DEPARTMENT OF HEALTH AND HUMAN SERVICES
NATIONAL INSTITUTES OF HEALTH
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
MINUTES OF THE SPECIAL EMPHASIS PANEL (SEP) ON 
MENTAL STRESS AND MYOCARDIAL ISCHEMIA
JANUARY 31, 1996
The meeting of the Mental Stress and Myocardial Ischemia SEP was
convened on January 31, 1996 at 8:30 a.m., at 6701 Rockledge
Drive, Room 7111, Bethesda, Maryland.  The meeting was open to
the public from 8:30 a.m. to 3:00 p.m.  Dr. Carl Pepine presided
as Chair. 
OPEN MEETING
I.  CALL TO ORDER
Dr. Peter Kaufmann of the National Heart, Lung, and Blood
Institute (NHLBI)/DECA called the meeting to order at 8:30 AM and
welcomed all present.  Dr. Cutler reviewed the purpose of Special
Emphasis Panels.  This Panel was convened to review current
knowledge concerning the  relationship between mental stress and
myocardial ischemia, and to advise the NHBLI regarding the most
fruitful directions for future research.  The entire meeting was
open to the public.
II.  REVIEW OF CONFIDENTIALITY AND CONFLICT OF INTEREST
PROCEDURES
Dr. Lawrence Friedman, Division Director, explained policies
and procedures regarding confidentiality and avoidance of
conflict of interest situations.
III.  DISCUSSION OF MENTAL STRESS AND MYOCARDIAL ISCHEMIA
During the morning session, Panel members reviewed evidence from
clinical and basic research showing that mental stress is an
effective trigger of myocardial ischemia, conditions under which
ischemia occurs, and possible interventions designed to reduce
frequency of myocardial ischemia in coronary heart disease (CHD)
patients.  During the afternoon session, panel members discussed
whether current knowledge in the field is sufficient for
application to clinical questions related to diagnosis,
treatment, or prognosis, and reached consensus regarding research
needed in order to realize the most immediate clinical benefits
of progress in this field.
A.  Clinical Manifestations of Myocardial Ischemia
Clinical studies of mental stress and myocardial ischemia were
reviewed by Drs. Krantz, Sheps, Burg, and Blumenthal.  
Mental stress as a trigger of ischemic events.  It is well known
that physical exertion can lead to myocardial ischemia when flow
through diseased coronary vessels fails to meet increasing
myocardial demand.  In the past 10-15 years, it has become clear
that mental stress can also trigger episodes of myocardial
ischemia in both laboratory and field settings.  In most studies,
ischemia was evoked almost as readily by mental stress as by
physical stress, even though myocardial oxygen demand remained
lower during the mental stress episodes than demand during
exercise.  However, most episodes of mental stress ischemia are
silent, rather than symptomatic.  Asymptomatic ischemia is
present in the majority of CHD patients, with as many as 70% of
episodes thought to be asymptomatic.  Many investigators believe
that most episodes of silent ischemia are in response to mental
stress, which could occur in everyday life at a much higher
frequency than physical stress, particularly since CHD patients
are likely to moderate their physical activity due to fatigue or
symptoms resulting from their illness.  Mental stress is more
difficult to control, since its source can be entirely external
to the patient.
Identification of risk.  Although the mechanisms through which
mental stress provokes ischemia are not well understood,
characteristic changes in sympathetic response and in the
circulation have been described under controlled conditions. 
These changes  are hemodynamically different from changes
observed during exercise stress testing, and may help to identify
patients who are at risk for cardiac events triggered by mental
stress.
