al” found that diseased
coronary segments constricted during mental
arithmetic while non-diseased, smooth seg-
ments either vasodilated or showed no
change in diameter
(Fig.
2).
Coronary vaso-
constriction or dilation to mental stress was
significantly correlated with the response to
intracoronary infusions of acetylcholine, sug-
gesting that coronary endothelial dysfunction
is a mechanism for paradoxic vasoconstric-
tion. A more detailed discussion of the inter-
action of myocardial supply and demand
mechanisms that may be relevant for trig-
gering of acute coronary syndromes is pre-
sented in a later section on myocardial ische-
mia.
EPIDEMIOLOGIC EVIDENCE FOR
PSYCHOSOCIAL STRESS
AS
A
TRIGGER
OF
ACUTE
CARDIOVASCULAR EVENTS
The epidemiologic literature linking psy-
chosocial stress to coronary artery disease
morbidity and mortality has been reviewed
elsewhere.21,
30,
35,
67, 74
This diverse literature
encompasses the effects of chronic stressors
including social isolation and lack of social
support,l’,
62,
73
the effects of stressful occupa-
tions on coronary artery disease the
effects of emotional distress and depression
chosocial prodromata preceding lethal ar-
rhythmias and sudden cardiac death:
21,36,41,58
and the triggering effects of acutely stressful
events
on
MI or sudden cardiac death.5,
21,
32*
37,
48,
50
Although it is often difficult to disen-
gage the acute, short-term effects from the
chronic effects of psychological stress, in this
section we confine our review to research in
the former category, dealing with mental
stress as an acute trigger of MI in individuals
presumed to have pre-existing coronary ar-
tery disease.
on prognosis in patients after MI,10,22,24 PSY-
Life Crises, Disasters, and Acute
Cardiovascular Events
Several studies have explored the relation-
ship of stressful life events to the occurrence
of MI or sudden cardiac death. For example,
Myers and De~ar,5~ in an uncontrolled study,
observed that stressful life events were re-
ported to have occurred among
40
of
100
274
KRANTZ
et
a1
Figure
2.
Effects of mental stress (mental arithmetic) on epicardial
coronary artery diameters in stenosed, irregular, and smooth seg-
ments. Stenosed segments constricted a mean of
-24%
2
4%,
irregular segments constricted
-9%
2
3%, while smooth segments
were unchanged (+3%
2
3%).
(From
Yeung
AC,
Vekshtein VI,
Krantz
DS,
et al: The effect
of
atherosclerosis on the vasomotor
responses
of
coronary arteries
to
mental stress. N Engl J Med
325:1551-1556, copyright 1991, Massachusetts Medical Society;
with permission of the New England Journal of Medicine.)
sudden death victims in the
24
hours preced-
ing death. Similarly, Cottington et all4 found
that
loss
events occurred to sudden death
victims more frequently than to controls.
These and related studies, however, are
subject to the criticism of biased recall of
stressful events by relatives or friends of sud-
den death victims, who served as informants
in these studies. Somewhat more convincing
are studies that have prospectively explored
the link between emotional trauma and MI or
sudden death by examining individuals who
have undergone severe life crises. Parkes et
a158 followed up a large cohort of middle-
aged widowers and observed a
40%
increase
in the mortality rate in the first
6
months
following bereavement; more than half of this
increased mortality was attributed to cardio-
vascular causes. It is possible, however,
to
partially attribute the increased mortality
among widowers to changes in lifestyle dur-
ing the grieving process
or
to unfavorable
environments shared by the widower and the
deceased rather than to stress per se.
Research also has documented an increase
in cardiovascular deaths and increased rates
of MI following several general disasters and
personal traumas. A recent set of studies has
explored the effect of Iraqi missile attacks on
Israel during the initial days of the 1991 Gulf
War on fatal and nonfatal cardiac events
among the population living close to Tel
A~iv.~~ Cases
of
acute MI treated in the inten-
sive care unit of a Tel Aviv medical center
were elevated during the week following the
missile attacks (January 17-25, 1991) com-
pared with the week prior to the attacks and
with an index period consisting of the same
week a year earlier (Fig.
3).
Mean age and sex
distribution were similar in all study periods.
In addition, data from a mobile intensive care
ambulance showed an increase in the sudden
death rate during January 1991 (41 deaths)
compared with the same period a year earlier
(22
deaths). A second report extended this
finding by examining mortality statistics
among the entire Israeli population during
this period. The day of the first missile strike,
excess mortality observed was greater among
women than among men (77% versus
41%,
P
<
0.01).37 Moreover, this mortality excess
occurred largely in the Tel Aviv area where
the missile attacks occurred and was attribut-
able to cardiovascular causes. In explaining
these findings of increased incidence of MI
and sudden death,
two
possible causes are
MENTAL STRESS AS A TRIGGER
OF
MYOCARDIAL ISCHEMIA AND INFARCTION
275
7
2
c
3
'i
24
3
10
ilr
11
12
ll
13
111
13
20
11
1
lu[l
21
22
23
24
25
January
Figure
3.
