(Circulation. 1996;93:1364-1371.)
© 1996 American Heart Association, Inc.
Articles |
Circadian Variation of Ambulatory Myocardial Ischemia
Triggering by Daily Activities and Evidence for an Endogenous Circadian Component
From the Department of Medical and Clinical Psychology, Uniformed Services University of the Health Sciences, Bethesda, Md (D.S.K., W.J.K., F.H.G., M.B.); the Division of Cardiology, St Luke's-Roosevelt Medical Center, New York, NY (A.R.); Shaare Tzedek Medical Center, Jerusalem, Israel (J.K.); Cedars-Sinai Medical Center, Los Angeles, Calif (Y.P.); and the Division of Cardiology, Georgetown University Medical Center, Washington, DC (J.S.G.).
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background The morning peak in myocardial ischemia has been related to diurnal variations in physical and mental activities and to postural changes upon awakening. This study assesses (1) the effects of exogenous activity triggers at different times of the day and (2) the contribution of an endogenous (ie, activity- and posture-independent) circadian vulnerability for ambulatory ischemia.
Methods and Results Sixty-three stable coronary artery disease patients underwent ambulatory ECG monitoring and completed a structured diary assessing physical and mental activities. During 2519 hours of observation, a morning increase in ischemia coincided with increases in physical and mental activities, and an evening decrease in ischemia coincided with a decline in activities. During the morning, ischemic versus ischemia-free periods were more likely to occur with high levels of physical activity (P<.001). High physical activity triggered ischemia to a lesser but still significant extent (P<.05) in the afternoon but not in the evening (P=NS). High levels of mental activity triggered ischemia significantly during the morning (P<.04) and evening (P<.04) but not in the afternoon. When a residualized score procedure was used to correct ischemic time for each patient's simultaneously measured activities, for hourly heart rates, or for activity-related heart rate fluctuations, the circadian variation in ischemia was still observed (P<.001), with a peak at 6 AM. A significant increase in ischemia occurred immediately after awakening (P<.05), but activity-adjusted increases in morning ischemia persisted (P<.05) for 2 hours after awakening.
Conclusions Exogenous factors (physical and mental activities) are most potent as triggers of ischemia during the morning hours, and the postural change after awakening contributes to the morning increase in ischemia. There is also evidence for an endogenous, activity-independent circadian influence on ischemic susceptibility that is independent of exogenous factors and that sustains the increase in ischemia upon awakening.
Key Words: circadian rhythm • ischemia • coronary disease • stress • electrocardiography
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Research has identified a circadian rhythm for transient myocardial ischemia out of hospital, with the greatest density of ischemic time occurring between 6 AM and noon.1 2 This circadian pattern corresponds to that exhibited for myocardial infarction and sudden cardiac death3 4 5 and parallels the circadian pattern of physiological parameters, including arterial blood pressure, HR, catecholamines, platelet aggregation, and vascular tone.6 7 8 9 Studies of activity-related triggers of ischemia reveal a correlation between ischemia and physical activity10 11 and mental stress12 13 14 15 and support the role of increased cardiac demand as a trigger of ambulatory ischemia.16 17
A recent in-hospital investigation18 demonstrated that the increase in activities upon awakening plays a crucial role in the circadian pattern of ischemia. When patients were instructed to be inactive until 4 hours after awakening, a corresponding 4-hour time lag was observed in the circadian variation of ischemia. However, closer inspection of these data suggests some elevation of ischemia after awakening that cannot be attributed to beginning the physical and structured mental activities of the day. In addition, the effect of activities on the morning ischemic increase has not previously been assessed out of hospital. It therefore remains undetermined whether the morning increase in ischemia during daily life results solely from changes in "exogenous" factors (ie, physical and mental activities) or whether these triggers of ischemia are superimposed on an "endogenous," activity-independent physiological circadian vulnerability for ischemia.
The present study investigates the relative contribution of time of day and triggers of onset of ischemia in a daily life setting using a well-validated structured diary system19 20 in conjunction with ambulatory ECG monitoring. The influence of activities on the circadian rhythm of ischemia was investigated by examination of (1) the effect of time of day on ischemia and on physical and mental activities and HR (circadian rhythm); (2) the effects of activities on ischemia (activities as exogenous ischemic triggers) during different phases of the day; (3) the effects of time on ischemia after adjustment for changes in activity levels ("endogenous" circadian vulnerability) and for time of awakening; and (4) the effects of time of day on ischemia after adjustment for the influence of activity-related HR changes before ischemia. We hypothesized that an endogenous circadian pattern of myocardial ischemia exists that is independent of exogenous triggers of ischemia and that heightens the effects of exogenous triggers such as physical and mental activities on myocardial ischemia.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
The study sample consisted of 63 patients (mean age, 62±8 years; 54 men, 9 women) with documented CAD based on angiography and/or prior myocardial infarction (n=39) or a high (>80%) probability of CAD according to Bayesian analysis of risk factors, symptoms, and exercise ECG and/or thallium test results21 (n=24). Those patients who did not have prior angiography or documented myocardial infarction were positive for ischemia, most assessed by thallium perfusion scintigraphy (see below). Study subjects were recruited for ambulatory 24- to 48-hour ECG monitoring consecutively from a population of stable outpatients at Cedars-Sinai Medical Center (n=53), or they were recruited for this study from the Washington, DC, area (n=10). Patients were included in the study if they met the following inclusion criteria: (1) positive for ischemia on exercise treadmill ECG (
1 mm horizontal or
downsloping ST-segment depression for three consecutive beats) or
thallium scintigraphy (presence of 2 of 20 reversible
myocardial segments, as described elsewhere22 ); (2) no
significant resting ST-segment depression, conduction abnormalities,
digoxin therapy, or ECG signs of left ventricular
hypertrophy; (3) positive ambulatory ECGs for
ischemia, as defined below; and (4) adequate completion of the
self-monitoring diary during the monitoring period. Informed
consent was obtained, and the present study was approved by
institutional review boards at the relevant institutions.
