733
U Clinical Progress Series
Circadian Variation and Triggers of Onset of
Acute Cardiovascular Disease
James E. Muller, MD, Geoffrey H. Tofler, MB, and Peter H. Stone, MD
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Direct events often precipitated the disease; the
infarct began in one case on climbing a high
staircase, in another during an unpleasant conversation, and in a third during emotional distress
associated with a heated card game.
A quote from the original description
of myocardial infarction published by
Obraztsov and Strazhesko in 1910.1
Coronary occlusion takes place irrespective of the
physical activity being performed or the type of rest
taken.
A quote from a study of the role of
effort in precipitating myocardial infarction published by Master in 1960.2
Nhe conflicting views presented above-the
earlier assertion that the onset of myocardial
infarction is frequently triggered by external
events and the currently accepted view of Master2
that infarct onset is generally unrelated to the day's
activities-must be reexamined in light of new information. The major advances in the understanding of
mechanisms and treatment of coronary artery disease accomplished during the past decade have provided a new basis on which to examine the onset of
myocardial infarction and sudden cardiac death. The
recognition of silent myocardial ischemia and its
precipitants, the identification of endothelial dysfunction, the rediscovery of coronary thrombosis, and
the lysis of obstructive thrombus by thrombolytic
therapy have not only produced immediate gains in
treating coronary artery disease but have also generated knowledge that may contribute to prevention.
This review will summarize the accumulated data
that, together with new information about circadian
variation of disease onset, suggest that daily activities trigger onset of most cases ofmyocardial infarction and sudden cardiac death.
History
The proposal by Obraztsov and Strazhesko1 in
1910 that activities frequently trigger infarction was
From the Cardiovascular Division, Brigham and Women's
Hospital, Harvard Medical School, Boston, Massachusetts.
Address for reprints: James E. Muller, MD, Harvard Medical
School, 164 Longwood Avenue, Boston, MA 02115.
challenged in the 1930s when studies of larger
numbers of patients revealed that, in many instances,
infarction occurred without an obvious precipitating event. A lively controversy developed with
investigators for3-5 and against6 the view that triggers were frequent. The debate ended with widespread acceptance of the conclusion of Master,2
based on retrospective questionnaires, that activities are of little importance in triggering onset.
This viewpoint has prevailed for the past 3 decades, even though it is based on studies conducted
without the benefits of modern methods of epidemiologic investigation, without enzymatic diagnosis of
myocardial infarction, and without the insight provided by recent advances in the understanding of the
pathogenesis of myocardial infarction. Data obtained
with these new techniques indicate that the original
proposal by Obraztsov and Strazhesko may be correct and that-just as the causative role of coronary
thrombosis was rediscovered in the early 1980s-it
will be rediscovered that daily activities frequently
trigger the onset of coronary thrombosis.
Epidemiologic Evidence of Morning
Increase of Events
The present proposal that daily activities are of
importance in triggering coronary thrombosis is
based, in part, on epidemiologic findings that the
events caused by coronary thrombosis-myocardial infarction and sudden cardiac death-do not
occur randomly throughout the day but that they
occur in a prominent circadian pattern with a morning increase in frequency (Figure 1).
Myocardial Infarction
Objective evidence that myocardial infarction is
at least three times more likely to begin in the
morning than in the late evening was obtained from
the Multicenter Investigation of Limitation of Infarct Size (MILIS)7 (Figure 1) and from the Intravenous Streptokinase in Acute Myocardial Infarction (ISAM) study.8 Both studies determined the
onset of myocardial infarction objectively on the
basis of the time of first appearance of creatine
kinase in the plasma. Their finding is supported by
a larger number of studies9-12 that used onset of
pain as a marker of time of myocardial infarction
Circulation Vol 79, No 4, April 1989
734
60
onset. The earlier studies received limited attention
because the reported morning increase in incidence
was thought to be simply the result of delayed
reporting of onset of myocardial infarction that
actually began during the night while the patient
was sleeping.
Several features of this morning increase were
recently explored. Hjalmarson et all' have found
that the morning increase is blunted or abolished in
subgroups of patients with characteristics such as
advanced age, diabetes, smoking history, and prior
infarction, while Goldberg et al12 have reported that
the increase in incidence occurs in the first 4 hours
after awakening.
