format and agenda responsive to the keyissues facing the scientific ... (numbering over 1,000 journal pages) prior to ...... Now let mereview the animal evidence ...
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Jp^ress, lleactivity; and Cardiovascular Di^ase .—ftoceedings 6f fie Working Confe/ence \
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DEPARTMENT OF HEALTH
.U.S.
AND H^f^AN
Public Health
Service
SERVICES National Institutes of Health
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Stress, Reactivity,
and
Cardiovascular Disease Proceedings of the
Working Conference
Co-Sponsored by The National Heart, Lung, and Blood
and The
Institute
University of Pittsburgh
School of Medicine
The
University of Pittsburgh
School of Public Health
The Western Psychiatric Institute and Clinics
Editors Stephen M. Weiss, Ph.D. Karen Matthews, Ph.D. Thomas Detre, M.D.
A
Judith
A Graeff.
Ph.D.
Conference Planning Committee Co-Chairs
A
Karen Matthews, Ph.D. Stephen M. Weiss, Ph.D.
Theodore Dembroski, Ph.D. Bonita Falkner, M.D. Katrina Johnson, Ph.D. Peter Kaufmann, Ph.D. Stephen B. Manuck, Ph.D. Redford Williams, M.D.
Conference Chair Thomas
Detre,
M.D.
DEPARTMENT OF HEALTH U.S.
AND HUMAN
SERVICES
Public Health
Service
National Institutes of Health
NIH
Publication No. 84-2698
November
1984
O
I
rn
i._
^
)^^^
TABLE OF CONTENTS
Participants
IX
Foreword
xm
CONFERENCE SUMMARY
"Status of and Prospects for Stress, Reactivity and Cardiovascular Disease" K.A. Matthews, S.M. Weiss and T. Detre
WELCOMING REMARKS
T.
OVERVIEW
"Stress and Reactivity" R.B. Williams, Jr.
13
"Implications for Atherogenesis" Clarkson
35
Detre
11
T.
PRESENTATIONS
"Reactivity, Hyperreactivity and Cardiovascular Disease" S.B. Manuck
41
"Implications for Hypertension" Julius
63
"Implications for Coronary Heart Disease" J. A. Herd
73
S.
Task Group Reports on REACTIVITY
Hemodynamic/electrophysiological N. Schneiderman and T. Pickering Biochemical R. McDonald and
85
107 D.
Goldstein
Psychological
109
B.K. Houston and C. Ewart
Demographic/Population L. Watkins and R. Rose
119
Task Group Reports on STRESSORS Physical J.C. Buell and W. McCrory
133
.
Psychological Krantz and R.R. Wing
237
D.S.
PRESENTATION
"Stress-Substance Interaction and Reactivity" Dembroski
T.
-1^47
Task Group Reports on STIMULATORS
Caffeine D. Shapiro and J.
PRESENTATION
I55 P.
Henry
Nicotine L. Epstein and J. A. Herd
159
Salt/Glucose B. Falkner and K.C. Light
171
"Pharmacologic and Behavioral Modulators of Cardiovascular Reactivity" R.S. Surwit
175
Task Group Reports on MODULATORS
Exercise B. Alpert and J. Dimsdale
197
Relaxation Therapies Chesney and R. Jacob
203
Pharmacologic Agents Shapiro and C. Grim
213
Alcohol R.W. Levenson and B.H. Natelson
219
M.
A. P.
ABSTRACTS
"Analysis of Heart Rate Variability in Diabetics" B.H. Natelson and W.N. Tapp "Some Working Hypotheses on the Significance of Behavioral-Evoked Cardiovascular Reactivity to Pathophysiology" P. A. Obrist, et al "Salt Loading Decreases Intraday Cardiac Variability in Dogs" D. Anderson, et al
225
227
229
ABSTRACTS
"Repeated Assessments of Left Ventricular Ejection Fraction in Ambulatory Subjects" J.E. Dimsdale
231
"How Much of the Blood Pressure Variability During 24 Hour Ambulatory Recordings can be Explained by Changes of Physical Activity?" T.G. Pickering, et al
'-^''•^
233
l."Do Chronically Repeated Pressor Episodes Eventually Cause Sustained High Blood Pressure?" 2."Clondine Suppression Testing in Essential Hypertension" D. Goldstein, et al
235 237
"Disrequlation Theory, Reactivity and Cardiovascular Disease" G.E. Schwartz "Ectopic Beats and ST Segment Depression are Related to Psychophysiological Response and Coronary Prone Behavior" J.R. Jennings and W.F. Follansbee
239
..^^....^^^
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241
"Children's Cardiovascular Reactivity--Racial Differences in Cardiac Index and Systemic Resistance Responses to Exercise" B. Alpert, et al
243
"Reactivity Testing in Private Practice" J.E. Dawson, Jr.
245
"Genetic, Familial and Racial Influences on Blood Pressure Control Systems in Man" C. Grim, et al
247
"Caffeine Potentiates Cardiovascular Responses to Stress" J.D. Lane
249
"Phenyl propanolamine/Caffeine: An Environmental Stress?" S.M. Mueller
"Effects of 3-Blockade on Cardiovascular Reactivity to Mental and Physical Strain" K. Orth-Gomer, et al
'''-"'
251
253
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CONFERENCE PARTICIPANTS
THOMAS DETRE, M.D., Conference Chair University of Pittsburgh, Pittsburgh, Pennsylvania KAREN A. MATTHEWS, Ph.D., Conference Coordinator University of North Carolina, Chapel Hill, North Carolina
STEPHEN M. WEISS, Ph.D., Conference Coordinator National Heart, Lung, and Blood Institute, Bethesda, Maryland A. ALEKSANDROV, M.D.
USSR Academy of Medical Sciences, Moscow, USSR
BRUCE ALPERT, M.D. LeBouheur Children's Medical Center, Memphis, Tennessee
DAVID ANDERSON, Ph.D. Veterans Administration Hospital, Tampa, Florida COL. JULES, BEDYNEK U.S. Army Surgeon General's Task Force on Fitness, Bethesda, Maryland
JAMES C. BUELL, M.D. St. Luke's Hospital, Phoenix, Arizona
MARGARET CHESNEY, Ph.D. SRI International, Menlo Park, California THOMAS B. CLARKSON, D.V.M. Bowman Gray School of Medicine, Winston-Salem, North Carolina
JACK DAWSON, M.D., P.C. Atlanta, Georgia
THEODORE DEMBROSKI , Ph.D. University of Maryland Baltimore County, Catonsville, Maryland KATHERINE DETRE, M.D., Dr. P.H. University of Pittsburgh, Pittsburgh, Pennsylvania JOEL DIMSDALE, M.D. Massachusetts General Hospital, Boston, Massachusetts
ELAINE EAKER, Ph.D. National Heart, Lung, and Blood Institute, Bethesda, Maryland
LEONARD EPSTEIN, Ph.D. University of Pittsburgh, Pittsburgh, Pennsylvania
IX
CRAIG EWART, Ph.D. Johns Hopkins Hospital, Baltimore, Maryland
BONITA FALKNER, M.D. Hahnemann University, Philadelphia, Pennsylvania
MARIANNE FRANKENHAEUSER, Ph.D. University of Stockholm, Stockholm, Sweden DAVID GOLDSTEIN, M.D., Ph.D. National Heart, Lung, and Blood Institute, Bethesda, Maryland
CLARENCE GRIM, M.D. Indiana University, Indianapolis, Indiana JAMES P. HENRY, M.D., Ph.D. Loma Linda University, Loma Linda, California ALAN HERD. M.D. Methodist Hospital, Houston, Texas J.
MICHAEL HORAN, M.D. National Heart, Lung, and Blood Institute, Bethesda, Maryland KENT HOUSTON, Ph.D. University of Kansas, Lawrence, Kansas B.
LT. COL. RICHARD L. HUGHES National Defense University, Fort McNair, Washington, DC
ROLF JACOB, M.D. University of Pittsburgh, Pittsburgh, Pennsylvania
RICHARD JENNINGS, Ph.D. University of Pittsburgh, Pittsburgh, Pennsylvania
J.
KATRINA JOHNSON, Ph.D. National Heart, Lung, and Blood Institute, Bethesda, Maryland
STEVO JULIUS, M.D. University of Michigan, Ann Arbor, Michigan
GEORGE A. KAPLAN, Ph.D. Department of Health Services, Berkeley, California JAY KAPLAN, Ph.D. Wake Forest University, Winston-Salem, North Carolina
PETER KAUFMANN, Ph.D. National Heart, Lung, and Blood Institute, Bethesda, Maryland
VICTOR KHRAMELASHVILI, M.D. USSR Academy of Medical Sciences, Moscow, USSR
DAVID S. KRANTZ, Ph.D. Uniformed Services University of the Health Sciences, Bethesda, Maryland JAMES D. LANE, Ph.D. Duke University, Durham, North Carolina
DONALD LEON, M.D. University of Pittsburgh, Pittsburgh, Pennsylvania ROBERT W. LEVENSON, Ph.D. University of California, San Francisco, California PAUL LEVINSON, M.D. National Heart, Lung, and Blood Institute, Bethesda, Maryland
KATHLEEN C. LIGHT, Ph.D. University of North Carolina, Chapel Hill, North Carolina
STEPHEN B. MANUCK, Ph.D. University of Pittsburgh, Pittsburgh, Pennsylvania
BARBARA McCANN, Ph.D. University of Pittsburgh, Pittsburgh, Pennsylvania
WALLACE McCRORY, M.D. New York Hospital-Cornell Medical Center, New York, New York ROBERT McDonald, m.d. University of Pittsburgh, Pittsburgh, Pennsylvania NEAL MILLER, Ph.D. The Rockefeller University, New York, New York
ROBERT E. MILLER, Ph.D. University of Pittsburgh, Pittsburgh, Pennsylvania SHIRLEY MUELLER, M.D. Indiana University, Indianapolis, Indiana
HECTOR F. MYERS, Ph.D. Fanon Research and Development Center, Los Angeles, California
BENJAMIN H. NATELSON, M.D. New Jersey College of Medicine and Dentistry, East Orange, New Jersey PAUL A. OBRIST, Ph.D. University of North Carolina, Chapel Hill, North Carolina
KRISTINA ORTH-GOMER, M.D. National Institute for Psychosocial Factors and Health, Stockholm, Sweden COL. EDWARD B. PARKS National Defense University, Fort McNair, Washington, DC
XI
THOMAS PICKERING, M.D. New York Hospital -Cornell Medical Center, New York, New York RICHARD ROSE, Ph.D. Indiana University, Bloomington, Indiana PATRICE G. SAAB, Ph.D. University of Pittsburgh, Pittsburgh, Pennsylvania NEIL SCHNEIDERMAN, Ph.D. University of Miami, Coral Gables, Florida
GARY E. SCHWARTZ, Ph.D. Yale University, New Haven, Connecticut
ALVIN P. SHAPIRO, M.D. University of Pittsburgh, Pittsburgh, Pennsylvania DAVID SHAPIRO, Ph.D. University of California, Los Angeles, California JIM L. SHIELDS, Ph.D. National Heart, Lung, and Blood Institute, Bethesda, Maryland IGOR SHKVATSABAYA, M.D. USSR Academy of Medical Sciences, Moscow, USSR
ORVILLE SMITH, Ph.D. University of Washington, Seattle, Washington RICHARD S. SURWIT, Ph.D. Duke University, Durham, North Carolina CARL THORESEN, Ph.D. Stanford University, Stanford, California
LAWRENCE F. VAN EGEREN, Ph.D. Michigan State University, East Lansing, Michigan LAURENCE WATKINS, M.D. Medical College of Georgia, Augusta, Georgia
REDFORD WILLIAMS, M.D. Duke University, Durham, North Carolina RENA R. WING, Ph.D. University of Pittsburgh, Pittsburgh, Pennsylvania
xn
FOREWORD
During
investigating
variability
the
cardiovascular
parameters.
example,
pressure,
cardiac
blood
output
measurement
there
years,
few
past
the
have
heart
rate,
consideration
under
by
consistency
measurements systemic
total
identify
to
the
as
traditional
The
attempted
well
as
interest
increasing
been
has
eliminating
of
for
of,
resistance value
"true"
the
of
sources
in
and
of
the
variance.