Ambulatory ECG Monitoring
Of the 63 patients, 60 (95%) were tested off
anti-ischemic medications, with ß-blockers withheld
for 48 hours, calcium channel blockers for 24 hours, and
long-acting nitrates for 6 hours. All patients underwent 24 hours
and 42 patients underwent 48 hours of ECG monitoring. A Cardiodata
AM recorder (frequency response, 0.05 to 100 Hz) was
used with ECG signal calibration at 1 mV=10 mm. Two sets of bipolar
leads were attached, with exploring electrodes in V5 and a
modified inferior position. When appropriate, the exploring
electrode site was modified to monitor the greatest ST-segment
depression during the patients' previous exercise test.
Calibrated 24-hour tapes were analyzed visually at 60 times
real time with a Cardiodata MK4 computer. An ischemic response
was defined as at least 60 seconds of horizontal or downsloping
ST-segment depression 1 mm measured at 80 ms after the J-point or 60
seconds of 1.5 mm of slowly upsloping ST-segment
depression23 24 remaining below the isoelectric baseline
measured at 80 ms after the J-point. Differentiation between ST slopes
did not alter results and is not considered further here. ECG data for
each ischemic episode were reviewed blindly by two
cardiologists (J.K. and A.R.), with disagreements settled by
consensus.
For each episode, the time of onset, duration, accompanying HRs (mean for the hour before, 10 minutes before, at onset of ST depression, and peak during ischemia), and magnitude of ST-segment depression were recorded. Analyses of ischemia data were based on all 63 patients; data involving hourly HR and HR 10 minutes before ischemia were based on 42 of 63 patients. To calculate ischemia-related HR increases, mean HR for the hour before each event was subtracted from HR at onset of ischemia. A similar approach was used to calculate increases 10 minutes before each episode. To determine HR fluctuations during nonischemic hours, peak hourly HRs were compared with average HRs during the preceding hour. The occurrence of ischemic episodes during each hour ("number of ischemic episodes") and the summed duration of ischemia per hour ("ischemic time," in minutes per hour per patient) were calculated for each hour of observation. The latter variable consisted of the total ischemic time summed over one or more episodes in each patient-hour.
Structured Diary
During the monitoring period, patients completed a validated and
previously published19 25 structured diary system to
assess physical and mental activities and moods throughout the day.
Previous studies showed that physical activity measures obtained by
this structured diary correlate significantly (r=.80) with
24-hour physical activity levels as measured by an automated activity
monitor.20 Adequate reliability and validity ratings of
the diary for assessing levels of mental activities has been
demonstrated (eg, patient-spouse correlations range from .51 to
.81; median .68).19 Patients were carefully instructed in
how to fill out the diary.19 Self-ratings of emotion
(eg, anger, anxiety) were made on five-point scales. Patients were
carefully and explicitly instructed to fill out a new diary page
whenever activities changed, and a new diary page was completed when
the patient began to engage in any new activity. For the 63 patients
during 2519 hours of observation, including sleep, there were 2281
valid diary entries; this amounted to an average of between 1 and 2
diary entries during each waking hour. We have
demonstrated19 that after the extensive training patients
receive with this technique, the diary is sensitive enough to detect
changes in physical and mental activities of less than one intensity
category of activities, as noted below.
To quantify the assessment of physical activity levels, diary entries of activities were used to construct a 6-point index of intensity of physical activity.20 Examples of scoring include 1, sleep; 2, resting, listening; 3, talking, eating, clerical work, etc; 4, driving; 5, shopping, dressing; and 6, stair climbing, walking, physical work. For mental activities, representative items in each category included 1, sleep; 2, rest, reading, watching TV; 3, talking, clerical work, etc; 4, driving, waiting; 5, thinking; and 6, anger or anxiety rated >2 on five-point ordinal scales.
Data Analysis
Individual diary entries were independently tabulated and
subsequently paired with event-by-event ischemia data
for each subject; ie, specific activities directly preceding each
ischemic event were matched with that ischemic event.