Whether or not a given patient is susceptible to mental stress-
provoked ischemia (MSI) is not simply related to the amount of
coronary atherosclerosis defined by angiography, but may be
related to the extent of coronary endothelial dysfunction.  For
example, hemodynamic changes observed in (CHD) patients during
bicycle exercise do not predict their responses under a protocol
to provoke mental stress.  Catecholamine levels reached in
response to mental stress are, on average, similar to those seen
shortly after acute myocardial infarction (MI), and are
associated with hemodynamic effects similar to those seen after
intravenous infusion of comparable amounts of epinephrine and
norepinephrine.  Although circulating catecholamines resulting
from mental stress may provide a background against which other
influences exert their effects, circulating catecholamines do not
appear to be the most important factor determining
susceptibility. 
Results from the Psychophysiological Investigations of Myocardial
Ischemia study (PIMI) and other research studies show that CHD
pathophysiology can be influenced by psychological
characteristics of CHD patients, particularly those related to
negative emotions such as anger, hostility, anxiety, and
depression.
Gender differences in susceptibility to mental stress-provoked
myocardial ischemia are also thought to be important.  Gender
differences in cardiovascular reactivity are well documented, but
not well understood.  In part, these are the result of
neuroendocrine influences, but could also be related to
differences in receptor density or distribution, hemodynamic
control variables, or psychological characteristics.  Females are
more likely than males to evidence large changes in ejection
fraction in response to mental stress, a finding reported for
both disease-free women and CHD patients.  Results from the PIMI
Reference Group Study showed that hemodynamic responses of normal
women, matched in age to female coronary disease patients, were
less predictable and displayed greater variability than those of
men.  
Preliminary studies show that susceptibility to MSI in the
laboratory, combined with ambulatory monitoring, improves
risk-stratification of CHD patients.  Although follow-up data are
available only from approximately 200 patients, patients in whom
mental stress provoked myocardial ischemia in the laboratory
experienced approximately a three-fold increased risk of cardiac
events (deaths and reinfarctions) compared with other post-MI
patients.  Thus, mental stress testing potentially is useful as a
diagnostic tool for identifying patients for whom special cardiac
rehabilitation programs would be beneficial.
Interventions to reduce risk of mental stress-provoked ischemia. 
An important clinical question is whether interventions can be
designed which target not only the physical rehabilitation needs,
but the cognitive rehabilitation needs of the post-MI patient. 
Dr. James Blumenthal presented newly developed evidence
(submitted for publication) that a four-month stress management
intervention reduced the number of cardiac events, including MI,
death, and revascularization procedures, relative to usual care
controls.  Patients with documented coronary artery disease and
evidence of exercise induced ischemia were assigned to either
usual care, exercise training, or stress management. 
Comprehensive assessments before and following the intervention
included ambulatory electrocardiographic monitoring and
radionuclide ventriculography during mental and exercise stress
testing.  Risk factors (e.g., lipids) and psychosocial
functioning were also assessed before and after treatment. 
Patients in the stress management group had a relative risk of
only .23, compared to .70 for exercise and 1.0 for usual care. 
In terms of potential mechanisms, participants in the stress
management group exhibited fewer ischemic events during
ambulatory monitoring, showed less ischemia during mental stress
testing, and achieved lower scores on measures of hostility and
distress relative to usual care controls.  These findings,
combined with other research showing that psychosocial
interventions such as cognitive behavior therapy greatly reduce
psychological risk factors, suggest that specific treatments are
available to provide for comprehensive rehabilitation of cardiac
patients.  However, such interventions have not been tested in a
sufficiently large sample of patients to draw firm conclusions
regarding their efficacy.
B.  Mechanisms of Mental Stress-Provoked Ischemia
Drs. Natelson, Bairey Merz, Schneiderman, and Pepine reviewed
research on mechanisms through which mental stress exerts its
effects.  
What mediates mental stress influences on the coronary
vasculature and myocardium?  Direct links between parts of the
central nervous system mediating cognitive and emotional behavior
and components mediating autonomic regulation of cardiac function
are known and their importance is recognized implicitly in all
studies of mental stress and cardiovascular function.  Because
cardiac function also depends on adequate perfusion of the
myocardium,  both remote (CNS) and local (endothelium-derived)
influences which affect vasomotion play an important role in
maintaining flow commensurate with cardiac demand.  