Innovations such as exercise stress testing, salt-loading, and glucose
tolerance tests, however, have demonstrated the value of assessing the range of these parameters, particularly under standardized laboratory
conditions.
Advances
measurement technology now permit continuous noninvasive
in
monitoring
parameters
cardiovascular
of
naturalistic conditions.
both
under
laboratory
and
New techniques have enhanced capabilities to
follow the subtle variations of, for example, neurohormonal patterning in
response
to
challenge.
various
Recent
forms
interest
stimulated extensive research factors
behavioral
to
the
levels
and
"coronary
in
on
environmental/behavioral
of
the
prone"
behavior
has
relationship of biomedical
development
of
coronary
heart
and
disease.
Using standardized laboratory challenge conditions, investigators have
identified individuals with hyperresponsive cardiovascular patterns as
potentially more
vulnerable
Additionally,
disease.
disease,
to
preliminary
particularly coronary
evidence
suggests
heart
that
the
deleterious effects of tobacco, salt, caffeine and similar substances
may
synergistically
interact
with
environmental
stressors
in
such
individuals.
Given
extensive
the
"reactivity",
interest
generated
the conference was
by
the
initial
studies
planned to accomplish the following
objectives:
1.
To assess the state of science in the following areas:
a)
of
stress and cardiovascular/neuroendocrine reactivity; xiii
relationship of stress-induced
the
b)
cardiovascular
hyperreactivity to
particularly
disease,
coronary
heart
disease;
effects
interactive
the
c)
smoking,
caffeine,
environmental
of
salt
similar
and
stress
and
substances
on
cardiovascular reactivity.
examine the theoretical
To
2.
and
conceptual
and
criteria
bases
for
these
studies.
establish
To
3.
standards
for
laboratory
most
pertinent
stressors.
develop
To
4.
consensus
the
on
physiological/biochemical variables to be studied.
5.
To establish standards of measurement/instrumentation.
6.
To establish criteria for "hypo" and "hyperresponders."
7.
To
establish
standards
for
determining
effects
the
of
"mediators," e.g., exercise, relaxation training, etc.
This
area
linkage
of
stress
of
physiological provide
investigation
information
various substances in
heart
a
better
disease
the
on
(e.g.,
salt,
presence
of
the
understanding with
along
synergistic
putative
caffeine,
alcohol)
environmental
It
on
of
the
related
the
relationship.
mechanisms underlying this
critical
function,
and
promises
will
also
effect
of
cardiovascular
stressors.
Thus,
this
conference attempted to establish consensus among key investigators in the field on issues of theory, design measurement, and instrumentation
pertinent
to
neuroendocrine
understanding reactivity
in
the the
role
of
development
cardiovascular of
and
cardiovascular
disease. After examining the current theory and research in this area, the participants reviewed, analyzed, and prioritized the most relevant
biological, psychological and behavioral xiv
parameters to be studied and
the will
most
methods
appropriate
serve as
duplication
a
as
accomplish
to
this.
This
coordinating guideline for researchers well
as
enhancing
quality
the
of
informatior
in
minimizing being
studies
considered in this exciting area of investigation.
The task of planning a conference of this magnitude and scope can only
appreciated
fully
be
by
those
for
need
such
a
conference
cosponsors,
the
by
planning committee of Drs. Theodore Dembroski Johnson,
Peter
formed
to
facing
the
endeavor.
Kaufmann,
develop
a
As
the
Manuck
Stephen
format and agenda
scientific
community
"science"
joy
the
and
Beginning with the recognition of
frustrations of such an activity. the
experienced
have
who
plan
Bonita Falkner, Katrina
and
emerging
shape,
took
Williams
Redford
responsive
this
in
,
conference
a
the
to
the
area
key of
was
issues
research
administrative and
logistic team, headed by Ms. Betty Lou Melani, and including Ms. Carol Holbay, Ms. Lori Liller, Ms. Margaret Malloy, Ms. Debra Reichbaum, Ms.
Laurie Sparky, and Ms. June Walker coordinated both the preparations and the support required during the conference.
After the conference
scientific editing was provided by Ms. Anne Borsuch, and preparing the
proceedings for publication was hartdled by Dr. Judith Graeff.
A
final
pursuit
note of appreciation--to of
conference
scientific itself,
has
the
excellence resulted
participants
both
in
this
in
their
themselves, own
work
thought-provoking
whose
and
the
document,
which should provide the scientific community with new standards and guidelines in this exciting new area.
S.M.W. K.A.M. T.D.
XV
CONFERENCE SUMMARY
STATUS OF AND PROSPECTS FOR STRESS, REACTIVITY, AND CARDIOVASCULAR DISEASE: THEMES FROM THE NHLBI-UNIVERSITY OF PITTSBURGH WORKING CONFERENCE
K.
In
A.
Matthews, S.M. Weiss and T. Detre
April
1984,
from
scientists
distinguished
a
the
major
NIH,
of
group
biomedical
67
universities,
U.S.
behavioral
and
Sweden,
and
USSR
the
working conference jointly
gathered in Olgebay Park, West Virginia, for
a
sponsored by National
Institute and the University
of
and
Graduate
Lung,
and Blood
Psychiatric
Western
Pittsburgh,
Medicine,
Heart,
of
School
Institute
Public
Clinic,
and
Health.
The
School
of
of
the
objectives
conference were to assess the state of science regarding the relationships among
stress,
theoretical
reactivity,
and conceptual
and
cardiovascular
diseases;
evaluate
to
the
bases of work in the area; and to identify the
most pertinent variables to be studied, including the physiological indices of
reactivity,
of
types
stressors
which
reactivity,
induce
and
the
mediators and modifiers of stress-induced reactivity.
To
accomplish
these
articles
(numbering
attended
plenary
groups
objectives, over
1,000
sessions
and
the
all
prior
pages)
journal
developed
throughout the 3-day meeting.
participants
reviewed to
recommendations
relevant
conference,
the
small
in
task
During the first working session of
the task groups, the conferees discussed the theoretical
issues, rationale,
and measurement strategies regarding stressors and reactivity in six areas: 1)
hemodynamic and electrophysiological measures of reactivity, led by Neil
Schneiderman and Thomas Pickering; led
by Robert McDonald
correlates
demographic
of
biochemical
and David Goldstein;
reactivity,
led
by
markers
familial
and
2)
B.
and
3)
measures of reactivity,
Houston
Kent
markers and
psychological
correlates
of
and
Craig
Ewart;
reactivity,
led
4)
by
Laurence Watkins and Richard Rose; 5) environmental elicitors of reactivity
primarily physical
in
nature,
led by James
Buell
and Wallace McCrory; and
elicitors of reactivity primarily psychological in nature,
6) environmental
led by David Krantz and Rena Wing.
During
the
evaluated
next the
set
of
task
theoretical
group
issues,
sessions,
the
potential
mechanisms
conferees of
reviewed
and
action,
and
measurement
regarding
strategies
reactivity
physical
to
2)
psychological
and
following seven groups:
stimulators
the
modulators
and
They
stressors.
met
of the
in
caffeine, led by David Shapiro and James Henry;
1)
nicotine, led by Leonard Epstein and J. Alan Herd; 3) salt and glucose,
Falkner
Bonita
by
led
Kathleen
and
Levenson and Benjamin Natelson;
Light;
led
Robert
by
led by Bruce Alpert and Joel
exercise,
5)
alcohol,
4)
Dimsdale; 6) relaxation therapies, led by Margaret Chesney and Rolf Jacob; 7)
pharmacologic agents, led by Alvin Shapiro and Clarence Grim.
highlighted
sessions
presentations
hyperreactivity implications
and
stress
on
significant
scientific
reactivity
(Redford
cardiovascular
and
of
all,
were developed on the above topics.
13 task group reports
Plenary
In
reactivity
the
disease
areas
Williams);
hypotheses
reactivity,
Manuck),
(Stephen
and
atherosclerosis
for
brief
through
the
(Thomas
Clarkson), hypertension (Stevo Julius), and coronary heart disease (J. Alan
briefly
Dembroski
Theodore
Herd).
stress-reactivity
stimulators
Richard Surwit performed
(e.g.,
reviewed
evidence
the
nicotine,
caffeine,
on
while
salt)
similar task with stress-reactivity inhibitors
a
(e.g., exercise, behavioral therapies, pharmacologic agents, alcohol).
of
these
Detre,
while
Karen
orchestrated
were
activities
Matthews
Stephen
and
the
by
Weiss
conference
chair,
All
Thomas
as
the
conference
from
the
conference
served
organizers.
major
The
and
themes
research
emerging
directions
deliberations will be the focus of this summary chapter.
Definition and Assessment of Reactivity
Most
task
groups
common element
discussed
in
the
what
definitions
from a comparison or control
environmental
is
stimulus.
The
of
a
a
boring task.
physiological
by
considers
environmental in
reactivity.
term,
the
reactivity as
value resulting from
primarily physical or psychological
performing
meant
stimulus
can
be
deviation
the
response to
a
The
a
discrete
one
that
is
nature, e.g., strenuous exercise or
According to this definition then, variability
parameter measured
throughout
the
day,
e.g.,
casual
blood pressure readings, would not precisely measure reactivity unless the
environmental
responding are specified.
is
lability of resting pressure on successive occasions would not
Similarly,
measure reactivity unless is
individual
to which the
stimuli
discrete environmental elicitor is known.
a
This
not to say that measures of variability or lability are unimportant or
uninteresting
for
human
physiology
Rather, that reactivity is
disease.
in which a clear environmental
The
conference
reactivity
participants
cardiovascular
of
term reserved for those situations
a
stimulus is apparent.
emphasized
complexity of the
the
different,
Two
deliberations.
their
in
pathogenesis
or
not
but
concept
necessarily
incompatible models of reactivity nicely illustrate this complexity. model
that
posits
more
representative
than
are
volume)
consistently
stress-induced are
the
levels
of
resting measures.
article this are
stress-induced measures,
resting
blood
Manuck
pressure
labels
throughout
levels
obtained
throughout in
day
laboratory and
the
Another model
ones.
the
of
are
(see
of reactivity
type
approximating atypical
the
One
daily events
"steady state"
model
this
pressure,
blood
because persons who exhibit this
at
levels
of
of
e.g.,
of
reactivity assumes
that
the
values
persons
display transient peaks of blood pressure throughout the day and that the
laboratory-induced
levels
are good measures
daily mean levels of pressure.
It
is
of the
peaks,
but not of the
important to note that both of these
models may accurately describe the physiological
patterns of subgroups of
the population.
The
notion
complexity
of of
levels the
of
stressors
reactivity
and
concept.
reactivity At
a
also
rudimentary
illustrates
the
are
the
level
specific stressors and responses, e.g., serial subtraction and epinephrine levels.
At
another
level
are
the
classes
or
systems
involved
in
the
stimulus and response parameters, e.g., mental effort and sympathomedullary system. the
This
At still another level
stressor and orchestrates list
of
levels
of
is
how the central nervous system perceives
the
appropriate response to that stressor.
organization
of
reactivity
is
obviously
not
exhaustive, but does illustrate the importance of considering numerous ways of assessing reactivity.