MYOCARDIAL INFARCTION
45
40
tUn 36
E 30
E 26
0 20
16
3
10
6
0
136
SUDDEN CARDIAC DEATH
_
-
120
105
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X
't 90
W
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a 76
0:60o
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m 46
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16
0
THROMBOTIC STROKE
40
W 30
0
0:
cn
210
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C)
i
TRANSIENT MYOCARDIAL ISCHEMIA
26
20
0
cc
CL 2
W
a
10
z
6
0
AM
PM
FIGURE 1. Bar graphs of time of day of onset of myocardial infarction, sudden cardiac death, stroke, and
transient myocardial ischemia in four different groups of
patients. 713,17, 23 The number of events is shown on the y
axis and the hour of the day on the x axis. Each of the
disorders exhibits a prominent increase in frequency of
onset in the period from 6:00 AM to noon. Data adapted
with pernission.
Sudden Cardiac Death
Because of the close relation between myocardial
infarction and sudden cardiac death, identification
of the increased morning incidence of myocardial
infarction led to efforts to determine the time of
occurrence of sudden cardiac death. The apparently
simple task of determining time of occurrence is
even more difficult for sudden cardiac death than
for myocardial infarction because of 1) the difficulty, in certain situations, of determining whether
or not a sudden cardiac event is actually the cause
of death, 2) the occurrence of unwitnessed deaths
for which the determination of time of death, as well
as cause of death, is uncertain, 3) the increased
likelihood that such unwitnessed deaths will occur
at night, and 4) the large number of subjects needed
to detect a morning increase. These methodologic
problems were solved in studies of two large databases-mortality records for Massachusetts for
198313 and the Framingham Heart Study.14
Results of examination of death certificates of 2,203
individuals who experienced out-of-hospital sudden
cardiac death in Massachusetts in 1983 showed a
circadian rhythm of occurrence remarkably similar to
that observed for myocardial infarction13 (Figure 1).
The time of sudden cardiac death was then examined
in the Framingham Heart Study population.'4 The
frequency of definite or possible sudden cardiac death
in this well-characterized population showed a prominent circadian variation similar to that observed in
the death certificate study.
A number of prior studies of time of death support the conclusions of the Massachusetts Death
Certificate Study and the Framingham Heart Study,
although no single study features their combination
of size and specificity of diagnosis.15l16
Stroke
Characterization of the time of stroke onset has
also been plagued by the problem of determining
time of onset of events detected when the patient
awakens. However, when such events are considered to have occurred randomly during the 8 hours
before awakening, there remains a prominent
increase in the interval from 6:00 AM to noon similar
to that observed for myocardial infarction and sud-
Muller et al Circadian Variation and Triggers of Cardiovascular Disease
SYSTEMIC BLOOD PRESSURE
PLATELET
160
735
AGGREGABILITY
0
100
8
U3
5.0
0
67 8
12 12 3456
9101112 12 3 4
6
67 8g
011
12 123 4
56e78a910 1112
HEARTr RATE
120
12 3 456
78911011
tPA ACTIVITY
100
I-
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cc
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60
X;
40
20
0
121 2 3 4 6 6 7 89101112 1 2 3 4 5 67 8 s
25
12
ss.o
CORONARY BLOOD FLOW
1 2 3 4 67 8
9101112 1 2 3 45 6
7s
910n
FL4SMA CORTISOL
8
1.
20
ot
.15
O
I
~~~~~~~~~~~~~~~~~50
0.0-
12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 910 11
BLOOD VISCOSITY
12 1 2-3 4 5 6 7 A 9 10 11 12 1 2 3 4 5 6 7 8 9
10
1
PLASMA EPINEPHRINE
5.5
80
70
5.0
Z
80
e3.50
4.5
W
40
30
I
4.0
2
10
12 1 2 3 4
6 7 8 9 10
AM
1112 1 2 3
TIME OF DAY
45
6 7 8 9 10 11
PM
1212 3 4 6
5 78910111212345
AM'
7891011
TIME OF DAY
FIGURE 2. Bargraphs of variation during a 24-hour period of eight physiologic processes possibly contributing to the
increased morning frequency of disease onset shown in Figure 1. Systemic blood pressure and heart rate measured
intra-arterially in five normotensive ambulant subjects29; coronary blood flow velocity measured by Doppler ultrasonic
flow probe in 21 dogs63; whole blood viscosity measured by Ostwald-capillary-viscometer in eight normal male
volunteers64; platelet aggregability measured by in vitro platelet aggregometry in 15 normal male volunteers65;
tissue-type plasminogen activity (tPA) measured by spectrophotometric assay in six normal volunteers (four male, two
female)68; plasma cortisol measured by competitive protein binding method in six normal male volunteers69; plasma
epinephrine measured by a radio isotope method in 15 normal male volunteers. 65 See text for discussion. Data adapted
with permission.
