Cardiovascular Research 1992;26:831-838
83 1
Review article Onset of acute myocardial infarction - circadian variation and triggers Mylan C Cohen and James E Muller
A
dvances in the recognition and understanding of triggering mechanisms of silent ischaemia, myocardial infarction, and sudden death have recently occurred. They are of importance because they may lead to improved treatment of coronary artery disease and generate insights that may contribute to prevention. Although triggering and circadian variation appear to be new topics of interest, the concepts have strong historical roots.
In their original clinical description of acute myocardial infarction in 1910, Obraztsov and Strazhesko noted, “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”.’ Their view, that infarction was triggered, was challenged in the 1930s as larger studies revealed that myocardial infarction often occurred without an obvious precipitating event. Authors argued fof and against4 the belief that triggers were frequent. The controversy was eventually suspended for many years as Master’s conclusion, based on retrospective questionnaires, that “coronary occlusion takes place irrespective of the physical activity being performed or the type of rest taken” gained widespread acceptance.6 However, studies conducted with modem epidemiological methods and with new understanding of the pathogenesis of myocardial infarction indicate that the original concept of Obraztsov and Strazhesko may be correct. The recent documentation of increased infarction onset in the morning hours7 has revitalised investigation of triggering. Sumiyoshi et a1 reported on activities prior to onset in 416 patients with infarction admitted to the National Heart Centre of Japan from 1977 to 1985.’ Fifty three percent of patients without prior angina reported their infarct began during moderate to heavy exercise, emotional stress, or excitement. In an effort to obtain control data, information was collected on the frequency of emotional and physical stress during the same month one year prior to infarction and compared to the frequency of stress in the month immediately prior to infarction. Although the frequency of stress in the month prior to infarction was significantly higher than that reported during the control period (58 versus
Epidemiological evidence that morning activities trigger onset That myocardial infarction does not occur randomly throughout the day, but shows prominent circadian variation with increased morning frequency, supports the concept that daily activities are important triggers. Evidence obtained from the MILIS’ (fig 1) and from the intravenous streptokinase in acute myocardial infarction (ISAM) study” (fig 2) clearly show that myocardial infarction is at least three times more likely to begin in the morning than in the late evening. Both studies determined the onset of myocardial infarction objectively, based on the time of first appearance of creatine kinase in the plasma. Their finding is supported by a larger number of studies” that used onset of pain as the marker for time of myocardial infarction onset. These earlier studies received limited attention, however, because delayed reporting of myocardial infarction onset, which might have started while the patient was sleeping, was thought to explain the increased morning incidence. More detailed analysis has indicated that the morning increase in myocardial infarction may be attenuated in certain subgroups such as those receiving prior p adrenergic blockade, elderly people, diabetics, smokers, and those with prior infar~tion.~ l3
Institute for Prevention of Cardiovascular Disease, Harvard Medical School, Kennedy 5, New England Deaconess Hospital, 1 Autumn Street, Boston, MA 02215, USA: M C Cohen, J E Muller. Correspondence to Dr Cohen.
Downloaded from by guest on June 7, 2016
History of the triggering concept
34%, pc0.0 I), recall bias complicates interpretation of the finding. Additionally, our group has reviewed reporting of possible triggers of infarction by patients enrolled in the multicentre investigation of the limitation of infarct size (MILIS). This study revealed that 48.5% reported a possible trigger? comparable to the findings of Sumiyoshi et aL8 However, it is not the report of the activities themselves, but the collection of appropriate control data that poses the greatest obstacle to clarifying the role of potential trigger activities in the onset of infarction. To overcome the methodological problems involved in collection of such data, Maclure has developed a case crossover design; in this design, each patient serves as his or her own control for relatively recent activities.l o A study funded by the National Heart, Lung and Blood Institute, currently uses this method. Over 2000 patients with infarction will be interviewed to determine their activities in the hours immediately before infarction onset and in a control period 24 hours earlier.
832
Cohen. Muller 45
I
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40 -
L
35
-
30
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0
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&P
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-
-
15-
10 5-
-
12 14
0
1f
CK-MB estimated hour of onset
2
4
6
10 l i
14 16 18
24 h period replotted
11 22
Figure I The number of infarctions beginning during each qf the 24 hours of the day is plotted on the lefl side of the figure. On the right, the identical data are plotted again to permit appreciation qf the relation between the end and the beginning of the c l q . A two harmonic regression equation jbr the frequency of onset of myocardial infarction has been fitted to the data (curved line). A prominent circodiun rhythm is present, with a primary peak incidence of infarction at 9 am and a secondary peak at 8 pm.