The
discussed
participants
conference
One is the appropriate control
issues.
interesting
several
value
to
assessment
compare to the response
The participants expressed some concern about the "traditional" way
value. that
reactivity measures are taken:
rest
period
events
prior
and
the
procedure
adjusted
for
prior
or
into
to
of
analyses
in
take
not
does
are measured during a
values
procedure
experimental
statistically
are
This
values.
to
control
account
the
the
that
day's
response persons'
uncertainties about the experimental session may inflate the control values problematic,
more
and,
appraisals
of
upcoming
the
differences
individual
that
experience
in
differentially
may
the
persons'
inflate
the
control values.
The conferees suggested several ways to avoid these anticipatory effects on
baseline values.
The simplest method
to
is
obtain
a
resting level
after
the stressors have been administered, e.g., during the last 10 minutes of a 30 minute resting period.
return
the
to
laboratory
knowing that no additional
method
is
to
An alternative procedure is to have the subject on
a
second
experimental
occasion
for
procedures are involved.
use ambulatory monitoring of measures
were taken during
a
maximally relaxing period
Each of these methods
has
baseline
course of the day.
certain advantages and disadvantages and should
be selected according to the overall
purpose of the investigation.
A delated assessment issue is how to describe reactivity values: levels or change scores or percentage change scores.
that
sufficient
data
should
be
available
to
absolute
Although no concensus
about the most suitable measures emerged at the conference, agreed
A final
selected because they
the
in
measures,
participants
allow the
reader
to
compute all those values.
Varying Roles of Reactivity in Cardiovascular Diseases
A theme which emerged from the conference deliberations is that reactivity
may vary in importance and in the role it plays in the etiology and course of atherosclerosis, coronary heart disease, sudden death, and hypertension. For
example,
Clarkson offered an
concerning the mechanisms
intriguing hypothesis at the conference
that might
link
reactivity to atherosclerosis.
of the atherogenic process
The predominant model
the endothelial
is
injury
model offered initially by Ross and Glomset and amended by Schwartz.
lining of the artery wall
is, repeated injury to the endothelial
to lead to accelerated cell
atherosclerotic
The altered permeability permits the
transient
environmental endothelial
entail
a
by
he
model
for
proposed
that
behavioral
beta-adrenergic
activation,
role
the
episodic
which
changes
to
of
increases
require
in
cardiac
in
and
coping
active
elevated
promote
reactivity
resistance
the
in
These increases in peripheral resistance
peripheral vasculature over time.
function of resulting structural
a
reactive
important factor in mechanically promoting
different
Briefly,
elicited
occur as
repeated
the
individual
the
in
that
injury and in preventing normal healing of these lesions.
hypertension. output,
suggested
Clarkson
pressure
blood
stress may be an
offered
Obrist
of
elevations
and the consequent acceleration of
into the cell
deposits.
placque
thought
death, which, in turn, alters the permeability
of the cell membrane to lipoproteins. influx of LDL cholesterol
is
That
changes
in
the arterioles
or
via intrinsic homeostatic processes which act to prevent an over-perfusion
of
tissues
body
(autoregulation).
Furthermore,
mechanism may be particularly relevant because output will
a
autoregulation
markedly increased cardiac
levels above that demanded
supply oxygen
the
by
the
tissues
cell
during the behavioral challenge.
It should be emphasized that the above hypotheses In
fact,
Julius
hypothesis part,
this
that is
and
of
some
reactivity because
of
other
the
plays
an
differences
conferees
etiologic in
have not been confirmed.
the
role
took in
exception
to
the
hypertension.
In
interpretation
of
the
data
showing that mild hypertensives are not necessarily more variable or labile in
casual
blood pressure measures;
the failure to show that hypertensives
are more reactive to physical stressors in some studies; and the absence of any population-based longitudinal
become hypertensive.
data showing that reactive normotensives
Nonetheless, these hypotheses nicely illustrate that
reactivity may not play
a
single etiologic role and that it may vary in its
importance for the specific diagnoses of cardiovascular disease.
Another
way
view
to
varying
the
roles
reactivity
of
consider how stress-induced reactivity may serve as
consequence
and
example,
it
pressure
are
who
parents,
exhibit
that
can
are
this
issue).
In
of
subsequent rate
in
stress-induced
marker
or
an
Krantz,
&
heart
or
sense,
a
to
blood
offspring
develop
to
as
in
Manuck
Falkner;
pressure
correlate
a
elevations
risk
blood
in
considered
be
hypertension
normotensive
that
elevated
at
Rose,
(see
Using
(see
is
precursor, correlate,
a
stress-induced
noted
been
elevations
response to stressors
reactivity
also
has
It
hypertension,
diseases.
precursor of hypertension
a
hypertensive
argued
been
has
issue).
this
cardiovascular
of
disease
in
for
risk
of
hypertension,
while
hypertension.
Finally, many secondary adjustments arise from hypertension,
necessarily
not
being
cause
a
subsequent
of
such as changes in cardiac performance, decreased baroreceptor sensitivity,
changes
structural
resistance
in
vessels,
ability (Folkow, 1983; Shapiro, Miller, King et that
of
some
secondary
these
information
and al
.
adjustments
1982).
,
inhibit
processing
It is
feasible
exacerbate
or
stress-induced reactivity as they compensate for an individual's elevated blood pressure.
Stressors as Elicitors of Reactivity
conference
The
concerning
discussion
which
reactivity
elicit
stressors
highlighted one of the fascinating, but imprecise aspects of any scientific concerned
inquiry
stress
of
level
with
stress.
which
experience
individuals
acknowledged
participants
The
response
in
to
that a
the
given
environmental event is crucial for determining the impact of that event and that
substantial
appraised.
In
differences
individual
exist
in
how
the
event might
be
consequence, the impact of some of the psychological as well
as
physical
stressors may vary substantially across experiments according
to
how
stressors
which
the a
challenge in
which
are
presented.
stressor,
physical
like
the
For
cold
pressor,
(e.g.,
adverse sensations to be overcome)
it
presented
differences
is
between
as
a
experiments
diagnostic in
the
those
example,
test,
willingness
is
should
pressor test and in perceived stressfulness of the test.
presented
as
in a
those experiments
vs.
to
experiments
yield
tolerate
important the
cold
This example also
points
arbitrariness of separating stressors
the
out
those
into
that are
"psychological" and those that are "physical."
Another theme that emerged during the conference was that stressors can be grouped not only according to the level and duration of stress experienced by
individuals
which
the
also according
but
elicit
stressors
(see
pattern of physiologic
the
to
Williams,
One way to slice
issue).
this
response
the physiologic pie is to distinguish those tasks which elicit increases in
cardiac output and muscle vasodilation from those which elicit increases in total
peripheral
slice
the
pie
is
catecholamines
distinguish
to
Cortisol
and
catecholamines. of
resistance and muscle
knowledge
elicit
elicit
which
those
physiologic
their
to
physiology
human
of
which
tasks
elevations
elevations
of
only
in
As a taxonomy of laboratory tasks develops, categorization
according
tasks
those
from
Another way to
vasoconstriction.
and
effects
future
to
contribute
will
investigations
to
of
the
ways
the
pathogenic effects of stress-induced reactivity.
The
conference
participants
relationship between "field"
or
that
person's
is,
do
several
in
responses
stressors.
life"
"real
perspective;
a
discussed
to
laboratory-induced
achieved throughout the course of the day? for levels taken during
a
laboratory stressors
way
One
different
was
levels Can
from
an
naturally occuring stressor?
to a
are typically acute measures, whereas levels
stressors are
a
There are minimal
induced by naturally occuring
there may be important modifiers of reactivity to natural
role
in
determining
to
reactivity to
the
A more
Laboratory-induced levels
mixture of chronic and acute responses to stressors.
prolonged and/or repeated exposure
levels
stand-in
data concerning this issue (see Manuck & Krantz, this proceeding).
theoretical way concerned models of reactivity.
to
assessment
generalize
they serve as
and
stressors
stressors due to
that may
laboratory stressors.
Thus,
A
not
final
play
a
concern
was the frequency with which individuals are exposed to naturally occuring
stressors which stressors.
elicit responses
Although individuals may respond similarly to
naturally occuring stressor,
experience
similar to those elicited by laboratory
the
if the
naturally occuring
not be informative.
a
laboratory and
individuals do not sufficiently often
stressor,
then
laboratory measures may
Variables Affecting Reactivity
Conference
participants
agreed
variables
sociodemographic
related
are
specific
that
psychological
and
reactivity and that population
to
differences in risk for cardiovascular diseases might be explained in part by
differences
population
Among
reactivity.
in
promising
most
the
predictors of reactivity are Type A behavior, hostility, anger, sex, age,
family history of hypertension
and
Matthews,
Matthews
1982;
differences
Rakackzy,
^
reactivity
in
(Frankenhaeuser, press).
in
currently
are
Houston,
1983;
1983;
Racial
and
ethnic
but
are
under
unknown,
investigation in several NHLBI funded projects.
The
also
conferees
might
impact
thought
Consumption
reactivity.
on
substances
certain
that
of
caffeine,
behaviors
health
and
salt,
sugar,
and
alcohol; smoking; pharmacologic agents; and modes of coping with stress may
reactivity,
influence
although
it
is
whether
unclear
effects
the
are
additive with the exposure to stress or synergistic (interactive) with the An illustration of this point comes from the study by
exposure to stress.
Dembroski and colleagues described in this issue. to
a
stressful
elevations
in
condition.
A
task
blood
and
smoking
pressure
synergistic
model
physiologic change, relative to
of
Several
although
heart
task
would
their study, exposure
effects
relative
rate,
predict
determining
in
to
geometric
a
a
control
increase
in
control condition.
made
groups
similar
a
point.
That
is,
individuals tend to engage in more than one of the above health
behaviors, 1984),
"substance"
the
a
additive
had
and
In
e.g.,
little
is
both
smoke
known
and
about
drink
their
alcohol
(see
interactive
Istvan
effects
&
since
Matarazzo, they
are
typically studied in isolation in laboratory studies.
It was
also noted that many of these substance/health behaviors may have
particularly
deleterious
effect
in
persons
predisposition for cardiovascular disease.
with
a
a
genetic/familial
Directions for Future Research
Because stress-induced reactivity has not been established as
cardiovascular
for
disease,
conference
the
a
risk factor
participants
expressed
considerable enthusiasm for the types of studies that would be a
population-based
epidemiological
appropriate
stressors
the
testing
association
the
of
They suggested that parametric studies
reactivity and subsequent disease. on
study
prelude to
a
specific
for
racial,
ethnic,
sex,
and
age
groups and evaluated for their reliability or reproducibility and validity or general izability would be crucial. on the physiologic parameters most
large
Specific
scale.
adjustments cleaning
up
importantly,
certain
to
noise
the
Clinical studies should be conducted
important and feasible to measure on
attention
substances/health in
measuring
behavioral
the
to
physiological
and
would
behaviors
for
useful
be
reactivity,
stress-induced
a
more
and
daily
for understanding reactivity in the context of normal,
living patterns where people do eat, smoke, and drink at the same time.
Animal studies ongoing simultaneously with human studies were thought to be
particularly valuable because of the
level
allowed and of the
of control
possibilities for studies that would not be feasible in humans. studies of substance ingestion,
studies which
Parametric
include continuous
invasive
measurement, and selective breeding of genetically predisposed individuals are examples of studies which would not be feasible in humans, but would be
yery
informative
for
understanding
human
physiology
mechanisms involved in cardiovascular diseases.
and
potential
Given that suitable animal
models for studying atherosclerosis and hypertension have been developed, it is most reasonable to pursue studies on the interactions of behavior and
substance ingestion or genetic susceptibility to disease. the
behavioral
determinants
of
atherosclerosis
by
Indeed, work on
Kaplan,
Manuck,
and
Clarkson in the cynomolgus monkey and of hypertension by Anderson, Henry, and
others
in
the
dog
and
rat
has
been most
fruitful
for
understanding
disease processes.