Daily incidence of acute myocardial infarction
(MI)
observed in Tel Aviv-area coronary care units during the period
of
the Iraqi missile attack period (January 8-25, 1991)
(filled
columns)
as compared with the same time period in 1990
(un-
filled columns). (Large arrow
=
beginning
of
the Gulf War;
small
arrows
=
missile attacks on Israel.)
(From
Meisel
SR,
Kurtz
I,
Dayan KI, et al: Effects of Iraqi missile war on incidence
of
acute myocardial infarction and sudden death in Israeli civilians.
Lancet 338:660-661, copyright 1991 The Lancet Ltd.; with per-
mission.)
most compelling: the stressful conditions
posed by fear
of
the missile attacks, and respi-
ratory difficulties resulting from the policy of
confining the affected population to sealed,
unventilated rooms. Supporting the former
explanation is the fact that women experi-
enced a higher excess
of
event rates and also
reported proportionately more distress re-
sulting from confinement in sealed rooms
during the first attack. On the other hand,
confinement was significantly longer during
the first missile attacks compared with subse-
quent attacks, during which time the Israeli
population appears to have adapted to the
situation. It should be noted however, that
excess cardiovascular mortality has
not
been
noted in other war-related settings (e.g., the
London blitz during World War II), perhaps
because cardiac mortality was masked by
other war casualties, because the perceived
level of fear was less intense, or because of
particular coping mechanisms that may have
been available to the London population dur-
ing the war.
Excess cardiac mortality attributed to acute
psychological stress also has been reported
following earthquakes and other natural di-
sasters in at least three different settings. Dur-
ing the
5
days after the 1981 Athens earth-
quake, the incidence of cardiac deaths nearly
doubled.72 Another study reported a
22%
in-
crease in ischemic heart disease deaths fol-
lowing blizzards in Ma~sachusetts.~~ In the
latter
two
studies, it is not possible to deter-
mine the relative roles of increases in physical
activity versus mental stress. An increased
incidence of acute MIS has recently been re-
ported during the 1994 Los Angeles earth-
quake for critical-care unit admissions for
acute MI (odds ratio
2.4)
but not for unstable
angina in the week following the earthquake,
compared with the week before the disaster,
particularly for hospitals within 15 miles of
the earthquake epicenter.45
Another approach to studying psychologi-
cal and behavioral antecedents
of
acute MI is
to assess the occurrence of possible triggers
prior to the events. Several studies of patients
276
KRANTZ
et
a1
hospitalized for acute MI have implicated
psy.chologically stressful events as possible
external triggers occurring prior to onset.
Tofler et a171 reported that among 849 patients
with acute MI, 48% reported one or more
possible triggers, the most common of which
was emotional upset. Behar et a15 identified
possible external triggers in
10%
of acute MI
patients. These triggers included heavy physi-
cal work, a violent quarrel at work or home,
and unusual mental stress within 24 hours
preceding the onset of pain. The lower per-
centage of possible triggers reported in the
latter study may be due to a somewhat differ-
ent method of data collection, which required
a reported possible external trigger to be ei-
ther an extraordinary physical activity or very
uncommon emotional stress5
A
more sophisticated approach has been
employed by Mittleman et al,49,
50
who used a
case-crossover design, a novel epidemiologic
methodology that compares each patient's
pre-MI activities to his or her usual levels of
activities, to assess the proximal physical and
mental triggers of onset of MI. In
a
multicen-
ter study of patients interviewed a median of
4
days post-MI, 39 of 1623 patients inter-
viewed (2.4%) reported episodes of anger
within the
2
hours prior to MI onset. The
relative risk of MI following episodes of
anger was 2.3. In an assessment of possible
modifiers of triggers of anger, this relative
risk was significantly lower among regular
users of aspirin. There were also nonsignifi-
cant trends for the relative risk to be lower in
women than men and in regular users of
beta-adrenergic medications versus nonusers.
It should be noted, however, that this meth-
odology cannot circumvent the inferential
problems related to retrospective bias, be-
cause patients' awareness of their
MI
may
have affected their reported emotional re-
sponses.
MENTAL STRESS AS A TRIGGER
OF
MYOCARDIAL ISCHEMIA
Although the final endpoints of primary
importance for the prevention of cardiovascu-
lar disease are MI and sudden cardiac death,
laboratory and field research on myocardial
ischemia as an intermediate measure has pro-
vided a pathophysiologic model for under-
standing mechanisms by which mental stress
may trigger clinical events. An additional ad-
vantage of studying ischemia is that it often
occurs without symptoms, which allows
studies of triggers unconfounded by re-
porting biases.