Each diary entry not associated with ischemia was used to
determine nonischemic activity. For most analyses,
hour-by-hour ischemic duration and activity levels are
presented. In addition, to provide sufficient numbers of
observations in each time period and to adjust for wake time,
event-by-event diary and ischemia data were grouped
into four 6-hour time blocks based on patient wake time: morning,
afternoon, evening, and night. ANOVA and t tests were used
to compare continuous variables, and 
2 tests
were used for frequency data to examine relations between time of day,
ischemia, and activity level. Effects of activity on
ischemia (the exogenous component) were examined using ORs by
tabulating the presence of high (5) versus low (<5) activity levels
at onset of ischemia compared with nonischemic
control periods during each time block. CIs (95%) were used to
indicate statistical significance. For analyses of diurnal
variation, mean HR was assessed for the 1 hour before and the 10
minutes before ischemia; HR at onset and peak HR during
ischemia were also tabulated. ANOVA was used to examine the
effect of phase of day. To assess the contribution of an
endogenous component to the diurnal variation of
ischemia, we examined the hourly duration of ischemia,
controlling for concomitant activities. For that purpose, maximal
physical and mental activity levels in each hour of the day were
regressed on the corresponding ischemic time. Each correlation
pair consisted of the patients' activity level (physical or mental)
and total ischemic time per hour per day by use of the formula
ei=Yi-
ii,
where ei is activity-adjusted residual
score, Yi is observed ischemic time, and
i is hourly ischemic time
predicted on the basis of the concurrent observed activity level. These
residual scores were taken as estimates of ischemia not
accounted for by activity. ANOVA was applied to activity-adjusted
scores to determine the presence of an endogenous circadian
variation of ischemia. In addition, to specifically control for
and assess the effects of postural changes upon
awakening,18 activity-adjusted ischemic time
was plotted taking into account time of awakening.
Data are presented as mean±SD or as frequencies. A two-tailed level of P=.05 was adopted as significant for statistical tests, except for the 24-hour, hour-by-hour analyses, for which Bonferroni correction for multiple statistical tests resulted in an adjusted level of P=.005.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Frequency, Duration, and Severity of Ischemia
During a total of 2519 hours of ambulatory ECG monitoring in the 63 patients, 203 ischemic episodes were observed (mean, 1.9±1.8 episodes per day per patient). The average duration of ischemic episodes was 9.7±11.6 minutes, and the mean ST-segment depression was 1.8±1.0 mm. Only 31 (15%) of the ischemic episodes were associated with chest pain. Clinical and other patient characteristics are shown in Table 1
.
|
Circadian Rhythm of Ischemia, Daily Activities, and
HRs
Fig 1 (left) shows that there was a morning peak in
ischemic time per hour between 6 AM and 11
AM, a secondary increase from 2 PM to 6
PM, and a tapering of ischemia in the late
evening and night. ANOVAs revealed a significant overall temporal
variation in ischemic time during the course of the day
(P<.001). Hour-by-hour analysis indicated a
significant increase in ischemia from 5 to 6 AM
(t=2.9; P<.005). None of the other
hour-by-hour changes were significant after application of the
Bonferroni correction for multiple tests.
|
The number of ischemic episodes (Fig 1
, right) showed dual
peaks occurring between 6 AM and 9 AM (14.6%
of morning episodes occurred before awakening) and 2 PM and
7 PM, with the late afternoon peak slightly higher than the
morning frequency peak. The pattern of results for ischemic
time and frequency reflected the fact that relatively fewer but longer
ischemic events occurred during the morning period. The
duration of ischemia is longer in morning episodes (15.2±15.1
minutes per episode) than during the afternoon, evening, and night
(P<.001) (Table 2).
|
Analysis of structured diary data using patients' activity in
each hour revealed a circadian rhythm for activities
(P<.001). Physical activities increased every hour during
the morning from 4 AM to 7 AM and stayed stable
during the day, with the decrease starting at 8 PM until
midnight. Mental activities also displayed an overall circadian
variation (P<.001); t tests showed a significant
hourly rise starting at 5 AM and continuing until 8
AM and a significant decrease between 8 PM and
midnight. The variation of ischemia (number of episodes and
ischemic time) and physical and mental activity levels during
the four time blocks are shown in Table 2. The morning increase in
ischemic time was paralleled by an elevation of
activity levels, but the subsequent decrease in ischemic time
was not accompanied by a decrease in mean activity level (Fig 2). In the late evening, both activity levels and
ischemia decreased to their lowest levels.
|
As displayed in Fig 3, mean and peak hourly HRs also
displayed a circadian rhythm, increasing in the morning and decreasing
at night. As with physical and mental activities, the morning increase
in ischemia was paralleled by an increase in mean and
peak hourly HRs. There was a circadian rhythm for HRs both for the hour
before and at onset of ischemia (Table 2); a similar but
nonsignificant circadian pattern was evident for HRs 10 minutes before
ischemia.
|
Relation of Activities During the Day and
Ischemia
Ischemia occurred significantly more often during high
levels (ie, scores 5) of both physical (P<.05) and mental
(P<.05) activities. Fifty-three percent of all
ischemic episodes occurred at high physical activity levels,
whereas activity level was high in 36% of the nonischemic
control diary entries (OR, 1.9; CI, 1.4 to 2.6; P<.05). In
addition, the mean duration of ischemic episodes at high
activity was significantly longer than episodes that occurred at low
activity (12.4±13.3 versus 7.0±8.3 minutes per episode;
t=3.3; P=.001). HR at ischemia was
significantly higher if ischemia occurred at high versus low
physical activity (101.0±16.6 versus 92.6±16.0 beats per minute;
P=.001) and high versus low mental activity (100.3±15.0
versus 93.3±17.3 beats per minute; P=.02).