736
Circulation Vol 79, No 4, April 1989
den cardiac death.1718 The time of stroke onset is
remarkably similar to that of myocardial infarction
and sudden cardiac death (Figure 1).
The epidemiologic data presented in Figure 1 are
likely to underestimate the true magnitude of the
morning increase in disease onset because, in these
databases, onset time is not adjusted for variable
time of awakening and variable work schedules. It
is far more likely as suggested by the study of
Goldberg et al,12 that the onset of disease is more
closely related to the activity cycle of the individuals than to the absolute time of day.
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Timing of Transient Myocardial Ischemia
Data indicating the increased morning incidence
of onset of the relatively infrequent cardiovascular
disasters-myocardial infarction, sudden cardiac
death, and stroke-have been supported by information about the much more frequent and more
easily studied disorder of transient myocardial ischemia. With improved techniques of ambulatory
electrocardiographic monitoring, Selwyn et al,19
Schang and Pepine,20 Cohn,21 Stern and Tzivoni,22
and others have clearly established that, in the
absence of anti-ischemic therapy, most patients
with stable angina exhibit episodes of transient
myocardial ischemia with ST segment depression
(70-90% of which are clinically silent) during routine out-of-hospital activities.
With episodes of transient ischemia occurring that
frequently and with continuous Holter monitoring
eliminating the possibility of bias resulting from
unobserved periods, the timing of episodes of transient ischemia has been possible with great accuracy.
These studies have consistently shown a peak incidence of episodes occurring between the hours of
6:00 AM and 12 noon (Figure 1). Furthermore, Rocco
et a123 were able to adjust the timing of episodes for
wake time and show that the increase in frequency
occurs in the first 4 hours after awakening and
beginning the day's activities, a finding similar to that
reported for myocardial infarction onset.12
Triggers of Transient Myocardial Ischemia
A number of studies have investigated the cause
of transient ischemia, the results of which may
contribute to improved understanding of the cause
of myocardial infarction and sudden cardiac death.
The parallel morning increases in transient ischemia
and these catastrophic cardiac events suggest that
the generally reversible event of transient ischemia
may, in the presence of a vulnerable plaque, trigger
the onset of the irreversible events of infarction and
sudden death, although transient ischemia and the
irreversible events may be merely associated and
not causally related.
Investigations of the possible triggers of transient
ischemia have attempted to identify activities or
pathophysiologic processes that occur before individual episodes or that have a temporal distribution
similar to that of the ischemic episodes. Barry et al25
have shown that when potential mental, as well as
physical, causes of ischemia are considered, over
half of transient ischemic episodes are preceded by
possible triggering activities. Furthermore, normalization of a triggering activity for the time spent
engaged in the activity, revealed a high likelihood of
occurrence during increased physical or mental stress.
Studies of the mechanism by which an activity
triggers transient ischemia have led to considerable
controversy over the relative contribution of decreases in myocardial oxygen supply (due to transient vasoconstriction or platelet aggregation causing
decreased coronary artery blood flow)20'23'25-28 and
of increases in myocardial oxygen demand (as determined by increases in heart rate and systemic arterial
pressure).23'29-32 The view that transient ischemia is
due to decreases in coronary artery flow is supported
by in vitro observations that an artery with atherosclerotic changes shows an exaggerated vasomotor
sensitivity to a number of normally occurring substances such as norepinephrine, histamine, and
serotonin33'34 and a paradoxical vasoconstrictor
response to acetylcholine.35 Patients with coronary
disease also have abnormal coronary endothelial function that may lead to paradoxical vasoconstriction in
response to a number of stimuli that produce coronary
vasodilatation in normal individuals. Angiographic
studies in patients have shown that, in the presence of
atherosclerosis, dynamic exercise,36 handgrip,37 exposure to cold,38 and infusion of acetylcholine39 produce
coronary vasoconstriction, when vasodilatation would
be the normal response. A decrease in regional coronary blood flow may also result from passive mechanical collapse of the epicardial coronary artery distal to
a fixed critical stenosis.40
Careful dissection of the supply-demand issue by
study of the ischemic threshold suggests that both
increased demand and decreased supply are frequent
causative factors. Quyyumi and coworkers41 recently
reported in patients with stable angina that exercise
performance was worse in the morning and at night
at times when forearm vascular resistance (and presumably coronary vascular resistance) was highest.