In
conclusion,
reactivity and
exciting
times
cardiovascular
are
ahead
disease.
in
There
the
are
area
many
of
stress-induced
hypotheses
to
be
tested
and
much
parametric
research
to
be
accomplished.
Whether
individual differences in stress-induced reactivity will prove to be
or a
not risk
factor for any of the cardiovascular diseases, research in this area will reveal
important
information about the exquisite
adjustments
between
the
behavioral and physiological systems and hone in on the important processes in
determining the etiology and course of cardiovascular disease.
that
the
conference
and
the
volume
important research issues in this area.
10
it
produces
facilitate
We hope
addressing
WELCOMING REMARKS
WELCOMING REMARKS
Detre
T.
It
is
a
National
what
to
Raymond
I
of the
name
the
in
Heart, Lung, and Blood Institute and the University of Pittsburgh
promises Seltser,
exciting
an
be
to
Graduate
of Medicine, will
School
privilege to welcome you
great pleasure and
conference.
Health,
Public
of
School
of
Two
and
deans,
our
Donald
Dr.
Dr.
Leon,
fact, actively participate in our proceedings.
in
want to extend our special welcome to our colleagues from Sweden and the
Soviet Union, who will work we will.
be working with us over the next several
Karen Matthews,
Stephen Weiss and Dr.
Dr.
And
days.
despite my best
efforts to the contrary, have insisted on putting us away in this beautiful
certainly
but
isolated
setting
ensure
to
complete
protection
from
all
distracting entertainment.
Perhaps very
they were
right.
substantive.
relationship difficult. the word
of We
The
The
time
available
methodological
stress
problems
cardiovascular
to
have been lamenting for years We often
stress.
fail
short and
is
involved
disorders
While cause
many
Moreover, such
of
provide
studies
our
exceedingly
about the promiscuous use of
differentiate between situations
to
experimental
valuable
is
examining the
in
are
are rather prosaic ordinary life events and those which force.
agenda
the
paradigms
stress
insights
involve
about
temporary change in cardiovascular functioning,
tour de
a
are
conditions
that
acute.
that
can
the
data obtained
cannot be generalized to conditions involving chronic stress.
Missing also
is
a
a
clear appreciation
that
the
different
types
of
stressors
may
have
different effects, depending on the stage of the disorder we are studying. I
suspect that we also err by looking at risk factors, disregarding their
biologic context. risk
factors
is,
Just how significant however, will
subjects
and
stage
organism
and
the
of
stage
the
of
a
risk factor or a constellation of
vary depending on
disorder.
disorder
the
Accordingly, will
also
age and
age
and
determine
sex
sex
the
of the
of
the
potential
effectiveness of an intervention aimed to reduce one or more risk factors regardless whether the type of intervention
11
is
"biologic,"
as
may be the
case with low cholesterol diet, or "psychological," as may be the case when
some form of relaxation therapy is administered.
Sometimes our frustration tolerance seems to be low. put
aside
unable
to
potentially
valuable
experimental
find measurable biologic
paradigms
correlates.
that nothing was wrong with the experimental
We have in the past,
Yet
it
biologic
and
response,
a
method
quite possible
paradigms; what we lacked was
either an appreciation of the often peculiar temporal stress
is
were
we
because
that was
relationship between
sensitive enough,
were looking at the wrong biologic system in our search for
or we
measurable
a
response.
We have become
increasingly aware that genetic and constitutional
factors
always set the ceiling for the level of functioning the organism is able to
achieve.
In
evaluating
treatments,
our
especially when
effect
their
is
modest, however, we tend to forget that whatever we do is limited by this ceiling.
Lastly,
most
perhaps
and
importantly,
all
of
us
are
aware
that
our
investigative efforts aimed to delineate the mechanism by which stress
biologically transcribed are still
in
their infancy.
Yet
it
is
is
precisely
this focus which must receive high priority in the coming years.
Because the questions are so many and the challenges facing us so complex, the
Heart,
National
should
not
should
be
follow devoted
Lung, the
and
Blood
traditional
instead
to
decided
Institute
format
of
a
that
consensus
elicit your creative
ideas,
this
meeting
conference bringing
but
forth
recommendations that will allow behavioral medicine to take the next giant step
forward.
I
wish you
well
in
warmest welcome.
12
your
endeavor,
and,
once
again,
our
OVERVIEW
STRESS AND REACTIVITY
R.
Williams, Jr.
B.
We are interested in the question of stress and reactivity because certain
characteristics,
psychological
shown
been
have
(2),
cardiovascular
such
Type A behavior
as
predispose
to
increased
to
assumption
implicit
An
disease.
persons
hostility
and
(1)
risk
of
"reactivity
(the
hypothesis") fueling our concern with stress and reactivity is that persons with
characteristics
such
cardiovascular events
neuroendocrine
and
hostility experience degrees
and
reactivity
everyday
to
of
environmental
that are at least partly responsible for the increased
(stressors)
observed
incidence
disease
Type A
as
when
persons
with
these
characteristics
are
followed in prospective longitudinal studies.
Before we can even begin to speculate regarding the role of reactivity in
pathogenesis, framework
it
is
which
to
base
upon
reactivity?
Do
reactivity?
necessary
first
however,
provide
speculations.
our
environmental
all
to
stressors
cause
theoretical
a
What
is
the
same
meant
by
kind
of
individuals respond to the same environmental stressors
Do all
with the same reactivity?
can draw upon empirical
If we
research in the
stress field to pose acceptable answers to questions such as these, then it will
possible
be
proceed
to
in
a
more systematic,
informed
and
reasoned
fashion to design the studies necessary to elucidate pathogenic mechanisms
underlying the relationships between certain psychological
characteristics
and cardiovascular disease.
presentation
In this
of variables
events
response
which
experimental
distinct designate
play
evidence
pattern
observations
into
could
response
about
patterns a
role
pattern
the
kinds
pathogenesis.
in
the
(which,
and
cardiovascular and neuroendocrine
of
supporting
patterns 1
model outlining the critical classes
a
study to gain an understanding of how environmental
we must
translated
are
present
shall
I
2)
of
for in
existence
of
descriptive humans
and
environmental
13
I
shall
two
review
qualitatively
purposes, animals,
stimuli
the
shall
I
along
which
with
appear
A consideration of brain mechanisms
specifically to elicit those patterns. responsible buttress
argument
the
understanding el
The
environmental
of
well
as
next
will
serve
add
as
critical
stimuli
to
our
to
their
for
citation.
organization
of
talk
this
as
without some thought on my part. environmental
is
outlined
was
chosen
not
When it comes to defining those types of
specific
much
for
just
patterns The
controversy.
of
physiological
process
naming
of
phenomena often leads among scientists to what may be termed
psychosocial
narcissism":
"label
room
have
I
elicit
which
stimuli
there
response,
the
patterns
existence,
their
for
classes
of
response
these
mediating
for
we all
love our own labels
labels others might choose.
for things
what follows
In
far more than
hope to present first
I
evidence supporting the objectively evident existence of two patterns of response
physiological stressful. patterns,
can
we
If
perhaps
then
conditions
under agree
on
can
we
that
least
at
enter
a
might
outlines
broad
the
dialogue
described
be
which,
in
as
those
of
together,
attempt to characterize the circumstances which elicit either pattern. we can avoid the work
of
the
"name debate," perhaps
it will
we If
easier to get on with
be
understanding the role of reactivity in
the
pathogenesis
of
cardiovascular disease.
A Theoretical Model
In
figure
While
I
1
is
illustrated
physiological
of
of
take
responses
into
environmental
how
cardiovascular disease, must
version
the
"biopsychosccial"
(reactivity) it
account
does if
events
that
could
illustrate several are
we
ever
to
model.
attempts at graphic
make no claims that it is better than others'
representation
we
my
transduced
are
play
a
role
causing
in
principles that
understand
the
into
I
feel
role
of
reactivity in cardiovascular disease.
First, and most relevant to the focus the
of this
talk,
the model
shows
that
"motor messages" sent by the brain to the body's organs following the
perception of some environmental event occur in organized patterns than as
isolated responses,
and
that these patterns
14
involve all
,
rather
three of
the motor effector systems available for the brain's communication with the
body
— the
somatomotor nerves, the autonomic nerves and the neuroendocrine This principle has been most cogently enunciated by the English
system.
physiologist S.M. Hilton, who suggests: "that a new approach may be made by starting from the view that the central nervous system is organized to produce not single, isolated Any variable which variables, but integrated patterns of response. can be described or measured independently is actually a component of In this system, the repertoire of patterned several such patterns responses (may be) very small." (3, p. 214)
Based
environmental patterns
reasoning,
this
on
events may produce
involving
response
of
then,
suggest
I
broad
that
relatively small
a
motor
three
the
classes
number of
effector
of
integrated
systems.
This
means that rather than studying only one or two physiologic parameters, we should study as many parameters as possible, so to identify more reliably patterns of response.
identify and agree on the nature of some
If we can
it might then
of these patterns,
be possible
to characterize
the critical
types of environmental stimulation which elicit them.
also indicates, the brain's interpretation and transduction of
As the model
environmental
events
into
the personality of the individual the
Type
reminds
model A
Type
and
as well
that different
us
response to the same environmental
attention
to
the
fact
responsible
also
hypertension
— can
that
his/her genetic makeup.
in
differences
certain
genetic
,
It
also influence what happens
in
Thus
producing
the
patterned
also calls our
characteristics--e.g.
predisposition
by
those in
stimulus situation.
increased
for
as
be modulated
can
personal ities--e.g.
result
behavior--can
B
of motor messages
patterns
to
,
those
essential
the motor outflow tracts
following any stimulus.
The
above
sequence of events--environmental
event,
interpretation
by
the
brain and transduction into patterns of motor messages, modulation by the
personality
and
organs--occurs on although
such
genes, a
and
effects
acute effects can
that we
be
motor
more or less acute basis within be
sustained as
involved with the given environmental however,
of
mindful
stimulus.
of certain 15
messages
target
limited time span,
a
long
on
the
as
The model
other processes
organism is
also suggests,
which occur over
longer, more chronic time periods.
developmental
which
beginning at birth and extending into adulthood,
processes,
involve
interaction
the
First, the personality is the result of
of
individual with his/her environment.
cumulative response
effect
across
repeated
of
the
life
lead
to
pathophysiological
predispositions
of
the
A second chronic process involves the
elicitations
span.
"reactivity hypothesis" holds,
genetic
the
of
extensive
If
various
the
patterns
intensive
and
enough,
of the
these repeated responses could, over time,
resulting
changes
in
development
the
of
cardiovascular disease.
the
For
remainder of this
presentation,
data which suggest the existence
response.
This will
the brain produces
o"''
be followed
review some experimental
shall
I
two qualitatively distinct patterns of
by a consideration of the means
by which
these patterns, and by some observations regarding the
types of environmental stimuli which elicit them.
Two Patterns of Physiologic Response
Obrist has called our attention to the importance of motor activity
Paul
musculature in determining patterns of response.
and the skeletal
follows
from
this
might
vasculature
observation
in the body,
of
responses
important
furnish
The skeletal
patterns.
that
clues
the
regarding
response
basic
muscle circulation is one of the most interesting
receiving anywhere from 15-20 percent of the cardiac output at
vascular
permit
it
bed
motor
vascular
activity bed
that
neural
has
exhibit
to
vasoconstriction. of
It
muscle
skeletal
rest up to 85 percent under conditions of heavy work or stress.
only
(4)
both
and
neuroendocrine
mechanisms
vasodilatation
active
It
is
the
which active
and
For these reasons and because it supports the functions so
deserves
important our
for
attention
life as
itself,
we
try
to
the
muscle
skeletal
identify
the
basic
physiologic response patterns.