To assess the consequences of physical activity on ischemia at
several phases of the day, we examined the relation of activity to
frequency and duration of ischemic episodes in each of the four
time blocks. During the morning, 77% of the ischemic episodes
were triggered by high physical activity levels; for the afternoon,
evening, and night, these figures were 51%, 37%, and 8%,
respectively. During nonischemic control periods, these
percentages of high activity were 48%, 36%, 30%, and 10%, in
morning, afternoon, evening, and night, respectively (see Fig 4,
left). ORs for each time block revealed that high
physical activity was significantly associated with the occurrence of
ischemia during the morning (OR, 3.7; CI, 2.0 to 6.7). This
activity triggered ischemia to a lesser but still significant
effect in the afternoon (OR, 1.8; CI, 1.0 to 3.3; P<.044)
but not during the evening (OR, 1.4; CI, 0.8 to 2.4; P=NS)
and night (OR, 0.8; CI, 0.1 to 6.3; P=NS). High versus low
physical activity did not significantly affect the duration of
ischemic episodes when analyzed separately for the four
phases of the day.
|
Of all ischemic episodes, 34% occurred at high mental activity levels, whereas high mental activity occurred in 25% of nonischemic control periods (OR, 1.6; CI, 1.1 to 2.3; P<.05). The mean duration of ischemic events was not affected by the level of mental activity (means, 9.0±10.3 [high] and 8.3±10.9 [low]; P=NS).
The percentages of ischemic events occurring with high mental
activity during the morning, afternoon, evening, and night were 44%,
33%, 34%, and 8%, respectively, whereas during
nonischemic periods, percentages of high mental activity
were 29%, 29%, 20%, and 13%, respectively (Fig 4, right).
Ischemia was triggered significantly more often by high mental
activity during the morning (OR, 1.9; CI, 1.0 to 3.6;
P<.054) and evening (OR, 2.0; CI, 1.1 to 3.9;
P<.035), whereas mental activity was not associated with
ischemia in the afternoon or at night (OR, 1.3; CI, 0.6 to 2.7;
P=NS; and OR, 0.6; CI, 0.1 to 4.5; P=NS,
respectively).
Daily Variation of Ischemia, Adjusting for Activity Levels,
HRs, and Awake Time
To assess the effect of time of day on ischemia after
control for effects of activities, hourly ischemic times for
each individual were corrected for concurrent activity levels. Fig 5 shows the diurnal pattern of residualized scores of
hourly ischemic time. Separate curves are displayed for the
physical and mental activity correction; values below zero indicate
that ischemic time was shorter than statistically predicted on
the basis of activity level. Analyses showed a significant
hourly fluctuation of the physical (P<.001) and mental
(P<.001) activity–adjusted ischemic times.
More specifically, after correction for physical activity, a major peak
was observed at 6 AM (P=.01), which was the only
significant hourly change. Controlling ischemic time for mental
activity levels revealed essentially the same pattern of results (Fig 5). In addition, analyses of hourly ischemic times were
repeated by statistically correcting for mean hourly HRs (Fig 5) and
for HR increases at onset of ischemia (data not shown),
respectively. In each case, the morning peak in ischemia
remained significant (P<.05).
|
Approximately 41% of patients awoke at or before 7 AM, and
78% of patients awoke before 8 AM. Because of the
important role of postural changes upon awakening (ie, getting out of
bed) as a trigger of the morning increase in
ischemia,18 statistical adjustments were applied
to the data to simultaneously control for both activities
and time of awakening. Specifically, we normalized for wake-up time
and corrected for concurrent activity levels (via residualized score
procedure, see "Methods"). Consistent with prior
research,18 we observed a significant increase in hourly
time in ischemia (adjusted for physical and mental activities)
at the hour of awakening (Fig 6), indicating the effect
of postural change on ischemia. However, compared with the
period before awakening, an increased vulnerability to ischemia
persisted after control for effects of both activities and postural
change with awakening. Specifically, until 2 hours after awakening, the
total number of minutes in ischemia per hour per patient was
still in excess (P<.05) of that statistically predicted by
activities.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The present data reveal a correspondence between the morning increase in ambulant myocardial ischemia in stable CAD patients and the early morning increase in physical and mental activities. Both activities and awakening (probably due to postural change) were significant triggers of ischemia, but the morning increase in ischemia was maintained independent of activities, and increased ischemic vulnerability was sustained for 2 hours after the initial postural change upon awakening. Thus, both external triggers of ischemia (ie, daily activities) and endogenous, time-related factors contribute to the morning increase in ischemia.