The mechanism of transient ischemia produced
by mental stress has also been examined.25,27,42-44
Verrier et a144 showed that in dogs with a partially
obstructed coronary artery, coronary vascular resistance increases 2-4 minutes after anger, leading to
an additional 35% reduction in flow. Deanfield et
a142 found that in patients with stable angina, a
regional reduction in coronary flow developed after
performing mental arithmetic. Thus, although myocardial oxygen demand rises after mental stress, as
indicated by increases in systolic blood pressure,27'42
the ischemia that ensues also results from a primary
decrease in coronary blood flow.
Cigarette smoking has caused a decrease in myocardial blood flow (decreased "2Rb uptake), indicating that vasoconstriction may be a mechanism by
which it triggers myocardial ischemia.45
Muller et al Circadian Variation and Triggers of Cardiovascular Disease
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The response of ischemic episodes to various
pharmacologic regimens may also provide indirect
evidence of the mechanisms causing the ischemic
process. Episodes of out-of-hospital ischemia, both
silent and symptomatic, in patients with stable angina
are significantly reduced or prevented by /-blockers,
supporting the etiologic role of increased myocardial
oxygen demand.46 Nifedipine, a calcium channel
blocker that causes reflex increases in heart rate,
when used alone may not be as effective in reducing
episodes of ambulatory ischemia as diltiazem, which
causes a reduction in heart rate.47 The anti-ischemic
efficacy of nifedipine is increased significantly, however, by the addition of a P-blocker that reduces the
heart rate.48
Concerning the role of platelets in stable angina,
metoprolol has reduced significantly the frequency
and duration of ischemic episodes without affecting
the morning surge in platelet aggregability,46 and
ticlopidine, a potent inhibitor of platelet activity, has
been ineffective in reducing episodes of transient
ischemia.49 These studies suggest that platelet aggregation plays only a small role in ambulatory episodes
of transient ischemia, although it may have a significant role in unstable angina and thrombus formation.
In summary, it appears likely that episodes of
ischemia in patients with stable angina during ambulatory activities are often caused by a combination of
transient coronary vasoconstriction and transient
increases in heart rate or systemic arterial pressure,
or both, although episodes may less frequently be
due to either mechanism alone. With either mechanism, the high frequency of triggering by mental
stress or physical activity is important. Clarification
of this triggering phenomenon may lead to improved
means of prevention, not only of transient ischemia,
but of the related conditions of myocardial infarction
and sudden death.
Autopsy and Angiographic Data Pertinent to
Onset of Myocardial Infarction and
Sudden Cardiac Death
Investigations of the triggers of myocardial infarction and sudden cardiac death are also aided by
recent advances in understanding the pathologic
basis of these disorders. In 1980, DeWood et a150
convincingly showed that occlusive coronary artery
thrombosis is the cause of most Q wave myocardial
infarctions,50 and although sudden cardiac death is
ultimately an electrical event, approximately one
third of the subjects have a fresh, occlusive coronary
thrombus at autopsy examination.51 Davies and
Thomas51 have presented data indicating that even
the two thirds of cases of sudden cardiac death
without occlusive thrombus demonstrable at autopsy
frequently have a nonocclusive thrombus in the
coronary artery that may have been a site for platelet
aggregate formation during life that caused death by
temporary proximal occlusion or distal embolization. In patients with rest pain and unstable angina,
coronary angiographic and angioscopic findings indi-
737
cate that nonocclusive thrombus is frequently
present.52,53 Thus, the occurrence of coronary artery
thrombosis appears to be a common, essential link in
the onset of most cases of myocardial infarction,
sudden cardiac death, and unstable angina.
Valuable autopsy and angiographic data are also
available concerning the cause of the thrombus.
Serial histologic sections of arteries occluded by
thrombus have revealed that, in most cases, the
thrombus formed over a ruptured atherosclerotic
plaque.54 This pathologic finding was recently supported by angiographic studies in patients demonstrating the presence of an out-pouching of contrast
media indicative of plaque rupture in patients who
have undergone successful thrombolysis.55
Two mechanisms of plaque rupture have been
proposed. Constantinides56 has advanced the concept that the rupture occurs from the lumen into the
plaque, whereas Barger et a157 have proposed that
rupture may occur from the plaque into the lumen.