Holter monitoring studies reveal that in
coronary artery disease patients, transient is-
chemia during daily life exhibits features that
may differ from myocardial ischemia elicited
during exercise testing in the laboratory. For
example, out-of-hospital ischemia occurs dur-
ing a wide variety of physical and mental
activities and not just during strenuous exer-
cise. Out-of-hospital ischemia also is predom-
inately silent (asymptomatic) and occurs at
relatively low heart rate elevations compared
to ischemia triggered by exercise testing.17
There also is a typical circadian rhythm for
myocardial ischemia51,
6o
and an unexplained
variability in the frequency of ischemic epi-
sodes when patients are repeatedly moni-
tored over time.56
There is convincing evidence to indicate
that the aforementioned features of out-of-
hospital myocardial ischemia are caused by
the differences between the circumstances of
controlled exercise testing and the stresses
of daily life activities. That is, the observed
features of out-of-hospital myocardial ische-
mia are produced by the interaction of patient
behaviors, including mental stress, with the
underlying pathobiology of coronary artery
disease. Unlike the controlled and graded ex-
ercise testing situation, patients out of the
hospital encounter a broad range of physical
and mental stimuli, and many of these
stresses occur suddenly and in an uncon-
trolled fashion.
Evidence for Mental Stress as a
Trigger of Myocardial Ischemia
Ambulatory
ECG
Studies
Freeman et a125 examined the relationship
of life stress to transient ischemia by compar-
ing a group of patients during a period of
uncertainty (i.e., following coronary angiog-
MENTAL STRESS AS A TRIGGER
OF
MYOCARDIAL ISCHEMIA AND INFARCTION
277
raphy but prior to finding out the results of
this diagnostic test) and subsequently during
a less stressful period when patients had had
time to adjust to their diagnosis. In addition
to ambulatory electrocardiographic monitor-
ing and diary ratings of distress, measures
of urinary catecholamine output also were
taken. Results indicated that silent ischemia
was significantly more frequent during the
first, more stressful period than during the
second, less stressful one. Patients with more
silent ischemia on the first occasion reported
more emotional upset and had higher urinary
norepinephrine levels compared with the sec-
ond period. These data provide further evi-
dence of an association between mental stress
and ischemia and also suggest that emotional
states may account for some of the unex-
plained within-patient variability in the oc-
currence of transient ischemia over time.
In several investigations, patient diary self-
reports have been correlated with the results
of ambulatory monitoring of the ST segment.
Schang and demonstrated that the
majority
(75%)
of
ischemic episodes were
asymptomatic and occurred at rest or during
very light activity such as slow walking or
sitting. Thus, ischemia in these patients was
only infrequently accompanied by strenuous
physical exercise. Several other studies have
since corroborated these findings.12
Barry et a14 further investigated the rela-
tionship between patients' perceived level of
physical and mental activity and the objective
occurrence of ST depression during daily life.
Patients completed a diary in which blocks of
time were marked off for time spent in vari-
ous
activities during the day. Patients were
instructed
1)
to make an entry whenever their
activities changed,
2)
to simultaneously clas-
sify activities as either
physical
or
rnentd,
and
3)
to classify the intensity of the activity as
either
rest,
usual,
or
stress.
Analysis of data
(Fig.
4)
revealed that the majority of episodes
of ST-segment depression occurred during
daily activities involving low or moderate
levels of physical activity. Examples of such
activities are talking on the phone, doing cler-
ical work, and conversing with a friend. Most
ischemic events also occurred during activi-
ties classified as "usual" physical or "usual"
mental activity, and a minority of
ST
events
a,
0.40p
0.32
2"
Sleeo Inactive Eatina Usual
Liaht
Heaw
"
Sleep
Relaxation Reading Usual Heavy
Tv
Figure
4.
For physical activities
(A)
and mental activities
(B),
ST
depression during ambulatory electrocardio-
graphic monitoring is plotted according to the type of
activity reported by patients in the study by Barry et al.
The duration of ST depression in each category is cor-
rected (or normalized) for the amount of time spent
in
each activity during the course of the day. Note that more
physically intense activities
(A,
right) and more mentally
stressful activities
(B,
right) are associated with more
ischemia per unit time.
(Adapted
from
Barry
J,
Selwyn
AP,
Nobel EG, et al: Frequency of ST-segment depression
produced by mental stress in stable angina pectoris from
coronary artery disease. Am
J
Cardiol
61
:989-993, 1988;
with permission.)
occurred during situations that the patient
described as stressful, or when patients were
asleep. Activities described as usual, by their
nature, also are engaged in more frequently
during the day. To control for this, the dura-
tion of ST-segment depression was divided
by the total time spent in each category.
When this was done, a graded relationship
was found between the occurrence of ische-
mia and the intensity of both mental and
physical activities. These findings suggest
that as the intensity levels of both mental and
physical activities increase, they are increas-
ingly likely to precipitate transient ischemia
during daily life. Because high levels of exer-
cise are relatively infrequent, however, and
mental activities are rather frequent during
daily life, usual mental activities may be a
more common trigger of transient ischemia.