Physiological mechanisms that may contribute to the early morning increase in ischemia and other cardiac events include blood pressure, HR, vascular tone, plasma catecholamine levels, and platelet and fibrinolytic activity.6 7 8 26 Many of these parameters are affected by physical and mental activities and/or by postural change.27 28 29 Mental and physical activities increase myocardial oxygen demand,16 17 18 and the present data reveal that the morning ischemic increase remained evident even after control for mean hourly HR and HR increases before onset of ischemic events. However, this study did not adjust for other major determinants of myocardial demand such as blood pressure, and it is possible that blood pressure rose disproportionately in the morning. Deedwania and Nelson17 observed morning increases in blood pressure in ambulatory CAD patients preceding the morning increase in ischemia, but these changes generally paralleled increases in HR.
In addition to affecting myocardial demand, physical and mental activities can also affect coronary vasoconstriction, with a resultant decrease in myocardial oxygen supply.9 30 31 Thus, it is likely that factors influencing myocardial perfusion and coronary artery tone (eg, sympathetically induced vasoconstriction and dysfunctional coronary endothelium) and/or hemostatic mechanisms (eg, platelet aggregation and fibrinolysis) may play a role as endogenous factors.6 7 8 26 The potential importance of vascular tone is suggested by the recent report of a significant relation between increased forearm vascular resistance and lowered ischemic thresholds in the morning.9 It is also known that there are overnight changes in hemoconcentration (eg, decreases in plasma volume) and other hemostatic mechanisms.32 33 34 These latter changes, occurring overnight, are probably not dependent on patient activities. In addition, the recent report of a circadian variation in thrombolysis35 is also consistent with the existence of an endogenous pattern for fibrinolytic activity.
The secondary ischemic peak evident in the late afternoon, as manifest by a greater frequency of ischemic events with a shorter duration in the evening, is similar to secondary peaks for ischemic activity observed in earlier studies.36 Diverging temporal patterns for ischemic frequency and duration may indicate that exogenous and endogenous triggers of the onset of ischemic events differ from factors that sustain ischemia. Our results indicate that high physical activity is associated with a prolonged mean duration of ischemic episodes compared with episodes that occur at low physical activity. However, there was no apparent diurnal pattern to the relation between physical activity and mean ischemic duration.
Study Limitations
As a naturalistic study, the present data make it possible to
assess the correspondence of activities, awakening, and
ischemia during daily life. However, this also presents a
limitation, since the disengaging of exogenous and
endogenous factors during daily life was accomplished by
statistical rather than by experimental means. However, similar results
have recently been obtained by experimentally separating time of
awakening and the increase in activity during the
morning.18 Our findings add to these prior observations by
assessing the effects of mental activities and of HRs and by providing
evidence for an activity-independent circadian influence that
potentiates the effects of exogenous triggers of ischemia in
the morning.
The present study makes use of adjusted scores for ischemia to examine the effect of time of day on ischemia while at the same time controlling for individual changes in physical and mental activities. Because ischemia occurred in <15% of hours of observation, relatively large numbers of patients were required to obtain sufficient variation in naturally occurring activities that coincide with ischemia. This problem is especially relevant to assessing possible exogenous triggers of nocturnal ischemia.
Clinical Implications
The present data indicate that activities are particularly
potent ischemic triggers in the morning and that
ischemia is greatest in the morning even after control for the
effects of activities. This heightened morning ischemic
vulnerability is paralleled by the finding1 that a
given HR increase above the ischemic threshold in CAD patients
occurring in the morning is more likely to trigger ischemia
than during other times of the day. Thus, therapeutic efforts to reduce
ischemic activity and the morning vulnerability to
ischemia in ambulant patients would be served by further
studies of pathophysiological processes (eg,
hemodynamic, hemostatic) that may mediate the linkage
between exogenous daily activities, such as exercise and mental stress,
and ischemia. Factors such as increased coronary tone,
decreased myocardial supply, and overnight hemostatic changes should
therefore be addressed by therapeutic efforts to control
ischemic activity and reduce the increased morning
vulnerability to ischemia.9 37 38
The presence of both exogenous and endogenous components of circadian ischemic variation may help reconcile conflicting findings regarding the role of HR as a trigger of ambulatory ischemic episodes and regarding the mechanisms of the effects of ß-blockers on the morning increase in ischemia. Research has demonstrated the importance of HR increases as a predictor of most episodes of ambulatory ischemia.38 39 40 It has further been reported by Andrews et al40 that ischemic episodes associated with HR increases were well treated with ß-blockers and that the minority of ischemic events not associated with HR increases were well treated with calcium channel blockers. However, results of this and prior studies41 42 indicate that the HR threshold for ischemia varies throughout the day, and systemic vascular resistance appears to exhibit a circadian rhythm that might account for a lowered threshold for ischemia in the morning.9 In this regard, it has been suggested that the variability in HR threshold for ischemia might be an indication of coronary tonus.41 In addition, the present data indicate that diurnal variations in mean HR and HR increases before ischemic episodes are not sufficient to account for the morning increase in ischemia. This points out the shortcomings of relying on measures of HR alone as a one-to-one index of either myocardial demand or physical activity levels. Moreover, the reduction of myocardial contractility is a possible non-HR mechanism through which ß-blockade could lessen ischemia. Further studies are needed to understand the relative importance of supply versus demand mechanisms during this vulnerable morning period for ischemia and the relation of these factors to ischemic episodes and to clinical events.