The latter theory is based on the presence of
extensive vasa vasorum in atherosclerotic plaques.
Because these vessels may originate upstream to a
coronary stenosis, under certain conditions, their
pressure could exceed that in the coronary lumen
distal to the stenosis, leading to explosive rupture of
the plaque into the lumen.
Although autopsy studies generally reveal severe
atherosclerotic stenosis at the base of a fatal coronary thrombus,58 angiographic evidence indicates
that in many patients surviving a myocardial infarction, the degree of stenosis is relatively mild, and
thrombus accounts for most of the obstruction to
blood flow. Brown et a159 reported that the degree of
"goriginal" stenosis in patients with myocardial infarction observed after treatment with streptokinase was less than 60% in two thirds of the cases.
Little et a160 recently studied the extent of prior
stenosis at sites in the coronary arteries that subsequently became totally occluded. In two thirds of
the patients with mild-to-moderate coronary disease, the site of occlusion had less than a 50%
stenosis on the preinfarction angiogram. Haft et a161
have also described "catastrophic" progression of
coronary lesions, which presumably results from
episodes of thrombosis. These findings may explain
the absence of prior symptoms in many patients
presenting with acute myocardial infarction or sudden cardiac death and support the suggestion made
in 1986 by Oliver62 that attempts to identify and
modify triggers of thrombus formation may have
great clinical benefit.
Morning Increase of Physiologic Processes That
May Trigger Cardiac Events
A coronary atherosclerotic plaque is exposed to a
number of systemic physiologic processes that could,
if the plaque were vulnerable, cause disease onset.
Many of these processes increase in intensity in the
morning as shown in Figure 2. Such increases
could,' alone or in combination,, account for the
738
Circulation Vol 79, No 4, April 1989
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morning increase in cardiac disease onset (Figure 1)
through a variety of mechanisms.
The arterial pressure surge,29 which is accompanied by a heart rate increase, could cause plaque
rupture. The coronary arterial tone increase63 could
worsen the flow reduction produced by a fixed
stenosis. The increase in blood viscosity,64 increased
platelet aggregability65 (resulting from assumption
of the upright posture66), and an insufficient countervailing increase in circulating tissue-type plasminogen activator activity67'68 could produce a state of
relative hypercoagulability. Such a thrombotic tendency could increase the likelihood that an otherwise harmless mural thrombus overlying a small
plaque fissure would propagate and occlude the
coronary lumen. The increased serum cortisol
levels,69 although decreasing during the period of
increased disease onset, could increase the sensitivity of the coronary arteries to the vasoconstrictor
effects of catecholamines,70 which have a prominent
surge after assumption of the upright posture.66
Although a 24-hour periodicity of disease onset
(Figure 1) and physiologic processes (Figure 2) is
well established, the degree to which the disease
periodicity results from a true, endogenous circadian rhythm or from the daily rest-activity cycle is
only partially characterized. Cortisol secretion, for
example, is well known to be an endogenous circadian process not dependent on daily activity,69
whereas the increase in morning platelet aggregability is abolished if the subject remains at bedrest.65
The rest-activity cycle seems to be a major determinant of disease onset because adjustment for time
of awakening shows that infarction onset12 and
increases of transient ischemia23 follow awakening,
but such adjustment could also align the population
for their endogenous circadian rhythms. Also, an
interaction between circadian and rest-activity cycles
may exist; for example, assumption of the upright
posture leading to sympathetic activation may be
more likely to cause intense vasoconstriction when
endogenously controlled cortisol levels are high.70
Although attention has focused on the morning as
the time of peak incidence of disease onset, similar
physiologic processes probably trigger disease onset
at other times of the day. The peak morning incidence of infarct onset and sudden death probably
results from the synchronization of the population
for triggers in the morning, whereas a secondary
evening peak in infarct onset observed in the MILIS
data may result from synchronization of the population for an additional trigger such as the evening
meal. For other periods of the day, exposure of the
population to potential triggers is random, and no
other prominent peaks of incidence are observed.