Gabbay et alZ6 corroborated and extended
these findings and assessed the effects of spe-
278
KRANTZ
et
a1
cific emotions on ischemia by using a more
sophisticated diary in a sample of
63
patients
undergoing ambulatory electrocardiographic
monitoring. Ischemia occurred most fre-
quently during physical and mental activities
of moderate intensity. Patients spent the
largest proportion of time engaged in low-
intensity physical and mental activities, but
the likelihood of ischemia was greatest dur-
ing intense physical and stressful mental ac-
tivities. The percentage of time in ischemia
(5%
of the time) was approximately equiva-
lent for high-intensity physical and high-in-
tensity mental activities, compared with
0.2%
of the time when patients were engaged in
low intensity activities. Strenuous physical
activity (e.g., walking) and the experience of
intense anger were potent ischemic triggers,
and heart rates at onset of ischemia increased
with physical and mental activity intensity
and with anger. Among smokers, ischemia
was more than five times more likely when
patients were smoking than when they were
not smoking. Coffee and alcohol drinking
also were related to ischemia, but this associa-
tion disappeared after controlling for concur-
rent cigarette smoking.
Thus, the triggers of ischemia in coronary
artery disease patients during daily life in-
clude not only strenuous exercise but also
low-exertional activities such as anger and
smoking. Mental activities appear to be as
potent as physical activities in triggering
daily-life ischemia. Cigarette smoking also is
a trigger of ischemia, but coffee and alcohol
drinking are related to ischemia only by vir-
tue of their associations with smoking.
There also is some evidence that mental
and physical activities contribute to the well-
established circadian rhythm (morning in-
crease) in ischemia. In a recent investigation,
Parker et a157 demonstrated that the increase
in activity upon awakening plays a crucial
role in the circadian pattern of ischemia. The
potency of out-of-hospital mental and physi-
cal activities as triggers of ischemia at differ-
ent times of the day has recently been exam-
ined by Krantz et al.39 The effect of physical
activities as triggers of ischemia was greatest
in the morning. High physical activity trig-
gered ischemia to a lesser but still significant
extent in the afternoon but not during the
evening. Mental activity triggered ischemic
events significantly during the morning and
evening, but not in the afternoon. Thus, phys-
ical and mental activities appear to be most
potent as triggers of ischemia during the
morning hours.
In summary, findings derived from ambu-
latory electrocardiographic monitoring stud-
ies suggest that a variety of physical and
mental activities are associated with the oc-
currence of transient ischemia during daily
life. Physical and mental stress both are par-
ticularly potent triggers. The data also sug-
gest that a different profile of activities (more
exercise-related, perhaps associated with
greater anxiety) accompanies painful versus
painless ischemic There also is
evidence that the activities that patients en-
gage in throughout the day may contribute
to, although they do not entirely account for,
the circadian rhythm of ischemia throughout
the day. Thus, a picture is emerging that indi-
cates that many characteristics of out-of-hos-
pita1 ischemia may be attributable to behav-
ioral influences, including the stresses of
daily life.
Laboratory Studies of the Causal
Effects of Mental Stress as a Trigger of
Ischemia
Because field studies are correlational, they
cannot be used to establish causal relation-
ships between mental stressors and ischemic
episodes and are not optimal for the study of
pathophysiologic mechanisms that may ac-
count for stress-ischemia relationships. Ac-
cordingly, a variety of new and sensitive non-
invasive means for evaluating the effects of
myocardial ischemia on cardiac function (e.g.,
radionuclide ventriculography, positron emis-
sion tomography) have provided insights into
the possible role of mental stress as a causal
factor for cardiac dysfunction
in
coronary ar-
tery disease patients.
Several studies have noted electrocardio-
graphic changes, such as
ST
depression, pre-
cipitated by psychologically stressful circum-
stances (e.g., public speaking, automobile
driving) in normal individuals and selected
patients.68*
69
In addition, a handful of labora-
MENTAL STRESS AS A TRIGGER
OF
MYOCARDIAL ISCHEMIA AND INFARCTION
279
tory studies have manipulated mental stress
and examined its effects on myocardial ische-
mia based solely on electrocardiographic
changes in the ST segment. The results of
these studies, however, have been inconsis-
tent at best.18,
63
For example, Specchia et aP6
compared the effects of mental arithmetic
testing on the electrocardiographic markers
of ischemia with the effects of exercise in
122 consecutive patients who had undergone
coronary angiography. They found that 22
(18%) of these patients displayed significant
ST-segment abnormalities, all of whom also
showed abnormalities during exercise testing.
Chest pain accompanied
ST
depression in
8
of these 22 patients. Based on the aggregate
results of these studies, it was apparent that
mental stress can induce electrocardiographic
evidence of ischemia in patients with coro-
nary artery disease, but the observed inci-
dence is relatively low
(<
20%), and is rarely
observable among patients without positive
exercise electrocardiograms.