In healthy individuals, acetylcholine stimulates coronary
vasodilation through the release of endothelium-derived nitric
oxide (NO).  This dilation is modulated by opposing alpha- and
beta-adrenergic effects, whose magnitude depends on cardiac work
being performed.  Diseased coronary arteries of humans and
animals respond with constriction rather than normal dilation in
response to acetylcholine (ACh).  Thus, under conditions of
increased cardiac demand in response to physical or mental
stressors, vagal influences may also contribute to paradoxical
vasoconstriction.  An association between mental stress and
ischemic events in daily life has been established in several
independent studies.  Episodes of ischemia are also associated
with decreased vagal tone as detected by changes in high
frequency heart rate variability.  It is not yet clear whether
vagal withdrawal is specifically related to mental
stress-provoked ischemic events, includes ischemia provoked by
exertion, or causally precedes the ischemic event.
If the above mechanisms are causally related to myocardial
ischemia, they should exhibit a circadian variation similar to
the well-described circadian variation in frequency of MI and
ambulatory ischemia.  Indeed, coronary segments with
dysfunctional endothelium exhibit an early morning exaggeration
in vasomotor activity in response to acetylcholine and to
nitroglycerine, while segments with normally functioning
endothelium do not show circadian variations.
While change in vagal tone, related in part to impaired
endothelial function, is likely to be one of the factors which
influence susceptibility of the myocardium to mental
stress-provoked myocardial ischemia, numerous other influences
undoubtedly are involved, either alone or in combination.  These
include changes in sensitivity to circulating or locally released
neuroactive substances and local endothelial effects in the
presence of atherosclerotic heart disease.  None of these are
well understood.  Evidence of coronary vasomotion provoked by
stimulation of specific central nervous system sites is available
from a small number of studies in animal models, and from recent
studies in humans showing evidence of thalamic activation during
myocardial ischemia.  However, central nervous system influences
are perhaps the least well-understood aspect of the control of
vascular tone and vasomotion.
Influence of gender on development of CHD.  Several gender
differences exist in CHD patients, including effects mediated by
estrogen at several levels of coronary pathophysiology,
interactions of the patient with the psychosocial environment,
and response to physical exertion.  The extent and severity of
exercise-induced cardiac ischemia and ambulatory ischemia is
related to psychological test scores of hostility in female, but
not male CHD patients.  Women also experience higher rates of
depression and have significantly different care-giver status
compared with men, thus also have different social support
relationships.  All three attributes: high hostility, depression,
and low social support have been linked with increased risk of
CHD, although the mechanisms remain speculative.  Finally, women
have higher cardiovascular reactivity than men, a trait
associated with increased rate of atherosclerotic disease. 
Elevated cardiovascular reactivity in women results in more
frequent and greater ejection fraction decrements in response to
mental stress.
Insulin metabolic syndrome.  Epidemiological studies have
identified a relationship between a constellation of factors
(consisting of central obesity, hypertension, hyperglycemia,
dyslipidemia) and risk of CHD.  These risk factors are associated
with aspects of insulin metabolism and cluster in individuals at
much higher frequencies than predicted by chance.  There is good
evidence that lifestyle contributes to the syndrome: excess
dietary fat, carbohydrate, and alcohol can lead to obesity, and
reducing obesity is associated with decreased blood pressure,
decreased hyperinsulinemia, and decreased insulin resistance. 
Decreased blood pressure and plasma insulin are intercorrelated
after aerobic exercise training even when body weight remains
unchanged.  Other evidence suggests a relationship between
insulin metabolism and increased activation of the sympathetic
nervous system (SNS) and the hypothalamo-pituitary-adrenal axis,
leading to accelerated development of the disease process.  A
possible relationship between the insulin metabolic syndrome and
SNS activation is particularly interesting, because the latter is
also often cited as a link between behavioral factors and CHD.