A summary of the types of physiologic change
likely to occur in patients with atherosclerosis during several potentially triggering daily activities is
presented in Table 1.28,36- 38,66,67,71-89 These activities may be more likely to cause adverse effects in
patients than in normal subjects because as noted
above, paradoxical vasoconstriction may occur in
coronary arteries afflicted with atherosclerosis. The
effects of daily activities on the sympathetic nervous system, systemic arterial pressure, and heart
rate are well characterized, but the response of the
coagulation system to these activities is more complex and less well understood. The conflicting results
reflect in part the choice of model and technique: in
vivo, ex vivo, or in vitro.
Also, unusual mechanisms of disease onset may
occur in only a minority of the population, such as
postural hypotension, which has been suggested as
a trigger of stroke onset, causing decreased perfusion.90 Other possible triggering changes are those
associated with acute infectious diseases.91
Ability of Agents That Block Potential Triggering
Processes to Prevent Myocardial Infarction and
Sudden Cardiac Death
The theories advanced above are indirectly supported by the demonstrated efficacy of aspirin therapy and ,-adrenergic blockade in preventing myocardial infarction and sudden cardiac death.92,93
Aspirin, which presumably acts primarily as an
antiplatelet agent, is thought to reduce the occurrence of sudden death and myocardial infarction by
preventing coronary thrombosis.
,3-Adrenergic blocking agents have prevented myocardial infarction and sudden cardiac death even
though these agents do not have potent antithrombotic or antiarrhythmic properties. A clue to mechanism is provided by the observations in the MILIS
and the ISAM databases that ,B-blockade eliminated
the morning peak in the incidence of myocardial
infarction onset.7 8 In addition, in the Beta Blocker
Heart Attack Trial, a morning increase was found in
sudden cardiac death in the placebo group but not in
the group randomly assigned to p8-blockade therapy,
suggesting that the beneficial effect was achieved by
blockade of the morning surge in sympathetic
activity.94 ,-Blockade, but not a short-acting calcium
blocker, has attenuated the morning increase in
silent myocardial ischemia.95 It has been suggested
that the ,8-blockers may prevent rupture of atherosclerotic plaques, just as they are considered to exert
a beneficial effect in dissecting aneurysm by prevention of rupture of the aortic wall (personal communication, Dr. William H. Frishman). With increased
knowledge of triggering mechanisms, it is likely that
the impressive gains already achieved by aspirin and
,B-blockade therapy can be increased.
General Theory of Triggering of
Coronary Thrombosis
Although incomplete, the available data permit
formulation of a general hypothesis regarding the
manner in which daily activities may trigger coronary thrombosis. The hypothesis presented in Figure 3 is proposed for the sake of the knowledge that
its confirmation or rebuttal may generate. It adds
the concept of triggering activities to the general
Muller et al Circadian Variation and Triggers of Cardiovascular Disease
739
Triggering of Coronary Thrombosis
Non-vulnerable
Atherosclerotic Plaque
..,.
...........
Vulnerable
Atherosclerotic
Plaque
..............
..
>
=.......
A:.
..
Physical
or Mental
Stress TrIggers
Plaque Rupture v
Minor Plaque Rupture
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1.
'\\
I I //
|
Ma]
..............
...............
Non-Occlusive
Thrombus
;; ;;;;;;;
Asymptomatic,
CoagulablUty
Increase or
jor Plaque Rupture
FIGURE 3. Illustration of a hypothetical
method by which daily activities may trigger
coronary thrombosis. Three triggering mechanisms, 1) physical or mental stress producing hemodynamic changes leading to plaque
rupture, 2) activities causing a coagulability
increase, and 3) stimuli leading to vasoconstriction, have been added to the well-known
scheme depicting the role of coronary thrombosis in unstable angina, myocardial infarction, and sudden cardiac death. See text for
detailed discussion.
Angina
,
_
or
Non-Q-MI
Vasoconstrictlon-
Trgers Complete
Occlusion
by Throbumbv
,OF *IF
\\\
Myocardlal hnforctlon or
Sudden Cardiac Dcath
scheme of the role of thrombosis in the acute
coronary syndromes advanced by Davies and
Thomas,51 Falk,58 Fuster et al,96 Willerson et al,97
and Badimon et al.98
It is proposed that the initial step in the process
leading directly to coronary thrombosis is the development, with advancing age, of what can be termed
a "Cvulnerable atherosclerotic plaque." Plaque vulnerability is defined functionally as the susceptibility
of a plaque to rupture. Development of such vulnerability is a poorly understood process but is presumably a dynamic, potentially reversible disorder caused
by changes in the constituents of the plaque, its
blood supply through vasa vasorum, or the functional integrity of the overlying endothelium.