In the past decade, studies have utilized a
variety
of
more sensitive noninvasive means
for evaluating the effects
of
mental stress on
myocardial ischemia (e.g., radionuclide ven-
triculography, positron emission tomogra-
phy, continuous monitoring of left ventricular
function, two-dimensional echocardiogra-
phy). Use of these techniques has resulted in
new insights concerning the role of mental
stress as a causal factor for cardiac dysfunc-
tion in coronary artery disease patients. The
results of these studies have revealed that
laboratory mental stressors can provoke is-
chemia in a substantial subset of coronary
artery disease patients. This ischemia is usu-
ally silent, only infrequently is accompanied
by electrocardiographic evidence of ischemia,
and occurs primarily among patients with ev-
idence of exercise-inducible ischemia.
For example, Deanfield et all6 used positron
emission tomography to measure diminished
myocardial perfusion during mental stress in
16
patients with typical angina and coronary
artery disease. These patients underwent a
mental arithmetic test and exercise while re-
gional myocardial perfusion and ischemia
were assessed. With mental arithmetic, 12
(75%)
of these patients had abnormalities of
perfusion, whereas only six of these patients
showed ST-segment depression and four had
angina. With exercise, all of the patients
showed abnormal regional perfusion in the
same cardiac segments that evidenced ische-
mia with mental arithmetic.
Rozanski et al6I used radionuclide ventricu-
lography to study the effects of a series of
mental stressors on left ventricular wall mo-
tion and ejection fraction and to compare
these effects with those of exercise. Thirty-
nine coronary artery disease patients and 12
normal controls were evaluated. Segmental
wall motion scores and ejection fractions were
determined from the ventriculography; heart
rate, blood pressures, and a continuous elec-
trocardiogram recording also were obtained
for each subject. Results of the study (Fig.
5)
revealed that among 29 of 39 coronary artery
disease patients with exercise-induced wall
motion abnormalities, 21 (72%) also showed
wall motion abnormalities to mental stress.
For a high proportion of these patients, left
ventricular dysfunction during mental stress
was severe, as evidenced by a concomitant
6%
or greater fall in ejection fraction. The
speech stressor was found to be the most
potent of the mental tasks and was signifi-
cantly different from the other mental tasks
in the induced frequency and magnitude of
wall motion abnormality. Indeed, in several
patients, the magnitude of wall motion abnor-
malities during the speech was comparable to
that induced by exercise in the same patient.
In contrast, among those patients who did not
demonstrate an exercise-induced wall motion
abnormality, ischemic abnormalities induced
by the mental stressors were infrequent. An-
other significant finding within this study
was that most of the mental stress-induced
ischemia was silent (i.e., without chest pain),
and electrocardiographic abnormalities were
observed in only a minority of these patients
during mental stress.
Other studies using sensitive cardiac im-
aging techniques also illustrate the ability of
mental stress to induce cardiac dysfunction
in patients with coronary artery disease. Gott-
diener et alZ8 used two-dimensional echocar-
diography to demonstrate frequent evidence
of transient wall motion abnormalities oc-
curring rapidly and asymptomatically during
mental stress. The magnitude
of
stress-in-
280
KRANTZ
et a1
Figure
5.
Percent
of
patients in a study by Rozanski et alsl with
mental stress-induced ischemia as indexed by left-ventricular
wall motion abnormalities
(WMA)
measured by radionuclide
ventriculography or by electrocardiography.
WMAs
in response
to
mental stress occurred in
21
of
29
patients who displayed
exercise-induced
WMAs.
Electrocardiographic evidence
of
is-
chemia was present in
only
six patients in the study.
duced wall motion abnormalities and the
number of mental stressors capable of induc-
ing ischemia were related to the functional
severity of exercise-inducible ischemia in
these patients, possibly reflecting a greater
functional severity of coronary disease among
those patients more susceptible to mental-stress
ischemia.
In
other research using a stationary
radionuclide detector capable of assessing beat-
to-beat changes
in
ejection fraction, LaVeau et
a14* and Burg et a18 demonstrated transient de-
creases in left ventricular ejection fraction oc-
curring rapidly upon the onset of mental
stress. Two studies7,
44
used an ambulatory
radionuclide detector to observe transient de-
creases in ejection fraction during mental
stress in patients who had similar falls in-
duced by exercise. Ironson et al3I reported
that an anger-inducing stressor was a particu-
larly potent psychological stressor in its abil-
ity to trigger left ventricular dysfunction (i.e.,
acute drops in ejection fraction) compared
with other stressors.
PATHOPHYSIOLOGY
OF
MENTAL
STRESS
ISCHEMIA
Although mental stressors produce reliable
increases in heart rate and blood pressure,
the magnitude of heart rate responses was
much less during the mental tasks than during
exercise in the same patient. Blood pressure
changes, however, were comparable between
exercise and mental tasks. Hemodynamic re-
sponses to mental stress and exercise observed
in one study61 are presented in Figure
6.