Genetic influences on risk of coronary heart disease.  After
taking into consideration all risk factors present in an
individual, a history of CHD in the family adds a statistically
significant additional amount of risk, suggesting a strong
genetic influence.  The Asymptomatic Cardiac Ischemia Pilot study
showed that the presence of ambulatory ischemia on treatment
imparts an additional 22% risk of a coronary event at one year,
while presence of family history before age 55 is greater:
increasing risk by 87%.
The role of three candidate genetic influences were described by
Dr. Pepine: a deficiency in the enzyme cystathionine beta-
synthase, leading to high plasma homocysteine concentrations and
atherosclerosis; an insertion/deletion polymorphism of the
angiotensin-converting enzyme gene which is also associated with
CHD; and the Lewis (a-b-) phenotype, which occurs at a higher
frequency in people of African descent than in Caucasians, and
has been associated with a twofold risk of CHD.  
The Lewis (a-b-) phenotype is particularly interesting because it
is determined by genes in the proximity of several genes involved
in LDL receptor regulation and insulin resistance.  Insulin
resistance is believed to be influenced by neuroendocrine changes
in response to activation of the hypothalamo-pituitary-adrenal
axis, especially through adrenaline, noradrenaline, and cortisol,
which are known to have a counter-regulatory effect on glucose
metabolism.  Links with increased very low density lipoprotein
and decreased HDL cholesterol as well as increased plasma
fibrinogen have also been described.
C. Discussion of Research Recommendations
When it became clear that risk in CHD patients was associated
with the degree of left ventricular dysfunction, the mechanisms
were not understood, nor was it clear that it would be possible
to intervene to improve function or to reduce risk.  Today, a
similar situation exists in connection with mental stress-
provoked myocardial ischemia.  There is conclusive evidence that
MSI, and preliminary evidence that susceptibility to MSI provides
prognostic information beyond that provided by exercise testing,
ambulatory electrocardiographic monitoring, and myocardial
perfusion tests, although the mechanisms through which MSI is
provoked or how this imparts risk for cardiovascular events is
not known.  Furthermore, data from some studies suggests that
exercise and stress management training can reduce the frequency
of MSI and the number of cardiac events.  However, more research
is needed to determine which kinds of interventions or
rehabilitation programs reduce susceptibility to MSI.
Several recommendations for research that would lead to a better
understanding of the mechanisms that influence susceptibility to
MSI, or that govern triggering of myocardial ischemia by mental
stress were made:
1.  Basic Behavioral Neurosciences
a.  The role of elevated circulating catecholamines in response
to stress is not understood, in part because cardiac events, some
of which are asymptomatic and thus are not detected, also cause
elevated plasma catecholamines.  Larger studies are needed with
repeated assays to evaluate the dynamics of circulating
catecholamines in the CHD patient, as well as the effects of
diverse neurotransmitter substances released into the circulation
during anxiety, pain, and stress.  
b.  Although work is progressing at an increased pace, much
additional research is needed to define gender differences in
hemodynamic changes due to mental stress, including effects
caused by redistribution of blood flow through different
peripheral vascular beds, and to understand how sex hormones
affect coronary reactivity to local neurohormones (ACh,
catecholamines) and to neural activation.  
c.  Neural control of vasomotion in normal coronary arteries is
understood much better than neural control of diseased coronary
vessels.  It is not known whether vagal activation produces the
same effects as infusion of ACh, whether sympathetic fibers
retain their original effectiveness; the role of fibers releasing
other neurotransmitter substances is also not known.  While
animal models do not necessarily replicate human CHD, study of
diseased endothelium will provide badly needed insight into
principles of interaction between overlapping systems.
d.  In connection with the insulin metabolic syndrome, research
is needed to determine why some individuals with similar levels
of insulin resistance may develop hypertension, others NIDDM or
dyslipidemias.
e.  Although research in nonhuman primates has demonstrated that
emotional stressors can interact with diet to promote coronary
risk, the role played by insulin metabolism and the SNS has not
been clarified.  Nonhuman primate models have been used
successfully to study the effects of emotional stress on
atherosclerosis.  They should continue to be developed.  
f.  Further studies are needed to assess the contribution of
coronary vasomotion and endothelial dysfunction to mental stress
ischemia.