The theory that onset of thrombosis is unrelated
to daily activities would presumably attribute disease onset solely to changes in the plaque, and the
diagram would therefore lead directly from the
plaque to coronary thrombosis. In the present formulation, however, it is proposed that onset may
frequently begin when a physical or mental stress
triggers a hemodynamic change sufficient to rupture a vulnerable plaque. (If such a trigger does not
occur during vulnerability, the plaque may change
and become nonvulnerable.)
The rupture in the plaque may be major or minor,
depending on factors such as the amount and type
of collagen exposed.98 A major plaque rupture produces a thrombogenic focus sufficiently intense to
cause occlusive coronary thrombosis leading directly
to myocardial infarction or sudden cardiac death. A
minor rupture leads only to a mural thrombus that
fails to produce symptoms or leads to unstable
angina or non-Q wave myocardial infarction. Again,
at this point external activities may lead to occlusion of the lumen. For example, an activity causing
a coagulability increase may trigger growth of the
thrombus, or a stimulus to vasoconstriction may
lead to complete occlusion of an already compromised lumen leading to infarction or sudden death.
Because normal individuals and even patients
with coronary artery disease are constantly exposed
740
Circulation Vol 79, No 4, Aptrl 1989
TABLE 1. Physiologic Changes Produced by Possible Triggers of Coronary Thrombosis
Coronary
Systemic
vascular
arterial
Heart
resistance or
Plasma
Possible triggers
pressure
rate
narrowing*
catecholamines
1 (36)
1 (36)
Exercise
t (71)
T (71)
Assumption of
T (76)
?
T (66,71)
(76)
upright posture
1 (37,71)
1 (37)
Handgrip
T (71)
T (71)
1 (38,71)
1 - (38,77,78)
Cold exposure
T (71)
T (71)
1 (81)
1 (81)
1 (82)
Cigarette smoking
T (81,84)
1 (28)
1 (87)
Mental stress
T (28)
T (28)
Reference numbers are indicated in parentheses.
, decrease; 1, increase; -, no change; ?, limited information.
Multiple responses reflect either variability within subject populations, or conflicting results.
*Responses observed with coronary atherosclerosis. Normal response is a resistance decrease,
**Acute effect of smoking is an increase in fibrinolysis; chronic effect is a decrease.
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to potentially triggering activities that do not produce coronary thrombosis, development of plaque
vulnerability is probably the rarest event in the
chain of causation described above.
An inverse relation probably exists between the
degree of plaque vulnerability and the intensity of
the triggering stimulus required to produce rupture.
For instance, an elderly individual with a severe
fixed stenosis in a coronary artery and an extremely
vulnerable plaque may develop thrombosis with
only a minor stress, whereas a young individual
with only a luminal irregularity may require a major
stress (such as heavy lifting producing markedly
increased arterial pressure) to trigger plaque rupture and coronary thrombosis. As yet, no data exist
to support these hypothetical mechanisms.
Various mixtures of triggering mechanisms may
account for thrombosis. For example, the combination of physical exertion (producing a minor plaque
rupture) followed by cigarette smoking (producing
an increase in coronary artery vasoconstriction and
a relatively hypercoagulable state) may be needed
to cause disease onset. Thus, the onset of infarction
or sudden death may, in some cases, be the result of
the unfortunate simultaneous occurrence of several
events each by itself of little consequence but
catastrophic when occurring together.
Significance
The primary immediate value of recognizing the
circadian variation of acute onset of cardiovascular
disease is the emphasis that can be placed on
pharmacologic protection during the morning hours
for patients already receiving anti-ischemic therapy. But even complete elimination of the morning
increase in onset of myocardial infarction and sudden cardiac death by effective therapy would prevent only a small fraction of the total morbidity and
mortality caused by these disorders. Although the
incidence of disease onset is greatest in the period
from 6:00 AM to noon, most infarcts and sudden
deaths occur at other times of the day, and their
Platelet
activity
1- (72,73)
1
(66)
1 - (78,79)
1 - (83,84)
1 (88)
Fibrinolytic
activity
T (67,74,75)
t (75)
T (80)
T 1 (83,85,86)**
T (89)
or dilatation.
prevention requires a broader approach. For this
reason, the primary significance of the recognition
of circadian variation of disease onset is the support
it provides for the broader concept that the onset of
coronary thrombosis at any time of the day is
frequently triggered by activities of the patient. This
concept provides a number of clues to the mechanisms of disease onset-clues that suggest a value
of studies ranging from the epidemiologic to the
molecular levels.