The
double product (systolic blood pressure
X
heart rate) at onset of ischemia is markedly
less for mental-stress ischemia than for exer-
cise ischemia, raising the possibility that a
primary reduction in myocardial oxygen sup-
ply also might be operative during mental
stress-induced ischemia. Recent research by
Yeung et al,75 in which constriction of epicar-
dial atherosclerotic coronary segments in re-
sponse to mental stress was observed, has
provided supportive evidence for this specu-
MENTAL STRESS AS A
TRIGGER
OF MYOCARDIAL ISCHEMIA AND INFARCTION
281
lation. These investigators, however, did not
observe a significant decrease in epicardial
coronary blood flow
in
atherosclerotic arter-
ies, suggesting that mental-stress ischemia
could not be attributed to epicardial coronary
constriction alone. Therefore, Dakak et all5
assessed the effect of mental stress (a chal-
lenging video game) on flow responses of the
coronary microcirculation (calculated from
epicardial coronary blood flow and mean
blood pressure) in
10
patients with mild coro-
nary artery disease and in five individuals
with normal coronary angiograms. They ob-
served that the coronary arteries
of
normal
patients dilated during mental stress, but in
patients with mild coronary artery disease,
there was evidence of impaired dilation of
coronary resistance vessels. Thus, it is reason-
able to hypothesize that ischemia produced
by mental stress is attributable, in part, to a
failure of the coronary microcirculation to di-
late during stress.
As
already noted, the relatively low heart
rates and double products associated with
mental stress-induced ischemia suggest that
factors that decrease myocardial oxygen sup-
ply may be operative. The significant blood
pressure responses (see Fig.
6)
produced by
the stressors, however, raise the possibility
that elevated myocardial oxygen demand also
contributes to stress-induced ischemia. In this
regard, there is a relationship between pa-
tients’ hemodynamic responses and their
susceptibility to mental stress-induced ische-
Figure
6.
Differences from control levels in heart rate, systolic
blood pressure (SBP), and diastolic blood pressure (DBP) pro-
duced by four mental tasks and at peak bicycle exercise in
patients with mental stress-induced ischemia in the study by
Rozanski et al. Note that increases in heart rate are lower with
mental stress but increases in SBP are comparable with mental
stress and exercise. DBP increases are greater with mental
stress.
(From
Rozanski
A,
Bairey CN, Krantz DS, et al: Mental
stress and the induction of myocardial ischemia in patients with
coronary artery disease. N Engl J Med 318:1005-1012, copy-
right 1988, Massachusetts Medical Society; with permission of
the New England Journal of Medicine.)
282
KRANTZ
et
a1
mia. Specifically, patients who evidence men-
tal. stress-induced ischemia evidence higher
blood pressure responses to stress.6,
38,
66
Summary of Characteristics of
Mental Stress-Induced Ischemia
Assessed in the Laboratory
In sum, the many results of recent studies
indicate that there are now multiple noninva-
sive means of assessing the effects of mental
stress in the laboratory. These studies under-
score the importance of relying on sensitive
imaging techniques to measure myocardial
ischemia. Measures of left ventricular wall
motion, ejection fraction, and myocardial per-
fusion are all suitable endpoints for detecting
mental stress-induced ischemia, but electro-
cardiography used alone is an inadequate lab-
oratory measure. The following are the salient
features of myocardial ischemia induced by
mental stress (Table
1):
It
is
typically silent; it
tends to occur at lesser heart rate and double
product elevations compared with ischemia
induced by exercise, but with comparable in-
creases in blood pressure; its induction is gen-
erally limited to patient populations who
have exercise-inducible ischemia; and its like-
lihood is moderately related to functional se-
verity
of
exercise ischemia. Interestingly,
many of these characteristics parallel the
characteristics of transient ischemia noted
Table
1.
CHARACTERISTICS
OF
MENTAL
LABORATORY STUDIES
STRESS-INDUCED ISCHEMIA AS NOTED IN
Occurs in
40%-70%
of coronary artery disease
-
Frequently not detected by electrocardiographic
Occurs at lesser heart rate and double-product
Blood pressure increases can be substantial and
Most frequently provoked among patients with
Moderately related
to
functional severity of exercise
Correlates with daily life ambulatory
patients3.
6. 6.
16.
26.
31.
61
markers3.
6.
8.
16.
26.
31.
61
. Usually sjlent3,
6.
8.
16,
26,
31.
61
elevations compared with exercise6,8.
28,
61
comparable
to
exercise6,
28,
38,
61
exercise-inducible ischemia3,
61
ischernia-correlates inversely with stage of onset of
exercise-inducible ischemiaz8.
61
electrocardiographic ischemia6,
44
or daily life low-
exertional ischemiaz6
-
Predictive of adverse prognosis33,
w,
62a
during ambulatory electrocardiographic mon-
itoring in patients with coronary artery dis-
ease. In addition, there is recent evidence that
mental stress ischemia in the laboratory is
predictive of ambulatory ischemia during
sedentary activities of daily life (see the fol-
lowing).