2.  Clinical Research
Mental stress clearly triggers ischemia in both laboratory and
ambulatory settings.  It is not known whether interventions
designed to reduce MSI would alter the disease process itself. 
Ideally, a greater understanding of the mechanistic role played
by mental stress in coronary artery disease would enable design
of interventions that serve to reduce ischemia while also
altering the course of disease.  New technology enables direct
pathophysiologic investigation of the impact of stress on
atherosclerotic risk factors (clinical and serologic),
atherosclerosis severity (Intima-Media Thickness), endothelial
function (brachial ultrasonography), and autonomic function
(heart rate variability, baroreflex sensitivity), as well as
myocardial ischemia.  
a.  A comprehensive longitudinal study which evaluates the role
of increased but transient natural environmental stress (>4
months) on risk factors, serologic parameters of plaque rupture,
endothelial function, myocardial ischemia and autonomic function
would further this end.  Study of genetic phenotypes thought to
influence SNS activity and other stress-related risk factors
would also be of interest.  Study power requirements are likely
to dictate a multicenter study to enable rapid accrual of a
sufficient number of patients.  Sample size calculations should
consider including morbidity and mortality endpoints. 
b.  Plausibly important psychosocial and physiological
differences have been identified between male and female CHD
patients.  Elucidating their significance is likely to benefit
patients of both genders, since some of the differences may have
gender-specific importance, but others represent  fundamental
commonalities underlying the atherosclerotic disease process. 
Future work should include study of the action of estrogen on
vascular/endothelial function, both directly and by influencing
the action of other risk factors.
c.  Knowledge concerning the prognostic value of mental stress
testing should be extended and refined and integrated with other
medical risk factors.
d.  Little is known regarding whether MSI predicts vulnerability
to a specific class of triggers of acute cardiac events.  Such
information could be helpful for refining clinical interventions.
3.  Pilot Clinical Trial
The Panel considered a full range of research possibilities that
would lead to clinical benefits.  In particular, the Panel
discussed in considerable detail the possibility of interventions
for patients with MSI, and concluded unanimously that a
randomized clinical trial would be of great value to optimize
treatment and rehabilitation programs for CHD patients.  An
additional benefit of a clinical trial would be that some of the
questions related to mechanisms, discussed earlier, might be
answerable through substudies.
The rationale for a clinical trial is grounded in early data
suggesting that susceptibility to MSI significantly raises risk
of MI, while an intervention that provides stress management
reduces the number of cardiac events, including death, MI, and
revascularization procedures.  Indirect evidence comes from
studies showing that exercise rehabilitation decreases
cardiovascular reactivity, which is linked with MSI.  Patients
susceptible to MSI can be identified with presently available
methods.  Since mental stress is a common occurrence of everyday
life and because of the increased risk associated with MSI,
effective interventions could make a significant impact on the
total ischemic burden including ischemia-related adverse clinical
outcomes of the coronary patient. Thus, the Panel concluded
unanimously that a randomized pilot clinical trial should be
conducted to determine whether a multimodal intervention can be
implemented to reduce recurrent MI and death in CHD patients at
high risk of MSI.  The objectives of a pilot study would be to
assess ability to identify and recruit patients at risk of MSI,
and to refine a multifactorial intervention comprised of a
combination of exercise and stress management, against a
background of usual medical care.  Such a clinical trial should
consider the additional lifestyle and risk factor change
interventions currently available.  For example, evidence
suggests that dietary fat reduction promotes regression of
coronary atherosclerosis, and that stress-management promotes
adherence to dietary regimens.  Thus, the clinical trial design
might incorporate aggressive dietary management as one of its
components.  The primary endpoint for assessing efficacy of
interventions should be the number of cardiovascular deaths and
re-infarction.