In
studies with humans,
a
number of investigators have used the relatively
simple but reliable method of venous occlusion plethysmography (5) to study skeletal
muscle
hemodynamics
under
various
experimental
conditions.
Representative of one group of these studies was the demonstration by Brod and
colleagues
(6)
of
an
active
vasodilatation 16
in
the
forearm
skeletal
arithmetic with harassment.
musculature during performance of mental
The
similarity of this skeletal muscle hemodynamic response in humans to that seen with stimulation of the hypothalamic "defense" area in animals (7) has led
conclusion
the
to
behavior
that
"fight
or
flight"
active skeletal muscle vasodilatation
an appropriate response,
is
where
conditions
under
key aspect of the integrated response
Thus
(3).
is
a
to
suggest that skeletal muscle vasodilatation may be
seems reasonable
it a
valid "marker" of
one important response pattern with relevance for the role of reactivity in For the time being,
cardiovascular disease. as pattern
Indeed,
refer to this pattern
Of course, the model presented earlier leads us to recognize
1.
muscle vasodilatation is only one ingredient of pattern
that the skeletal 1.
let us
in
their pioneering study, Brod and coworkers (6) were able to
demonstrate that at the same time the muscle vasodilatation was occurring,
vasoconstriction
also
was
occurring
the
in
tract of their subjects, and it follows as well
gastrointestinal
neuroendocrine system is also participating in pattern
But what of the other pattern,
presentation?
this
Based
increases during personal
on
"pattern 2," that
observations
interviews
(8),
interview
personal
During
(9,10).
blood
my colleagues and
mental
that the
1.
diastolic
of
and
promised to describe in
I
muscle hemodynamic response to mental arithmetic, a
kidney
skin,
I
pressure
studied the
sensory intake task and
a
performance
arithmetic
we
found, as had many others, an increase in forearm blood flow and a decrease in
forearm
vascular
vasodilatation.
In
resistance,
to
behaviors
a
significant
skeletal
muscle
interview
provided
associated with muscle
increase ,
indicating
an
The muscle hemodynamic response
muscle vasoconstriction.
personal
the
active
contrast, during the sensory intake task we found that
forearm vascular resistance showed active skeletal
indicating
further
clues
vasoconstriction:
regarding
among
those
motoric subjects
who avoided attending to the interviewer, forearm vascular resistance fell,
while among those who attended closely to the interviewer, an increase in forearm vascular resistance was observed.
Thus,
it
observed
appears,
during
in
addition
defense
to
behavioral
the
skeletal
activations,
muscle there
vasodilatation is
a
second,
qualitatively distinct pattern of muscle hemodynamic response which can be
17
elicitated, one characterized by active vasoconstriction. 1,
pattern
As with
for the time being let us refer to this second pattern, characterized by
active skeletal muscle vasoconstriction, as pattern 2,
truly
marker
a
of
Hilton referred,
one
integrated
the
of
Similarly, if it
of
patterns
response
is
which
to
should also be possible to demonstrate characteristic
it
neuroendocrine responses accompanying the muscle vasoconstriction.
suggestion
The
that
patterns, pattern
with muscle vasodilatation as as
marker,
a
Anderson
research.
animal
of
with
concerned
be
to
vasoconstriction
with muscle body
1
need
we
and
response
basic
two
marker, and pattern
a
is
also
based
Brady
(11)
cite
extensive
an
on
?
research
dogs
in
which leads them to conclude that behavioral states (e.g., shock avoidance)
activation
associated with
mediated
responses
increased
preavoidance)
of
which
Based
resistance.
mediated
by
of
face
the
in
lead
inhibition
system
solely
observations
on
output
behavioral
skeletal-motor
the is
cardiac
while
resistance;
peripheral
pressure
by
system
skeletal -motor
the
of
leads
increases skeletal
pressor
to
decreased
of
during
(e.g.,
increased
to
total
in
muscle
blood
peripheral
vasoconstriction
during alert observation of another cat and vasodilatation during attack, Zanchetti
(12) also suggested the existence of a dual
cardiovascular
response pattern subserving emotional behavior: (skeletal "...one type muscle vasoconstriction) being the usual companion of immobile confrontation of the preparatory stage, the other type (skeletal muscle vasodilatation) being characteristic of emotional movement (the classical 'defense pattern')."
Given
that
existence
the
the
of
distinct
qualitatively
skeletal
muscle
hemodynamic response patterns of vasodilatation and vasoconstriction which appear to characterize two general response patterns--pattern 2
— has
been
diverse research
demonstrated
array
environmental
of
group
recently
stimuli
undertook
neuroendocrine components of pattern to
evaluate
behavior
the
pattern)
effect and
of
experimental
numerous
in
a 1
in
both
study
factors
to
and pattern 2.
personality-related
genetic
studies
humans
(13)
(family
1
and
and pattern
employing animals,
our
characterize
the
Another purpose was
characteristics history
disease) on the expression of the two response patterns.
a
of
(Type
A
cardiovascular
elicit
To
pattern
arithmetic task with 2,
we
we
1,
had
males
perform
mental
a
prize to the best performer; and to elicit pattern
a
perform
these same subjects
had
undergraduate
31
choice
a
reaction
time
The
task.
tasks were presented in counterbalanced order on two separate occasions, at the same time of day, with
followed
by
20-minute
a
diastolic
and
during
taken
period
task
(DBP)
between the two experimental
1-week interval
Hemodynamic measures
sessions.
(SBP)
a
included
pressure
blood
20-minute baseline period
a
heart
rate
forearm
and
systolic
(HR),
flow
blood
fFBF);
forearm vascular resistance (FVR) was calculated as the mean blood pressure
divided by the
FBF.
addition,
In
Cormed continuous
a
exfusion
pump was
used to obtain integrated venous blood samples throughout the baseline and task
assayed
plasma
The
periods.
frozen
and
epinephrine,
norepinephrine,
for
down
spun
was
to
Cortisol,
be
subsequently
prolactin,
growth
During
mental
hormone and testosterone.
The
main
results
arithmetic decrease
performance, FVR
in
vasodilatation. highly
interest
of
a
significant
were
observed,
With
respect
significant
shown
are
increase
indicating
in
prolactin
2.
FBF
in
and a
expected
the
neuroendocrine
to
increases
figure
in
(not
significant
responses,
increase
of
prolactin,
all
norepinephrine,
shown),
significantly
showed
which
hormones
three
increases
larger
in
were
there
epinephrine and Cortisol, while testosterone changed not at all. exception
muscle
skeletal
showed
a
With the
significant
Type A than
Type
in
B
subjects.
During
reaction
different.
time
performance,
the
pattern
Overall, there was no change in FVR,
of a
responses
was
result largely accounted
for by the failure of the Type A subjects to show the expected
which was observed in the Type
B
subjects.
significant increase overall, the Type A and
contrast to mental responsive, change.
during
Also
unresponsive,
in
reaction
contrast
during
to
reaction
time
task
increase,
While norepinephrine showed B
subjects did not differ.
arithmetic, where epinephrine and Cortisol the
quite
these
two
hormones
mental
arithmetic,
where
time
performance
a
a
In
were quite showed
testosterone
significant
no
was
overall
increase in testosterone was observed, and that of the Type A subjects was
significantly greater than in the Type
19
B
subjects.
It was not surprising that epinephrine and Cortisol
as
components of pattern
Henry
1.
concluded on the basis of an
has
(14)
increases were observed
extensive review of the stress literature that Cortisol and epinephrine are released
conditions
under
activated,
and
lease
at
vasodilatation which
where
critical
the
is
widely
one
classical
the
accepted
fight/flight
situation
with
along
that,
muscle
the
where
marker for pattern
the defense reaction, or fight/flight response.
response
is
1
the
is
muscle
observed is
Thus, our findings suggest
vasodilatation,
increased
epinephrine and Cortisol are also components of the pattern
secretion
of
response.
1
The increased testosterone response during the reaction time task is not as
easy to interpret at the present time, although there are some intriguing clues as to why this hormone should be secreted under conditions requiring
males to attend closely to environmental
literature suggests
male-male
levels
which
the
decrease them
to
is
of
attention
stress
of
else
as
a
studies, has
focusing and
engaged
males
two
on
testosterone
exogenous
of
task, as well
a
behavior and
There are animal
(15).
Whatever
(16).
general, the stress
effect
usual
suggest that administration
the effect of increasing persistence in
narrowing
In
exceptions of male sexual
the
confrontations,
dominance
testosterone however,
that with
stimuli.
in
a
dominance confrontation may be doing, they are certainly paying very close
attention
one
to
another.
Thus,
secretion during an experimental environmental
stimuli
"vigilance hormone." in
further
observed (16)
is
studies, real
is
may
be
finding
our
of
increased
testosterone
condition requiring close observation of
reflecting
this
function
hormone's
as
a
Though it will be important to replicate this finding our
confidence
that
the
testosterone
response
we
bolstered by the observation of Zumoff and coworkers
that Type A men excrete more testosterone glucuronide in urine during
working but not nocturnal hours in comparison to Type
If our
B
findings are replicated, it would suggest that,
association
of
epinephrine
and
Cortisol
neuroendocrine component of pattern
2
is
with
men.
in
pattern
addition to the 1,
a
reliable
increased testosterone secretion.
Thus, it appears that the principle of integrated patterns of autonomic and
neuroendocrine response that
is
part of the model
been supported by the study described above.
20
shown
in
figure
1
has
Not only have qualitatively
distinct skeletal muscle hemodynamic components of two patterns been widely
qualitatively distinct patterns of neuroendocrine response have
observed; also
observed
been
conditions
experimental
association with
in
known
to
elicit the muscle hemodynamic components.
there is evidence for the participation, also as suggested in
In addition,
the model, of personality factors 1
in modulating the expression of patterns
Type A males showed greater secretion of Cortisol and epinephrine
and 2:
during the condition
known
elicit pattern
to
and greater secretion of
1,
testosterone during the condition used to elicit pattern
2.
Finally,
role of the genes in modulating expression of patterns
and
2
some support in the findings of the study cited. a
larger Cortisol those with
history of hypertension,
family
positive
a
and
response to the
DBP
1
the
also finds
Among those subjects with Type A subjects
the
reaction time
showed
a
while among
task;
negative family history, the Type A subjects' Cortisol and DBP
responses were either smaller or not different from those of the Type
B
subjects.
truth the interpretations
It would be unwise, of course, to accept as final I
offer here
number of
for
findings
the
Replications
subjects.
these findings
in
of
detail,
a
single
study
clearly
are
needed.
such
have
I
a
small
described
however, because they illustrate the principles
advanced at the beginning of my presentation.
First, physiologic responses
stimuli occur in patterns; and we found discrete patterns
to environmental
of cardiovascular
and
neuroendocrine
conditions,
experimental
involving
shown
as
response
to
figure
2.
in
two
different
Second,
types
whatever
of the
ultimate number of such patterns that are found, there is much evidence for two patterns, one characterized by muscle vasoconstriction--pattern 2; and we
found
pattern
that when 1
and
neuroendocrine suggests
that
we
pattern
conditions
used
not
2,
were
responses
personality
and
transduction of environmental and
both Type A
only
the
shown
muscle
qualitatively genetic
situations
in
prior
hemodynamic
different.
factors
studies
may
modulate
into patterns
but
The
elicit
to
also
model
the
the
also
brain's
of motor messages;
behavior pattern and family history of hypertension were
found to affect and
interact in affecting the responses observed.
although more work will
be
Thus,
required to be sure the specific details are
21
correct, the evidence from the study
I
have described is
with the principles which underly the model
and pattern
have chosen to call
I
from neurophysiological
to be gleaned
is
2
have presented today.