CLINICAL SIGNIFICANCE OF
MENTAL-STRESS ISCHEMIA
Correspondence With Ischemia
During Daily Life
Although the aggregate results of numer-
ous studies indicate that mental stress can
induce wall motion abnormalities and
ejection fraction decreases in a sizable subset
(40%
to
70%)
of coronary artery disease pa-
tients, several aspects of these data raise ques-
tions regarding the clinical significance of
mental stress-induced ischemia. DeedwaniaI9
has noted that most mental stress-induced
ischemic episodes are brief in duration,
asymptomatic, and of lesser magnitude than
exercise-induced ischemia. The possible clini-
cal significance of ischemia elicited by men-
tal-stress testing is bolstered by three recent
studies that reveal a correspondence between
ischemia induced by mental stress and ambu-
latory ischemia assessed during daily life in
an out-of-hospital setting. In one study, Gott-
diener et alZ8 observed that in coronary artery
disease patients, ischemia (echocardiographi-
cally assessed wall motion abnormalities)
during daily life was predictive of increased
risk of ischemia during sedentary activities of
daily life (Fig.
7).
These findings have been
corroborated by
two
studies demonstrating
that patients with mental stress-inducible
wall motion abnormalities6 and transient
ejection fraction decreases in response to
mental stressu evidenced an overall greater
likelihood of ischemia assessed during ambu-
latory electrocardiographic monitoring.
Prognostic Significance of Mental
Stress-Induced Ischemia
Additional evidence for possible clinical
import of mental stress-inducible ischemia
MENTAL STRESS AS A TRIGGER OF MYOCARDIAL ISCHEMIA AND INFARCTION
283
Figure
7.
A,
Duration
of
ambulatory ischemia during sedentary activities in
patients with ischemia induced by mental stress in the laboratory (Group
I)
versus those without (Group
II)
in the study by Gottdiener et al.
6,
The
number of episodes of ischemia also was greater in Group
I
patients.
From
Gottdiener
JS,
Krantz DS, Howell
RH,
et al: induction
of
myocardial ischemia
with mental stress testing: Relationship to the triggers of ischemia during
daily life activities and to ischemic functional severity.
J
Am Coll Cardiol
24:1645-1651,
1995;
with permission from the American College of Cardiol-
ogy.)
comes from several recent investigations that
raise the possibility that the presence of men-
tal stress-induced myocardial ischemia may
predict subsequent clinical events in patients
with coronary artery disease. The clinical sig-
nificance of exercise testing as a predictor
of
prognosis has been well established, and
ambulatory electrocardiographic studies have
shown that patients with daily life ischemia
have a worse prognosis than those who do
not manifest ischemia.20,
6o
Jain et a133 reported
that
10
of 15 patients with mental stress-
induced transient ejection fraction decreases
of greater than
5%
had adverse cardiac events
(consisting of nonfatal MI or unstable angina)
over a 2-year follow-up, compared with only
4 of
14
patients who did not evidence this
dysfunction (Fig.
8).
Although provocative,
these results should be regarded as prelimi-
nary, because the sample size was small,
many of the events were classified as unstable
angina, and documented MIS were infre-
quent. Two other research groups recently
presented corroborating evidence for the clin-
ical significance of mental stress ischemia
among coronary artery disease patients with
prior positive exercise tests. Over a period of
3 years, Santiago et aldza followed up 79 pa-
tients with recent positive exercise stress tests
who had been assessed previously for mental
stress-induced wall motion abnormalities
with multiple stressors. New cardiac events
(cardiac death, nonfatal MI, coronary artery
bypass surgery, angioplasty) occurred in 28
(35%) of patients. New events occurred in
14
of
28
patients (50%) with mental-stress
ischemia, compared to 16 of 51 patients (31%)
without mental-stress ischemia. This consti-
tuted a relative risk of 2.2 for the presence of
mental-stress ischemia, which did not reach
levels of statistical significance in the rela-
tively small sample size studied. Jiang et a134
prospectively followed 126 patients with sta-
ble angina who underwent mental-stress and
exercise testing using radionuclide ventricu-
lography. Twenty-eight (22%) experienced at
least one clinical event (cardiac death, MI,
coronary artery bypass surgery, angioplasty)
over an average follow-up of 3.2 years. Men-
tal-stress ischemia, defined as a transient de-
crease in ejection fraction of greater than 5%,
was associated with an increased risk of clini-
cal events (odds ratio
=
2.93,
P
<
0.03). This
effect remained significant even after control-
284
KRANTZ
et
a1
Follow-up Duration
Figure
8.
Cardiac events at
1
and
2
years after undergoing mental stress
testing among
30
coronary artery disease patients in the study by Jain et al.
Transient left-ventricular
(LV)
dysfunction was associated with a greater fre-
quency of adverse events in this preliminary study. (MI
=
myocardial infarction;
UA
=
unstable angina;
MS+
=
patients with transient
LV
dysfunction
in
response to mental stress;
MS-
=
patients without transient
LV
dysfunction
to
mental stress.)