On the epidemiologic level, studies must be conducted in which patients who experience a nonfatal
myocardial infarction and witnesses to a sudden
cardiac death are interviewed to determine whether
or not the event had an identifiable trigger. Because
potentially triggering activities occur frequently without producing an event, the studies must be controlled for the frequency of potential triggers at
times when an event did not occur.
The certainty with which an activity can be
identified as a trigger will also vary in individual
cases. In a patient whose plaque is only slightly
vulnerable, the activity required to produce disease
onset may be extreme, and the activity can be
recognized as a trigger by its intensity. Other features that may aid in recognizing an activity as a
trigger are its occurrence immediately before the
event, its ability to produce physiologic changes
likely to trigger thrombosis, and its absence as part
of the patient's routine activity. However, in a
patient with an extremely vulnerable plaque, even
nonstrenuous, routine, daily activities may be sufficient to trigger the cascade leading to infarction or
sudden death. In such instances, identifying the
triggering activity may be impossible even though it
was present. Thus, the group of patients with identifiable triggers will be a subset of those in whom
external triggering actually occurred.
On the clinical level, increased study of the
relation between daily activities and potentially
triggering physiologic responses, such as the eight
processes presented in Figure 2, could clarify the
Muller et al Circadian Variation and Triggers of Cardiovascular Disease
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manner in which these and other processes cause
disease onset.
On the basic science level, a need exists for
complete characterization of the control mechanisms
of potentially adverse physiologic changes. When
these mechanisms are understood more fully, it may
be possible to eliminate unnecessary surges in arterial pressure, vasoconstriction, and coagulability that
contribute to disease onset. Further study is also
needed of the factors determining plaque vulnerability and of the possibility that reduction of plasma
cholesterol may exert its beneficial effect by reducing
the susceptibility of a plaque to rupture as well as by
preventing the development of stenotic lesions.
A more complete understanding of triggering mechanisms should permit progress in the prevention of
most cardiac deaths that occur unexpectedly in an
out-of-hospital setting. The means of prevention
would not be to eliminate potential triggering activities-an undesirable and unattainable goal-but to
design regimens that can be evaluated in randomized
studies for their ability to sever the linkage between
a potential triggering activity and development of a
catastrophic coronary thrombosis.
Summary
Information obtained during the past decade suggests the need to reexamine the possibility that the
onset of myocardial infarction and sudden cardiac
death is frequently triggered by daily activities. The
importance of physical or mental stress in triggering
onset of coronary thrombosis is supported by the
findings that 1) the frequencies of onset of myocardial infarction, sudden cardiac death, and stroke
show marked circadian variations with parallel
increases in the period from 6:00 AM to noon, 2)
transient myocardial ischemia shows a similar morning increase, and episodes are often preceded by
mental or physical triggers, 3) a ruptured atherosclerotic plaque, often nonobstructive by itself, lies
at the base of most coronary thrombi, 4) a number
of physiologic processes that could lead to plaque
rupture, a hypercoagulable state or coronary vasoconstriction, are accentuated in the morning, and 5)
aspirin and 8-adrenergic blocking agents, which
block certain of these processes, have been shown
to prevent disease onset.
The hypothesis is presented that occlusive coronary thrombosis occurs when 1) an atherosclerotic
plaque becomes vulnerable to rupture, 2) mental or
physical stress causes the plaque to rupture, and 3)
increases in coagulability or vasoconstriction, triggered by daily activities, contribute to complete
occlusion of the coronary artery lumen.
Recognition of the circadian variation-and the
possibility of frequent triggering-of onset of acute
disease suggests the need for pharmacologic protection of patients during vulnerable periods, and provides clues to mechanism, the investigation ofwhich
may lead to improved methods of prevention.
741
Acknowledgments
We are grateful for helpful comments on the
manuscript by Dr. Eugene Braunwald, Dr. Thomas
Smith, and Dr. John Rutherford and for assistance
in its preparation from Ms. Kathleen Carney, Ms.
Gail Aylmer, and Ms. Gail MacCallum.
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Circadian variation and triggers of onset of acute cardiovascular disease.
J E Muller, G H Tofler and P H Stone
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Circulation. 1989;79:733-743
doi: 10.1161/01.CIR.79.4.733
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