I
Further support for the importance of what
strong accord
in
pattern
1
studies in animals
relating to brain areas where stimulation leads to increased or decreased peripheral resistance due to muscle vasoconstriction or vasodilatation.
How (and When) Does the Brain Produce Pattern
1
and Pattern 2?
stimulation of points in the premotor cortex, the amygdala, the
Electrical
mesencephalic tegmentum and the central gray matter of the anesthetized cat known
been
long
have
characterized
to
result in
cardiac
increased
by
pattern of cardiovascular adjustment
a
vasodilatation
output,
in
skeletal
muscle and vasoconstriction in skin and viscera; moreover, stimulation of these
points
same
indistinguishable reactions
levels sites
from
also
been
shown
animal
of
the
result
to
results
hypothalamic in
motoric
behavior
occurring
defense
in
naturally
during
seen
that
Stimulation
(18).
monkey has
awake
the
in
defense
increased
areas
in
the
corticosteroid
plasma
Thus, there is ample evidence that mammalian brains contain
(19).
capable
producing
of
the
integrated
pattern
of
cardiovascular and
neuroendocrine response which our study (13) suggests is characteristic of pattern
1
in humans.
With respect to brain mechanisms responsible for the production of pattern 2,
the
evidence
therefore, and
is
much
less
extensive.
I
am
for calling to my attention a most
coworkers
resulted in
a
In
(20).
awake
cats,
motoric behavior typical
indebted
to
James
Henry,
interesting study by Stock
stimulation
of
the
basal
amygdala
of the defence reaction which was
associated with tachycardia and increased aortic blood flow measured distal to
the renal
areas
fed
by
arteries the
(and thus
iliac
probably due to muscle vasodilatation
arteries).
This
behavioral
response pattern, of course, is identical to that to brain areas mediating pattern 1.
22
I
and
in
cardiovascular
just described relating
When the central amygdala is stimulated, however, of responses
but
ears
the
stimulation
Motorically the animal
observed.
is
of
flattened
not
are
and
amygdala.
basal
the
is
not
retracted
as
with
pattern
was
described
as
more
head
the
This
that seen with stimulation of the basal amygdala:
secondary
resistance
alert and activated,
is
The cardiovascular response also differed from
similar to attack behavior.
peripheral
quite different pattern
a
muscle
to
instead of the decreased
vasodilatation
with
seen
stimulation of the basal amygdala, stimulation of the central amygdala led to
pressor
a
response
associated
increased
with
resistance
peripheral
probably mediated by vasoconstriction in the iliac vascular bed.
While
the
cardiovascular amygdala
characteristic least
at
behavioral
pattern
of
brain
one
with
area
capable
pattern
2.
The
case
for
role
the
of
these
two
complexes in mediating the full blown expression of pattern as
described
further
of
the
in
study
shows
preceding
section
stimulation
of
will
the
increased plasma epinephrine and Cortisol
be
basal
and
1
greatly
and
central
the
1,
producing
and cardiovascular responses more characteristic of what
calling
been
be
to
associated
appears
adjustments
appears
behavioral
amygdala
basal
have
I
amygdaloid
and pattern
2
strengthened
if
result
in
amygdala
to
stimulation of the central
amygdala to result in increased plasma testosterone.
Recent theorizing by Floyd Bloom and coworkers (21) about the functions of the
locus
ceruleus
(LC)
may
provide
additional
insights
regarding
systems responsible for mediating the elicitation by environmental of
pattern
the
2
The
response.
the
It
is
is
a
collection
stimuli
of adrenergic
of the fourth ventricle at the level
bodies located near the wall pons.
LC
brain
cell
of the
known to supply most of the noradrenergic (NE) innervation to
entire cerebral
cortex
and
cerebellum and much
of
the
noradrenergic
innervation of the hypothalamus.
Based
on
anatomic and
their
exhaustive
projections,
colleagues
review
of
the
literature
pertaining
to
physiology and function of the LC-NE system.
conclude
that
this
system
"acts
at
many
target
the
Bloom
sites
to
somehow enhance the reliability and efficiency of feature extraction from sensory input" (21, p. 899).
Among the lines of evidence cited in drawing
23
this conclusion:
toward
syringe
a
in monkey,
1)
filled
associated
behaviors
LC-NE discharge increases with orientation
with
with
reduced LC-NE discharge;
decreased and
solution;
vigilance--e.g. both
in
3)
drinking
favored
a
rat
2)
rat,
in
grooming--result
,
and monkey the most
in
intense
activity in LC-NE neurons was observed at times when "surveillance of the environment
external
increased"
(21,
p.
(i.e.,
vigilance)
is
suddenly
and
dramatically
The interpretation given these findings is worth
873).
quoting: "Thus it would appear that LC-NE neurons vary their spontaneous activity in relation to vigilance levels. Increased vigilance, as during spontcineous or sensory-evoked arousal or during orientation to an unexpected or preferred stimulus, is associated with tonically enhanced LC-NE discharge, whereas decreased levels of vigilance, as during sleep, grooming or consumption behaviors, correspond to periods of diminished activity in the LC." (21, p. 873)
Given the apparent involvement of the LC
in
vigilance behaviors,
and
the
association of stimulation of the central amygdala with increased vigilance and LC
increased peripheral
projection
the
to
resistance,
central
it
amygdala
is
noteworthy,
has
therefore,
described
been
observations suggest that the LC-NE system may play an
(22).
that an
These
important role
in
mediating the motoric and physiological manifestations of pattern 2, when that pattern is elicited by environmental an hypothesis
is
stimulation.
Supportive of such
the observation that NE neurons originating in the LC are
responsible for peripheral
sympathetic nerve response of two rats to shock
induced fighting, but not the adrenal medullary response to footshocks when
administered to one rat (23).
While much of the evidence cited above is circumstantial, it does make the rather strong
case
that
brain mechanisms
plausible
behavioral and physiologic manifestations of pattern have described can be produced.
clues
to
as
the
specific
types
In
do 1
exist whereby the and pattern 2, as
I
addition, this evidence contains some
of environmental
situations which elicit
these two response patterns.
Finally, this evidence highlights the important principle suggested by the model
in
figure
immobility) responses.
do
1,
that motoric behaviors
not
themselves
"cause"
(such
as
autonomic
fight/flight or tonic and
neuroendocrine
Rather, it appears that along with autonomic and neuroendocrine
24
responses,
patterns
integrated
behaviors
motoric
the
are
third
a
which
response
of
but
result
component from
of
the
brain's
the
interpretation and transduction of environmental events.
What are the Adequate Stimuli for Patterns
I
1
and 2?
To draw firm conclusions regarding the
have saved the hardest for last.
nature of effective stimuli for eliciting patterns
1
and 2 is hard because
so much of the research upon which we must base answers to this question is
This is because
fragmented and incomplete.
single study to answer this
a
question would have to sample many physiologic parameters in many types of subjects under many types of conditions.
And that is just the easy part;
the hard part is that they must be the right parameters in the right types
The sheer logistic task of finding
of subjects under the right conditions.
enough
for
surface
body
intravenous
and,
the
possibly,
electrodes,
strain
needles
intraarterial
transducers
gauges,
would
that
and
required
be
makes it unlikely that the ideal study in this area will ever be done.
Nevertheless,
extensive
the
research
that
been
has
done
many
contains
clues, and it may be possible to begin to answer this question by recalling the experimental been
conditions,
in
both
studies,
human and animal
that have
found to elicit one or another response component of pattern
1
and
pattern 2.
With
respect
muscle
to
pattern
1,
following
the
epinephrine
vasodilatation,
and
have
Cortisol
reported
been
responses
situations which elicit fight/flight or defense behavior,
arithmetic with harassment (6);
without
harassment
effortful
or
(9)
mental
2)
word
or
both:
testing
coping, such as shock avoidance in humans
arithmetic
(24);
(4)
1)
such as mental
work, such as mental
association
elicit
to
3)
active,
and animals
(11);
and 4) uncontrollable aversive stimulus situations (25).
I
am
sure
I
have
inadvertantly
examples of experimental
elicit
one
Nevertheless,
or
more the
left
potentially
other,
important
behavioral challenges which have been reported to
components
cited
out
what
of
examples
25
do
I
contain
have some
called
common
pattern
1.
elements.
situations
Certainly,
pattern
eliciting
adaptive--i .e.
neuroendocrine
effectiveness
of
confer
might
they
,
fight
anxiety
or
flight
or
appear
vasodilatation,
muscle
the
associated
and
output
and
1,
fear
induce
that
increased
components
some
survival
behavior
might
capable
of
cardiac
would
appear
advantage--when
the
whether
determine
the
organism lives or dies.
work also elicit pattern 1?
But why would simple mental
have no ready
I
answer, but would like to speculate that perhaps mental work, thinking, if
you will, evolved from the motor functions of the brain.
If so, then it is
possible that intense "mental" effort activates the same motor systems in brain
the
possibly
subserve
that
intense
would
effort.
"motor"
explain
why
If
linkage,
this
so,
mental
work
produces the same physiologic response pattern as hard physical work.
This
vestigal
a
one,
how
and
hard
linkage may not be vestigal, however, in that the neuroendocrine components of
epinephrine
l--e.g.,
pattern
ACTH--may
and
actually
facilitate
such
aspects of thinking as cortical activation and memory consolidation.
What
are
conditions
the
while
Again,
surely
which
have
incomplete,
reported
been the
to
following
elicit
pattern
contains
list
2?
some
representative examples of studies in which muscle vasoconstriction (either directly measured or inferred from other measures), testosterone secretion, or
have
both
pornographic movie upside
down
and
preavoidance animal
who
(4);
out
period appears
confrontations
observed:
been
(15);
in
focus
the
dog
about and
passive
sensory intake,
2)
of
1)
6)
to
coping, as
as
watching
in
reading words
in
(9);
3)
alert
(11);
4)
vigilant observation
attack
(12);
immobility,
male-male
5)
under some conditions,
as
a
projected during
a
of another
dominance
shock-induced fighting
in the rat (23).
As with those conditions which have been reported to elicit elements of the
pattern
1
response,
there
are
also
common
threads
which
seem
to
tie
together those conditions cited above as eliciting the pattern 2 response.
Whether
under
emotionally
arousing
confrontation and shock-induced fighting)
26
conditions or
(e.g.,
male-male
under relatively nonarousing
conditions which appear to elicit pattern
responding have in common the
2
element of attentive observation of some aspect of the environment.
paraphrase
To
Beginning
well
attention
to
Paul
Obrist
over
two
the
so
much
ago,
the
(4),
decades
importance
mental
of
science
in
Laceys
work
(26)
calling
were
sensory
and
rediscovery.
is
intake
our two
as
classes of behavior which are associated with different patterns of somatic To the extent that pattern
and physiologic responses. I
have
described,
ultimately
are
recognized
1
and pattern 2, as
valid
as
of
ways
conceptualizing reactivity, and to the extent that mental work and sensory intake are at least among the key behaviors eliciting pattern 2,
1
and pattern
respectively, the Laceys deserve much credit for calling our attention
to these phenomena.
In
any event,
I
should like to give them much credit
for informing my thinking on these matters.
How Do Pattern
By now
I
1
and Pattern 2 Lead to Cardiovascular Disease?
there is more than enough to think about without
suspect you feel
having to ponder how this all
cardiovascular disease.
I
relates to the etiology and pathogenesis of
Beyond that,
I
leave it to others to
shall
My own thoughts on this issue are presented
confront this thorny question.
elsewhere (27).
Therefore,
agree!
I
can only leave it as an exercise for you to
draw your own conclusions as to implications of what
I
have said for causal
mechanisms.