Because ischemia occurs relatively frequently, studying the triggers of daily-life transient ischemia has the advantage of being amenable to investigation by means of the methods used in this study. Although transient ischemia has been linked to adverse prognosis,43 the primary questions of importance for the prevention of cardiovascular morbidity and mortality relate to the end points of myocardial infarction and sudden cardiac death, which are rare events. Given the presence of vulnerable plaque in coronary arteries, ischemia is probably a predisposing factor for these rarer clinical events,44 and recent investigations suggest the importance of physical and mental triggers for both ischemia and myocardial infarction.10 45 46 Thus, further research on triggers of daily-life transient ischemia may provide an important method for clarifying triggers of myocardial infarction and sudden cardiac death.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This research was supported by grants from the NIH (HL-47337), the John D. and Catherine T. MacArthur Foundation, and the Uniformed Services University of the Health Sciences (R-07233).
|
Footnotes |
|---|
Reprint requests to David S. Krantz, PhD, Department of Medical and Clinical Psychology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD 20814-4799. E-mail krantz@usuhsb.usuhs.mil.
The opinions and assertions expressed herein are those of the authors and are not to be construed as reflecting the views of the Uniformed Services University of the Health Sciences or the US Department of Defense.
Received August 7, 1995; revision received October 25, 1995; accepted October 30, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Rocco MB, Barry J, Campbell S, Nabel E, Cook EF, Goldman L, Selwyn AP. Circadian variation of transient myocardial ischemia in patients with coronary artery disease. Circulation. 1987;75:395-400.
2. Mulcahy D, Keegan J, Cunnigham J, Quyyumi A, Crean P, Park A, Wright C, Fox K. Circadian variation of total ischemic burden and its alteration with anti-anginal agents. Lancet. 1988;2:755-759. [Medline] [Order article via Infotrieve]
3. Goldberg RJ, Brady P, Muller JE, Chen Z, de Groot M, Zonneveld P, Dalen JE. Time of onset of symptoms of acute myocardial infarction. Am J Cardiol. 1990;66:140-144. [Medline] [Order article via Infotrieve]
4. Muller JE, Stone PH, Turi ZG, Rutherford JD, Czeisler CA, Parker C, Poole WK, Passamani E, Roberts R, Robertson T, Sobel BE, Willerson JT, Braunwald E, for the MILIS Study Group. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med. 1985;313:1315-1322. [Abstract]
5.
Muller JE, Ludmer PL, Willich SN, Tofler GH, Aylmer G,
Klangos I, Stone PH. Circadian variation in the frequency of
sudden cardiac death. Circulation. 1987;75:131-138.
6. Tofler GH, Brezinski D, Schafer AI, Czeisler CA, Rutherford JD, Willich SN, Gleason RE, Williams GH, Muller JE. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med. 1987;316:1514-1518. [Abstract]
7. Millar-Craig MW, Bishop CN, Raferty EB. Circadian variation of blood-pressure. Lancet. 1978;1:795-797. [Medline] [Order article via Infotrieve]
8. Turton MB, Deegan T. Circadian variations of plasma catecholamine, cortisol and immunoreactive insulin concentration in supine subjects. Clin Chim Acta. 1974;55:389-397. [Medline] [Order article via Infotrieve]
9.
Quyyumi AA, Panza JA, Diodati JG, Lakatos E, Epstein
SE. Circadian variation in ischemic threshold: a
mechanism underlying the circadian variation in ischemic
events. Circulation. 1992;86:22-28.
10.
Mittleman MA, Maclure M, Tofler GH, Sherwood JB,
Goldberg RJ, Muller JE. Triggering of acute myocardial
infarction by heavy physical exertion: protection against triggering by
regular exercise. N Engl J Med. 1993;329:1677-1683.
11.
Willich SN, Lewis M, Lowel H, Arntz HR, Schubert F,
Schmoder R. Physical exertion as a trigger of acute myocardial
infarction. N Engl J Med. 1993;329:1684-1690.
12. Gottdiener JS, Krantz DS, Howell RH, Hecht GM, Klein J, Falconer JJ, Rozanski A. Induction of silent myocardial ischemia with mental stress testing: relationship to the triggers of ischemia during daily life activities and to ischemia functional severity. J Am Coll Cardiol. 1994;24:1645-1651. [Abstract]
13. Burg MM, Jain D, Soufer R, Kerns RD, Zaret BL. Role of behavioral and psychological factors in mental stress-induced silent left ventricular dysfunction in coronary artery disease. J Am Coll Cardiol. 1993;22:440-448. [Abstract]
14. Barry J, Selwyn AP, Nabel EG, Rocco MB, Mead K, Campbell S, Rebecca G. Frequency of ST-segment depression produced by mental stress in stable angina pectoris from coronary artery disease. Am J Cardiol. 1988;61:589-593.