(From
Jain D, Burg B, Soufer
R,
et al: Prognostic implication
of mental stress-induced silent left ventrical dysfunction in patients with stable
angina pectoris.
Am
J
Cardiol
76:31-35,
1995;
with permission.)
ling for risk factors and for exercise ischemic
response.
Although results of these prognostic stud-
ies are promising, they suffer from several
limitations: The populations studied are lim-
ited to coronary artery disease patients with
prior positive exercise tests; the sample sizes
are relatively small; and the samples experi-
enced relatively few so-called “hard events”
(i.e., documented MI or sudden cardiac
death). Nevertheless, they do provide evi-
dence for possible clinical significance of is-
chemia triggered by mental stress, and justify
further research in this area in larger and
more diverse patient groups. Assuming that
these results prove reliable, we may speculate
regarding possible mediators of the relation-
ship between inducible mental-stress ische-
mia and prognosis. First, because of the asso-
ciation between mental-stress ischemia and
ambulatory ischemia,6,
28,
44
we may speculate
that mental stress ischemia patients are at
increased risk
by
virtue of the presence of
more ischemia during daily life. Second, be-
cause mental-stress ischemia is more likely in
patients with more functionally severe dis-
ease, mental-stress testing may be uncovering
more severe disease in these patients in a
manner that supplements conventional exer-
cise-stress testing. Third, mental-stress testing
may be uncovering a greater susceptibility of
vulnerable patients to a variety of mental-
stress triggers of clinical events during daily
life.
A
fourth possibility
is
that mental stress
testing uncovers an aspect of myocardial sup-
ply and demand conditions that more closely
approximates the conditions experienced dur-
ing daily life. Further investigation of the
aforementioned possibilities will contribute to
increased understanding of the possible clini-
cal relevance of mental stress testing.
CONCLUDING COMMENTS AND
THERAPEUTIC APPLICATIONS
Research on mental stress as a trigger of
myocardial ischemia and infarction has dem-
onstrated that mental stress can act as a trig-
ger of clinical events. Indeed, mental stress
may be comparable in importance to strenu-
ous
physical activities as a trigger for clinical
MENTAL STRESS AS A TRIGGER
OF
MYOCARDIAL ISCHEMIA AND INFARCTION
285
events, because patients with coronary artery
disease engage in strenuous exercise only in-
frequently. Moreover, because the mecha-
nisms involved in the triggering effects of
mental stress may be more related than exer-
cise to mechanisms associated with coronary
vasoconstriction and a reduction in myocar-
dial supply, further research is needed to
identify those patients who are susceptible to
the pathophysiologic effects of mental stress
and to assess pharmacologic and nonpharma-
cologic means for preventing the triggering
of clinical events by mental stress. One pre-
liminary study3 has suggested that beta-ad-
renergic blockade may be only partially bene-
ficial in treating ischemia triggered by mental
stress, perhaps because mental stress elicits a
hemodynamic profile involving relatively low
heart rate increases but substantial increases
in blood pressure, and beta-blockers do not
reduce mental stress-induced blood pressure
surges. Thus, further research assessing the
effects of calcium-channel blockers, alpha-ad-
renergic blockers, and other pharmacologic
agents are warranted. In addition, a recent
epidemiologic study@ observed that trig-
gering of MI by mental stress was less evident
in patients taking aspirin. This might suggest
that the antiplatelet effects of aspirin can
moderate the triggering effects of mental
stress.
An alternative or adjunctive, nonpharma-
cologic treatment approach such as psychoso-
cia1 treatment or behavior therapy also may
prove useful in reducing the adverse conse-
quences of mental stress in triggering cardio-
vascular events. In this regard, results from
a randomized stress reduction trial in post-
MI patients suggests that modification of
environmental stress through psychosocial
support may be beneficial in preventing
morbidity and mortality in these patients.
Frasure-Smith and Princez3 evaluated a psy-
chosocial intervention in which
453
survivors
of MI reporting high levels
of
life stress were
randomized to a simple and cost-effective
counseling and social-support intervention to
help them deal with environmental and psy-
chosocial sources of distress. This interven-
tion was associated with a
51%
reduction in
subsequent cardiac deaths. In addition, fur-
ther studies of the use of psychotropic agents
to reduce stress may be warranted in selected
patient populations. In addition to further
studies of psychosocial and pharmacologic
interventions to counter the acute triggering
effects of stress, the fact remains that
psy-
chosocial stress is pervasive and often un-
avoidable. Therefore, further research on
pathophysiologic mechanisms mediating the
associations between acute stress and cardiac
pathology (see Fig.
1)
as well as on possible
moderators of this ass~ciation~~ must also re-
main a priority.
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Address
reprint
requests
to
David
S.
Krantz, PhD
Department of Medical and Clinical Psychology
Uniformed Services University of the Health Sciences
4301 Jones Bridge Road
Bethesda, MD 20814-4799