Summary and Conclusions
Reactivity might be understood as environmental sends
a
messages"
events
pattern to
of
target
and,
based
a
on
in
the
outcome
autonomic
somatomotor, organs
process whereby the brain
the
and
This
body.
of
that
interprets
interpretation,
neuroendocrine transduction
"motor
process
is
modulated by the past history (as reflected in the personality) and genetic make up of the individual.
There may be only
of response associated with psychosocial such
as
exercise,
diving,
and
27
(as
digesting
a
limited number of patterns
opposed to physical a
meal)
stimuli.
stimuli, I
have
described two such patterns today, along with possible mechanisms whereby they are produced by the brain.
I
have
tried
in
this
presentation
bewildering array of complex data.
the complexity,
and that where
stimulated to ponder what
I
summarize
No doubt
with which some may justly quarrel. to
to
I
I
I
what
to
some
may be
have made inferential
hope that
I
a
leaps
have brought some order
may have erred, you will
at
least be
have said and collect the data necessary to set
it right.
For those who might like
patterns
1
and 2,
I
a
summary of the key points made herein regarding
offer for your perusal
table
1.
I
welcome efforts to
correct the errors and, especially, efforts to fill in the gaps.
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23.
Williams, R.B., Richardson, J.S., Eichelman, B.S. Location of central nervous system neurons mediating blood pressure response of rats to shock-induced fighting. J. Behav. Med. 1_:177-185, 1978.
24.
Williams, R.B., Frankel , B.L., Gillin, J.C, Weiss, J. response during a word association test and interview. ]0:571-577, 1973.
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Lundberg, U., Frankenhaeuser, M. adrenal correlates of distress 24:125-130, 1980.
Nucleus locus ceruleus: New specificity. Physiol. Rev.
Cardiovascular Psychophysiol
Pituitary-adrenal and sympathetic effort. J. Psychosom. Res.
and
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Lacey, J.I., Lacey, B.C. On heart rate responses and reply to Elliott. J. Pers. Soc. Psychol. 30:1-18, 1974.
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R.B. Williams, response Neuroendocrine patterns In Biobehavioral mechanisms of disease. Wiliams, Perspectives on behavioral medicine: Neuroendocrine behavior New York, Academic Press, In press, 1984.
30
behavior:
A
and stress: R.B. (Ed.): control and
f^PMFO
ENVIRONMENTAL
1
Developmental
PERSONALITY
Processes
(Learned Expectations)
ENVIRONMENTAL EVENTS
V
STIMULUS HISTORY
"Motor" Messages
GENES 2.
Somatomotor Nerves Autonomic Nerves
3.
Neuroendocrine
1.
Substances
TARGET ORGANS (Behavior)
SYMPTOMS and
DISEASE
illustrating model how personality FIGURE 1. Theoretical factors, environmental events and genes interact via the brain's transduction to produce integrated patterns of physiologic response.
31
NS p 1967. Acta. Med. Scand. Suppl
essential
hypertension.
.
7.
Horan, M.J., Kennedy, H.L., Padgett, N.E. Do borderline hypertensive patients have labile blood pressure? Ann. Int. Med. 94 (part 1): 466-478, 1981.
8.
Wood, D.L., Sheps, S.G., Elveback, L., Schirger, A. Cold pressor test as a predictor of hypertension. Hypertension 6:301-306, 1984.
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R.A., Hanne, N., Silverberg, D.S., Bar-Or, 0. Follow-up of normotensive men with exaggerated blood pressure response to exercise. Am. Heart J. 106(2) :316-320, 1983.
10.
K.R. Thomas, C.B., Duszynski, Blood pressure levels in young adulthood as predictors of hypertension and the fate of the cold pressor test. The Johns Hopkins Med. J. 251:93-100, 1982.
11.
Thomas, C.B. Developmental patterns in hypertensive cardiovascular disease. Fact or fiction. Bull N.Y. Acad. Med. 45:831-850, 1969.
12.
Harris, R.E., Solokow, M., Carpenter, L.G., Friedman, M., Hunt, S. Response to psychologic stress in persons who are potentially hypertensive. Circulation 7:874-879, 1953.
13.
Kalis, B.L., Harris, R.E., Sokolow, M., Carpenter, L.6. Response to Am. psychological stress in patients with essential hypertension. Heart J. 53:572-578, 1957.
14.
Folkow, B., Rubinstein, E.H. Cardiovascular effects of acute and chronic stimulation of the hypothalamic defense area in the rat. Acta. Physiol. Scand. 68:48-57, 1966.
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Liard, J.F., Tarazi R.C., Ferrario, CM., Manger, W.M. Hemodynamic and humoral characteristics of hypertension induced by prolonged Circ. Res. stellate ganglion stimulation in dogs. conscious 36:455-464, 1975.
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Talman, W., Alonso, D,, Reis, D. Chronic lability of arterial Clin. Sci. 59 pressure in the rat does not evolve into hypertension. (Suppl 6):405a-407a, 1980.
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Anderson, D., Kearns, W., Better, W. Progressive hypertension in dogs Hypertension avoidance saline infusion. by conditioning and 5:286-291, 1983.
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70
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21.
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22.
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T.G. Coleman, of hypertension.
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71
IMPLICATIONS FOR CORONARY HEART DISEASE J.
Alan Herd
Atherosclerosis is Through
wall.
process in which lipids are deposited in the arterial
a
not
process
some
cells
endothelial
understood,
well
are
lifted from the lining of the artery and lipids gain access to the intima. In
response
the
to
altered
composition,
intimal
Lipids accumulate in
intima and proliferate.
cells move into the arterial
muscle
smooth
vascular
Later, lipids, fibrous
the smooth muscle cells and produce lipid streaks.
tissue, and other proteoglycan materials are deposited in the extracellular space.
proliferation, hemorrhage, necrosis, and
Chronic inflammatory cell
Although lipid infiltration into the
calcification occur at later stages. arterial
wall
atheromatous
muscle
is
an
plaque
important part of atherogenesis, the formation of the
initiated
is
Thus,
cells.
the
by
proliferation
mechanisms
pathophysiological
the
of vascular
smooth
promoting
the
primary proliferative process of vascular smooth muscles may be critical for the development of coronary artery disease.
Studies by several investigators have demonstrated that smooth muscle cells do
not proliferate
et al.
in
Ross
1974).
lipoproteins
were
addition,
these
platelets
and
culture except in the presence of blood serum (Ross
et
(Ross
al.
necessary
authors
calcium
for
(Ross
Glomset,
and
optimal
et al.
reported
growth
cell
in
serum
that
culture.
In
demonstrated that addition of
1974)
platelet-poor
to
1973)
plasma
increased
the
activity of
plasma serum in promoting the proliferation of arterial smooth muscle cells in
culture.
shown
As
in
figure 1, five percent dialyzed plasma serum had
little or no effect on proliferation of arterial smooth muscle cells unless the
serum
was
experiments,
allowed
equal
to
numbers
clot of
in
the
presence
smooth muscle
of
cells
platelets.
were added
dishes and incubated in medium containing one percent serum. days, the dishes were separated into four groups. in
serum-free
containing
medium.
five
The
percent
remaining dialyzed
groups
serum
these
culture
to
After seven
One group was incubated
were
from
In
incubated
whole
blood
in
a
medium
containing
platelets, five percent dialyzed plasma serum exposed during the process to
73
platelets,
were
and
present.
activity
percent dialyzed
five
demonstrated
Results
dialyzed
of
serum
serum
plasma
much
that
directly
was
in
of
which
the
growth-promoting
indirectly
or
platelets
no
derived
from
These experiments further illustrate the importance of humoral
platelets.
factors in promoting proliferation of vascular smooth muscle cells.
Acceleration
of
atherosclerosis
atherosclerosis
elevated
is
of many
influence
the
and epidemiologic evidence
One with both clinical
factors.
under
occurs
insulin
of
levels
linking it to
Patients
blood.
in
risk
with
atherosclerosis frequently have abnormalities in glucose tolerance (Stout, Bierman oral
Brunzell
and
compared
glucose
disease
(Stout
increase
mortality
myocardial
of
middle-aged
in
development of atherosclerosis,
insulin
without
evidence
infarction
without
observations
These
atherosclerosis.
men
elevated
elevated
addition,
In
have
subjects
control
to
1981).
risk
the
and many
1975),
and
levels
coronary
and
overt
suggest
elevated
of
signs
responses
plasma
plasma
insulin
heart
disease
diabetes
of
levels
vascular
of
insulin
that
to
or
influences
increase
risk
for coronary heart disease.
Neurohumoral influences
on
epinephrine, insulin
with
provide
factors
risk
coronary
and
metabolic
several
exploring
behavioral
Neuroendocrines,
including
lead
disease.
heart
norepinephrine,
a
Cortisol,
for
influence Clinical
processes.
the
and
interaction
of
epidemiologic
evidence relates plasma levels of Cortisol to lipid metabolism and severity These effects may be mediated by effects of
of coronary artery disease.
insulin
sensitivity,
promoting
the
physiological
basic
both
through
process
influences
on
aggravating
of atherogenesis.
neuroendocrine
hyperlipoproteinemia
and
behavioral
and
Thus,
factors
the
which
affect
insulin
sensitivity warrant further discussion.
Cortisol and Atherosclerosis
has the opportunity to study the association
Troxler (Troxler et
al
of plasma
and coronary atherosclerosis
Cortisol
.
1977)
the United States Air Force.
in
young male aircrew of
Coronary angiography was part of the clinical
74
carried
evaluation
findings
electrocardiographic
medical
preclude
could
that
triglycerides,
cholesterol,
serum
Cortisol,
of
because
out
conditions
flying
percent
Plasma
duty.
body
or
blood
fat,
pressure, age, smoking habits, and coronary angiograms were measured on 71 men.
part of this evaluation, a standard 2-hour oral glucose tolerance
As
test was administered between 8 a.m. and 10 a.m.
tolerance
specimen
plasma
test
analyzed
was
Coronary angiograms were scored on
A portion of each glucose
for
Cortisol
concentration.
scale of 0-6 according to amount of
a
obstruction observed in the right and left coronary arteries.
Forty-eight
percent of the subjects showed no evidence of coronary artery disease, 20
percent
mild
showed of
obstruction elevated
morning
atherosclerosis
of
was
In
percent
found.
relation
Cortisol
a
both
direct effect
a
indirect effect on triglycerides
as
on
plasma
factors,
discriminator in that
a
degree of correlation was
of
levels
and had
high
risk
other
to
between
coronary
severe
to
severe
to
correlation
moderate
and
Cortisol
In
moderate
showed
Significant
arteries.
plasma
addition,
may have
Cortisol
32
second only to serum cholesterol
was
population. levels
and
coronary
the
serial
Cortisol
disease,
cholesterol
and
cholesterol
found between
triglycerides.
metabolism and
an
influence on the interaction
through its
of insulin in lipid metabolic processes.
Insulin and Atherosclerosis
Epidemiologic studies have demonstrated and
levels
incidence
the
of
a
myocardial
relation between plasma
infarction
insulin
coronary
and
heart
disease mortality in middle-age men (Ducimetiere, Eschwege, Papoz, Richard, Claude and Rosselin 1980).
serum well
triglycerides, as
Ducimetiere et
systolic
blood
al
.
pressure,
measured serum cholesterol, body weight
recorded history of cigarette smoking.
In
The population was
glucose load.
height
as
addition, they measured
plasma glucose and plasma insulin levels before, and oral
and
2
hours after a 75 g
7,246 nondiabetic working men aged
43-54 years who were
initially free from heart disease and were followed
for 63 months
average.
insulin
level
on
the
and
the
They demonstrated that the fasting plasma
fasting
insulin-glucose
ratio
were
positively
associated with risk for myocardial
infarction and coronary heart disease
mortality
the
independent
of
all
75
other
factors
(figure
2).