15. Rozanski A, Bairey CN, Krantz DS, Friedman J, Resser K, Morrell M, Hilton-Chaften S, Hestrin L, Bietendorf J, Berman D. Mental stress and the induction of silent myocardial ischemia in patients with coronary artery disease. N Engl J Med. 1988;318:1005-1012. [Abstract]
16. Panza JA, Diodati JG, Callahan TS, Epstein SE, Quyyumi AA. Role of increase in heart rate in determining the occurrence and frequency of myocardial ischemia during daily life in patients with stable coronary artery disease. J Am Coll Cardiol. 1992;20:1092-1098. [Abstract]
17.
Deedwania PC, Nelson JR. Pathophysiology of
silent myocardial ischemia during daily life:
hemodynamic evaluation by simultaneous
electrocardiographic and blood pressure monitoring.
Circulation. 1990;82:1296-1304.
18.
Parker JD, Testa MA, Jimenez AH, Tofler GH, Muller JE,
Parker JO, Stone PH. Morning increase in ambulatory
ischemia in patients with stable coronary artery
disease. Circulation. 1994;89:604-614.
19. Hedges SM, Krantz DS, Contrada RJ, Rozanski A. Development of a diary for use with ambulatory monitoring of mood, activity, and physiological function. J Psychopathol Behav Assess. 1990;12:203-217.
20. Patterson SM, Krantz DS, Montgomery LC, Deuster PA, Hedges SM, Nebel LE. Automated physical activity monitoring: validation and comparison with physiological and self-report measures. Psychophysiology. 1993;30:296-305. [Medline] [Order article via Infotrieve]
21. Rozanski A, Diamond GA, Forrester JS, Berman D, Morris D, Swan HJC. Comparison of alternate referent standards for cardiac normality: implications for diagnostic testing. Ann Intern Med. 1984;101:164-171.
22.
Klein J, Chao SY, Berman DS, Rozanski A. Is
`silent' myocardial ischemia really as severe as
symptomatic ischemia?
Circulation. 1994;89:1958-1966.
23. Deanfield J, Kensett M, Wilson R, Shea M, Horlock P, de Landsheere C, Selwyn A. Silent myocardial ischaemia due to mental stress. Lancet. 1984;2:1001-1005.[Medline] [Order article via Infotrieve]
24. Cohn PF. Silent Myocardial Ischemia and Infarction. 2nd ed. New York, NY: Marcel Dekker Inc; 1989.
25. Krantz DS, Hedges SM, Gabbay FH, Klein J, Falconer JJ, Bairey Merz CN, Gottdiener JS, Lutz H, Rozanski A. Triggers of angina and ST-segment depression in ambulatory patients with coronary artery disease: evidence for an uncoupling of angina and ischemia. Am Heart J. 1994;128:703-712. [Medline] [Order article via Infotrieve]
26.
Chau NP, Mallion HM, de Gaudemaris R, Ruche E, Siche
JP, Pelen O, Mathern G. 24-hour ambulatory blood pressure in
shift workers. Circulation. 1989;80:341-347.
27.
Cage JE, Hess OM, Murakami T, Ritter M, Grimm J,
Krayenbuehl HP. Vasoconstriction of stenotic
coronary arteries during dynamic exercise in patients with
classic angina pectoris: reversibility by
nitroglycerin.
Circulation. 1986;73:865-876.
28.
Siess W, Lorenz R, Roth P, Weber PC. Plasma
catecholamines, platelet aggregation and associated
thromboxane formation after physical exercise, smoking or
norepinephrine infusion.
Circulation. 1982;66:44-48.
29. Jern C, Erikson E, Tengborn L, Risbert B, Wadenvik H, Jern S. Changes or plasma coagulation and fibrinolysis in response to mental stress. Thromb Haemost. 1989;62:767-771. [Medline] [Order article via Infotrieve]
30. Yeung AC, Vekshtein VI, Krantz DS, Vita J, Ryan TJ, Ganz P, Selwyn AP. The effect of atherosclerosis on the vasomotor response of coronary arteries to mental stress. N Engl J Med. 1991;325:1551-1556. [Abstract]
31. Panza JA, Epstein SE, Quyyumi AA. Circadian variation in vascular tone and its relation to alpha-sympathetic vasoconstriction activity. N Engl J Med. 1991;325:986-990. [Abstract]
32. Ehrly AM, Jung G. Circadian rhythm of human blood viscosity. Biorheology. 1973;10:577-583. [Medline] [Order article via Infotrieve]
33.
Koeltringer P, Langsteger W, Lind P, Eber O, Reisecker
F. Morning increases in blood viscoelasticity of patients with
ischemic stroke. Stroke. 1990;21:826-827.
34.
Kubota K, Sakurai T, Tamura J, Shirakura T. Is
the circadian change in hematocrit and blood viscosity a factor
triggering cerebral and myocardial infarction?
Stroke. 1987;18:812-813.
35.
Kurnick PB. Circadian variation in the efficacy
of tissue-type plasminogen
activator. Circulation. 1995;91:1341-1346.