Response variables for the pilot trial should include frequency
and duration of ambulatory ischemia, ischemia provoked by mental
stress in the laboratory, cardiovascular reactivity, lifestyle
risk factor change, and serum lipid levels.  A full-scale
clinical trial (and, to a lesser extent, the pilot study) would
enable developing hypotheses regarding the mechanisms through
which MSI, or interventions which reduce MSI, affect clinical
outcomes.
ADJOURNMENT
The meeting was adjourned at 3:00 p.m. on January 31, 1996.
CERTIFICATION
I hereby certify that the foregoing minutes are accurate and
complete.
____________________________________
Carl Pepine, M.D.
Chair
SEP on Mental Stress and Myocardial Ischemia
____________________________________
Peter G. Kaufmann, Ph.D.
Federal Official
SEP on Mental Stress and Myocardial Ischemia
Attachment: Panel Roster
Note: A complete set of handouts are available from the Executive
Secretary.
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
SPECIAL EMPHASIS PANEL (SEP) ON 
MENTAL STRESS AND MYOCARDIAL ISCHEMIA
PARTICIPANT LIST
JANUARY 31, 1996
BETHESDA, MARYLAND
CHAIR:
Carl J. Pepine, M.D.
Professor of Medicine
Co-Director, Division of Cardiovascular Medicine
University of Florida College of Medicine
1600 Archer Road/P.O. Box 100277
Gainesville, FL 32610-0277
PARTICIPANTS:
C. Noel Bairey Merz, M.D.
Assistant Clinical Professor of Medicine,
UCLA School of Medicine
Medical Director, Preventive and 
Rehabilitative Cardiac Center
Cedars-Sinai Medical Center
444 S. San Vicente Blvd., Suite 901
Los Angeles, CA 90048
James A. Blumenthal, Ph.D.
Professor of Medical Psychology
Department of Psychiatry
Duke University Medical School - Box 3119
Durham, NC 27710
Matthew M. Burg, Ph.D.
Assistant Clinical Professor of Medicine
Section of Cardiovascular Medicine
Yale University School of Medicine
135 College Street
New Haven, CT 06510-8056
David S. Krantz, Ph.D.
Professor of Psychiatry
Georgetown University Medical Center
3800 Reservoir Road
Washington, DC  20007
Benjamin H. Natelson, M.D.
Professor of Neurosciences
New Jersey Medical School
88 Ross Street
East Orange, NJ 07018
Neil Schneiderman Ph.D.
Professor of Psychology, Medicine, 
and Biomedical Engineering
Department of Psychology
University of Miami
Coral Gables FL 33124
David S. Sheps, M.D., M.S.P.H.
Professor of Medicine
Division of Cardiology
University of North Carolina at Chapel Hill
Chapel Hill, NC 27599-7075
NHLBI PROGRAM STAFF:
Jeffrey Cutler, M.D.
Director, Clinical Applications and Prevention Program
Division of Epidemiology and Clinical Applications
National Heart, Lung, and Blood Institute
II Rockledge Center
6701 Rockledge Drive, MSC 7936
Bethesda, MD 20892-7936
Lawrence Friedman, M.D.
Director, Division of Epidemiology and Clinical Applications
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Bldg. II, MSC 7938
Bethesda, MD 20892-7938
FEDERAL OFFICIAL:
Peter Kaufmann, Ph.D.
Group Leader, Behavioral Medicine Research Group
Clinical Applications and Prevention Program
Division of Epidemiology and Clinical Applications
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Bldg. II, MSC 7936
Bethesda, MD 20892-7936