They
concluded
constitute
levels
insulin
high
that
factor for coronary heart disease complications
independent
an
risk
middle-age nondiabetic
in
men.
Metabolic Effects of Cortisol and Epinephrine
It
some
for
known
been
has
time
glucocorticoid excess
that
prolongs
the
removal of glucose during a glucose tolerance test in normal humans (Fajans
Conn
and
disease
Cushing's
whereby poorly
hypersecretion
Also,
1954).
has
influence
may
Shamoon
understood.
et
However,
removal
Soman
from
and
in
mechanism
the
glucose
of
(Shamoon,
al.
hormones
cortical
adrenal
effect.
diabetogenic
a
glucocorticoids
of
blood
Sherwin
is
1980)
examined the influence of Cortisol on glucose metabolism during continuous during a period of five hours.
infusion of Cortisol
women were studied after consuming
standard carbohydrate diet and fasting
a
The effect of Cortisol
overnight before observations were made. on
glucose
plasma
glucose
and
illustrated in figure 3. in
plasma
glucose
without
from
blood
kinetics
the
in
Infusion of Cortisol
influencing
normal
which
infusion
subjects
human
is
increased levels of glucose
glucose
of
rates
reduced
was
adult men and
Normal
production.
resulted
Removal
of
cortisol-induced
in
These effects of Cortisol on glucose metabolism occurred in
hyperglycemia.
the absence of significant
changes
in
plasma
or
glucagon concentrations.
Concomitant effects on fatty acid and amino acid metabolism suggested that Cortisol
interfered with the cellular action of insulin.
Behavioral
Many
Influences on Cortisol and Epinephrine
investigators
reported
have
results
behavioral
influences on physiological
performed
have
particular,
demonstrated
changes
in
heart
effects rate
processes. on
and
under a variety of behavioral conditions. behavioral
psychological
influences
on
of
The majority of studies
cardiovascular
blood
concerning
experiments
pressure
function.
have
been
In
studied
Other investigators have studied
neuroendocrine
processes.
In
general,
factors have been shown to influence secretion of Cortisol,
epinephrine,
characteristics
and of
norepinephrine. experimental
Although
conditions
76
used
the to
psychological test
behavioral
influences are not well-defined, some general characteristics of situations
influencing secretion of Cortisol and epinephrine can be stated.
provoking increased secretion of Cortisol
One characteristic of situations is
Bassett test
tested
1981)
normal
group
One
procedure.
Davis
situation.
novelty of an experimental
under
young men
subjects
of
et
graded
a
(Davis,
al.
exercise
experienced
was
Gass
and
tolerance
exercise
with
testing and the other group had no previous experience with the procedure. The subjects
both groups had similar capacities
in
could
relationship
significant
between
demonstrated
be
for physical
work.
No
oxygen
maximal
uptake, venuous lactate concentrations, Borg ratings of perceived exercise, or
responses
serum Cortisol
post exercise
the
Serum
increased 59 percent in the experienced subjects and 138 percent
Cortisol the
However,
levels was greater in the naive subjects.
increase in serum Cortisol
in
during exercise.
response in naive subjects compared
determinant in the increased Cortisol to experienced
relationship
heart
uptake,
rate,
or
venous
lactate
Apparently, the magnitude of response observed in Cortisol
concentrations.
concentrations
oxygen
maximal
to
response bore little
Furthermore, this Cortisol
subjects.
the major
concluded that novelty was
The authors
naive subjects.
influenced
was
more
psychological
by
factors
than
the
physiological effects of exercise.
Improving Insulin Action on Metabolic Processes
which
Conditions
interfere
with
influence
the
insulin
of
metabolic
on
processes are said to increase insulin resistance. When insulin resistance was
first
defined,
insulin-glucose mellitus action
or
was
injected
uptake
patients
reduced
of
in
with
measured
patients severe
on
glucose
levels and
by
with
The
measuring
by
of
determining
glucose
insulin
rate
the
non-insulin-dependent
obesity.
obtained
was
intravenously
administration
was
it
inference the
in
or
diabetes
that
insulin
of
insulin
effects
plasma
of
by
combining
intravenously and measuring
plasma
glucose concentrations during the next 60 minutes (Reaven 1983).
Ultimately,
an
important manifestation
of
insulin
resistance
is
elevated
levels of glucose in plasma, levels that are higher than would be expected 77
in
proportion to concentrations or insulin in plasma.
of the average blood sugar concentration in an individual
weeks
several
concentration
the
is
of
hemoglobin
over
Ale.
mellitus
diabetes
with
elevated
plasma
levels
concentrations of hemoglobin Ale may rise to 15 percent. synthesis level
red
is
slow
a
irreversible
nearly
and
reaction
form
of
proportion
a
concentration of hemoglobin.
and
period of
a
This
hemoglobin is present in red blood cells of normal subjects in of up to 5 percent of the total
indicator
A useful
patients
In
glucose,
of
Since hemoglobin red
in
cells,
the
of hemoglobin Ale reflects concentrations of glucose at the time the
blood
cell
circulation
approximately
for
concentration
Because
formed.
was
of
hemoglobin
blood
cells
remain
in
the
it
takes
several
weeks
for
the
days,
120
Ale
red
to
abrupt
reflect
changes
levels
in
of
Thus, measurement of hemoglobin Ale gives an objective
glucose in blood.
assessment of the average concentration of glucose over
long
periods
of
time (Koenig and Cerami 1980).
Improving insulin sensitivity can be achieved through several
The effect of physical training on insulin production in obesity
measures. has
been demonstrated by Bjorntorp et al
and
Sullivan
muscle
increased
program
training
These
1970).
which
strength.
Body
primarily
due
tolerance
test
.
investigators
program
training
physical
glucose
weight
before
reduction
the
in
concentrations
administration of glucose. indicating was
an
increased
not
sensitivity
apparently
maximal
actually
increased body
in
after
and
oxygen
and
during
the
A
fat.
in
normal
program
a
substantial
plasma
following
However, there was insulin
uptake
training
the
a
Authors interpreted results of these studies as
sensitivity of tissues.
insulin
decreased,
of
during
studied obese patients
increase
an
to
performed
(Bjorntorp, de Jounge, Sjostrom
increased
showed no change in blood glucose values.
mass
therapeutic
the
effect
occurred
of
physical
Since
training
body
fat
on
insulin
of
adipose
independently
of
any
contributing
to
coronary heart disease
change
tissue function.
Summary
The
pathophysiological
include
a
mechanisms
mix of genetic factors, traditional
78
risk factors, and behavioral
influences.
neuroendocrine
factors
may
influences
behavioral
The
effects
through
as
mediated
be
much
as
cardiovascular
on
tht
funct\
Plasma levels of Cortisol are related to lipid metabolism and their effet on
metabolism may
lipid
causing
hyperinsulinemia.
expected
promote
to
mediated
be
High
by
effects
circulating
atherogenesis
levels
direct
by
sensitivity
insulin
on
of
effects
would
insulin
vascular
on
,
be
smooth
muscle proliferation and elevating circulating levels of triglycerides and low
density
Evaluation
lipoproteins.
of
between
link
this
behavioral
factors and atherogenesis might be aided by measurements of hemoglobin Ale,
measurements
of
receptor concentration and affinity in red blood
insulin
cells and monocytes,
the measurement of
and
insulin to glucose
ratios
in
plasma.
The
behavioral
psychological
specific that
to
further
with
cope
research
characteristics
of
neuroendocrine
on
factors.
perception
exceed
efforts
influences
tasks
enhance
necessary
situations
new situations
particular,
self-competance
of
is
In
elicit
or
neuroendocrine to
apparently
factors
and
tasks
intense,
sustained
responses.
However,
determine
eliciting
involve
psychological
the
exaggerated
neuroendocrine
responses.
Corrective measures physiological by
the
physiological
approaches.
and behavioral
The
influences of physical inactivity and obesity can be overcome
appropriate
pattern, psychosocial
cognitive
include
corrective
measures.
The
influences
of
behavior
factors, and conditioning might best be corrected by
restructuring,
relaxation
training,
and,
where
necessary,
isolation of individuals from provocative situations.
REFERENCES Bjorntorp, P., DeJounge, K., Sjostrom, L., and Sullivan, physical training on insulin production in obesity. 19. 631-638.
The effect of Metabolism , 1970,
L.
Davis, H., Gass, G., and Bassett, J. Serum Cortisol response to incremental work in experienced and naive subjects. Psychosomatic Medicine. 1981, 43, 127-132.
79
Ducimetiere, P., Eschwege, E., Papoz, L., Richard, J., Claude, J., and Relationship of plasma insulin levels to the incidence Rosselein, G. of myocardial infarction and coronary heart disease mortality in a middle-aged population. Diabetologia , 1980, 19, 205-210. An approach to the prediction of diabetes mellitus Fajans, S. and Conn, J. modification of the glucose tolerance test with cortisone. by Diabetes , 1954, 3, 296-304.
and diabetes mellitus. A. Hemoglobin Ay Koenig, R. and Cerami Review of Medicine , 1980, 31, 29-34.^ ,
Annual
Insulin resistance in noninsul in-dependent diabetes mellitus. Reaven, 6.M. Does it exist and can it be measured? The American Journal of Medicine , January 17, 1983, 3-17.
Atherosclerosis and the arterial Ross, R. and Glomset, J. cell. Science , 1973, 180, 1331-1339.
smooth muscle
A platelet-dependent Ross, R., Glomset, J., Kariya, B., and Harker, L. serum factor that stimulates the proliferation of arterial smooth Proceedings of the National Academy of Science muscle cells in vitro 1207-1210. of the USA , 1974, 71, .
The influence of acute Shamoon, H. Soman, V., and Sherwin, R. physiological increments of Cortisol on fuel metabolism and insulin binding monocytes in normal humans. Journal of Clinical to Endocrinology and Metabolism , 1980, 50, 495-501.
Stout, R., Bierman, E., and Brunzell, J. Atherosclerosis and disorders of In Diabetes: lipid metabolism in diabetes. Its Physiological and Biochemical Basis , Val lance-Owen, J. (Ed). 1975, Lancaster: MTP Press,
Stout, R. The role of insulin in atherosclerosis in diabetics and Diabetes , 1981, 30 (Suppl. 2), 54-57. nondiabetics. A review. The Troxler, R., Sprague, E., Albanese, R., Fuchs, R. and Thompson, A, association of elevated plasma Cortisol and early atherosclerosis as Atherosclerosis demonstrated by coronary angiography. 1977, 26, 151-162. ,
80
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rx"^
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/
^
10--'
5% plasma serum
^
y
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3
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5
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r— 10
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culture
FIGURE 1. Response of arterial^ smooth muscle to platelet factors in plasma serum. Equal numbers (3 x 10 ) of primate arterial smooth muscle cells were added to a large series of 35-mm petri dishes and incubated in medium containing 1% serum pooled from several Macaca nemestrina. After 7 days (arrow) the dishes were separated into four groups. One group was incubated in serum-free medium. The remaining groups were incubated in medium containing: 5% dialyzed serum from whole blood containing 3.95 x 10 platelets per mil; 5% dialyzed plasma serum which had been exposed during the process of recalcification and serum formation to an equivalent number of platelets, derived from the same pool of blood; 5% dialyzed plasma serum in which no platelets were present during the process of serum formation. This experiment demonstrates that 5% dialyzed plasma serum has little or no proliferative effect unless allowed to clot in the presence of platelets.
81
FASTING
INSULIN
PLASMA
INSULIN
2 H PLASMA GLUCOSE
GLUCOSE
INCIDENCE
p