36. Peters RW, Zoble RG, Liebson PR, Pawitan Y, Brooks MM, Proschan M. Identification of a secondary peak in myocardial infarction onset 11 to 12 hours after awakening: the cardiac arrythmia suppression trial (CAST) experience. J Am Coll Cardiol. 1993;22:998-1003. [Abstract]
37.
Stone PH. Unraveling the mechanisms of
ambulatory ischemia: how and why.
Circulation. 1990;82:1528-1530.
38. Lambert CR, Coy K, Imperi G, Pepine C. Influence of beta-adrenergic blockade defined by time series analysis on circadian variation of heart rate and ambulatory myocardial ischemia. Am J Cardiol. 1989;64:835-839. [Medline] [Order article via Infotrieve]
39. Deedwania PC, Carbajal EC. Role of myocardial oxygen demand in the pathogenesis of silent ischemia during daily life. Am J Cardiol. 1992;70:19F-24F. [Medline] [Order article via Infotrieve]
40.
Andrews TC, Fenton T, Toyosaki N, Glasser SP, Young PM,
McCallum G, Gibson RS, Shook TL, Stone PH. Subsets of ambulatory
myocardial ischemia based on heart rate activity: circadian
distribution and response to anti-ischemic
medication. Circulation. 1993;88:92-100.
41. Banai S, Moriel M, Benhorin J, Gavish A, Stern S, Tzivoni D. Changes in myocardial ischemic threshold during daily activities. Am J Cardiol. 1990;66:1403-1406. [Medline] [Order article via Infotrieve]
42.
Benhorin J, Banai S, Moriel M, Gavish A, Keren A, Stern
S, Tzivoni D. Circadian variations in ischemic threshold
and their relation to the occurrence of ischemic
episodes. Circulation. 1993;87:808-814.
43.
Rocco MB, Nabel EG, Campbell S, Goldman L, Barry J,
Mead K, Selwyn AP. Prognostic importance of myocardial
ischemia detected by ambulatory monitoring in patients with
stable coronary artery disease.
Circulation. 1988;78:877-884.
44. Muller JE, Abela GS, Nesto RW, Tofler GH. Triggers, acute risk factors and vulnerable plaques: the lexicon of a new frontier. J Am Coll Cardiol. 1994;23:809-813. [Abstract]
45. Gabbay FH, Krantz DS, Kop WJ, Hedges SM, Klein J, Gottdiener JS, Rozanski A. Triggers of myocardial ischemia during daily life in patients with coronary artery disease: physical and mental activities, anger, and smoking. J Am Coll Cardiol. In press.
46.
Mittleman MA, Maclure M, Sherwood JB, Mulry RP, Tofler
GH, Jacobs SC, Friedman R, Benson H, Muller JE. Triggering of
acute myocardial infarction onset by episodes of anger.
Circulation. 1995;92:1720-1725.
This article has been cited by other articles:
 |
|
 |
|
  P. H. Wirtz, L. S. Redwine, C. Baertschi, M. Spillmann, U. Ehlert, and R. von Kanel Coagulation Activity Before and After Acute Psychosocial Stress Increases With Age Psychosom Med, May 1, 2008; 70(4): 476 - 481. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. T. Kuipers, C. L. Sauder, J. R. Carter, and C. A. Ray Neurovascular responses to mental stress in the supine and upright postures J Appl Physiol, April 1, 2008; 104(4): 1129 - 1136. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Burg, R. Lampert, T. Joska, W. Batsford, and D. Jain Psychological Traits and Emotion-Triggering of ICD Shock-Terminated Arrhythmias Psychosom Med, November 1, 2004; 66(6): 898 - 902. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. U. Viola, C. Simon, J. Ehrhart, B. Geny, F. Piquard, A. Muzet, and G. Brandenberger Sleep Processes Exert a Predominant Influence on the 24-h Profile of Heart Rate Variability J Biol Rhythms, December 1, 2002; 17(6): 539 - 547. [Abstract] [PDF]
|
|
|
|
 |
|
 W. J. Kop, R. J. Verdino, J. S. Gottdiener, S. T. O'Leary, C. N. Bairey Merz, and D. S. Krantz Changes in heart rate and heart rate variability before ambulatory ischemic events J. Am. Coll. Cardiol., September 1, 2001; 38(3): 742 - 749. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. J. Kop Chronic and Acute Psychological Risk Factors for Clinical Manifestations of Coronary Artery Disease Psychosom Med, July 1, 1999; 61(4): 476 - 487. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. A.J.L. Scheer, L. J. P. van Doornen, and R. M. Buijs Light and Diurnal Cycle Affect Human Heart Rate: Possible Role for the Circadian Pacemaker J Biol Rhythms, June 1, 1999; 14(3): 202 - 212. [Abstract] [PDF]
|
|
|
|
 |
|
 J. E. Muller, P. G. Kaufmann, R. V. Luepker, M. L. Weisfeldt, P. C. Deedwania, and J. T. Willerson Mechanisms Precipitating Acute Cardiac Events : Review and Recommendations of an NHLBI Workshop Circulation, November 4, 1997; 96(9): 3233 - 3239. [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||