Timing and triggers of transient myocardial ischaemia Transient myocardial ischaemia is more frequent and more easily studied than the cardiovascular catastrophes of myocardial infarction, sudden cardiac death, and stroke. Continuous Holter monitoring eliminates bias resulting from unobserved periods, allowing precise determination of the timing of transient myocardial ischaemia. Such studies have 140 120
5 r n
100
-
80
-
3
60
-
40
?
v-
r-
-*-
-
20 0-
Time of day
Figure 2 Bar graph of incidence of myocardial infarction of I741 patients of the ISAM (intravenous streptokinase in acute myocardial infarction) study. There is a marked circadian variation (p
83 1
Review article Onset of acute myocardial infarction - circadian variation and triggers Mylan C Cohen and James E Muller
A
dvances in the recognition and understanding of triggering mechanisms of silent ischaemia, myocardial infarction, and sudden death have recently occurred. They are of importance because they may lead to improved treatment of coronary artery disease and generate insights that may contribute to prevention. Although triggering and circadian variation appear to be new topics of interest, the concepts have strong historical roots.
In their original clinical description of acute myocardial infarction in 1910, Obraztsov and Strazhesko noted, “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”.’ Their view, that infarction was triggered, was challenged in the 1930s as larger studies revealed that myocardial infarction often occurred without an obvious precipitating event. Authors argued fof and against4 the belief that triggers were frequent. The controversy was eventually suspended for many years as Master’s conclusion, based on retrospective questionnaires, that “coronary occlusion takes place irrespective of the physical activity being performed or the type of rest taken” gained widespread acceptance.6 However, studies conducted with modem epidemiological methods and with new understanding of the pathogenesis of myocardial infarction indicate that the original concept of Obraztsov and Strazhesko may be correct. The recent documentation of increased infarction onset in the morning hours7 has revitalised investigation of triggering. Sumiyoshi et a1 reported on activities prior to onset in 416 patients with infarction admitted to the National Heart Centre of Japan from 1977 to 1985.’ Fifty three percent of patients without prior angina reported their infarct began during moderate to heavy exercise, emotional stress, or excitement. In an effort to obtain control data, information was collected on the frequency of emotional and physical stress during the same month one year prior to infarction and compared to the frequency of stress in the month immediately prior to infarction. Although the frequency of stress in the month prior to infarction was significantly higher than that reported during the control period (58 versus
Epidemiological evidence that morning activities trigger onset That myocardial infarction does not occur randomly throughout the day, but shows prominent circadian variation with increased morning frequency, supports the concept that daily activities are important triggers. Evidence obtained from the MILIS’ (fig 1) and from the intravenous streptokinase in acute myocardial infarction (ISAM) study” (fig 2) clearly show that myocardial infarction is at least three times more likely to begin in the morning than in the late evening. Both studies determined the onset of myocardial infarction objectively, based on the time of first appearance of creatine kinase in the plasma. Their finding is supported by a larger number of studies” that used onset of pain as the marker for time of myocardial infarction onset. These earlier studies received limited attention, however, because delayed reporting of myocardial infarction onset, which might have started while the patient was sleeping, was thought to explain the increased morning incidence. More detailed analysis has indicated that the morning increase in myocardial infarction may be attenuated in certain subgroups such as those receiving prior p adrenergic blockade, elderly people, diabetics, smokers, and those with prior infar~tion.~ l3
Institute for Prevention of Cardiovascular Disease, Harvard Medical School, Kennedy 5, New England Deaconess Hospital, 1 Autumn Street, Boston, MA 02215, USA: M C Cohen, J E Muller. Correspondence to Dr Cohen.
Downloaded from by guest on June 7, 2016
History of the triggering concept
34%, pc0.0 I), recall bias complicates interpretation of the finding. Additionally, our group has reviewed reporting of possible triggers of infarction by patients enrolled in the multicentre investigation of the limitation of infarct size (MILIS). This study revealed that 48.5% reported a possible trigger? comparable to the findings of Sumiyoshi et aL8 However, it is not the report of the activities themselves, but the collection of appropriate control data that poses the greatest obstacle to clarifying the role of potential trigger activities in the onset of infarction. To overcome the methodological problems involved in collection of such data, Maclure has developed a case crossover design; in this design, each patient serves as his or her own control for relatively recent activities.l o A study funded by the National Heart, Lung and Blood Institute, currently uses this method. Over 2000 patients with infarction will be interviewed to determine their activities in the hours immediately before infarction onset and in a control period 24 hours earlier.
832
Cohen. Muller 45
I
-
40 -
L
35
-
30
-
0
.c
&P
25
UI
gm
-
*-
20
-
-
15-
10 5-
-
12 14
0
1f
CK-MB estimated hour of onset
2
4
6
10 l i
14 16 18
24 h period replotted
11 22
Figure I The number of infarctions beginning during each qf the 24 hours of the day is plotted on the lefl side of the figure. On the right, the identical data are plotted again to permit appreciation qf the relation between the end and the beginning of the c l q . A two harmonic regression equation jbr the frequency of onset of myocardial infarction has been fitted to the data (curved line). A prominent circodiun rhythm is present, with a primary peak incidence of infarction at 9 am and a secondary peak at 8 pm.
Timing and triggers of transient myocardial ischaemia Transient myocardial ischaemia is more frequent and more easily studied than the cardiovascular catastrophes of myocardial infarction, sudden cardiac death, and stroke. Continuous Holter monitoring eliminates bias resulting from unobserved periods, allowing precise determination of the timing of transient myocardial ischaemia. Such studies have 140 120
5 r n
100
-
80
-
3
60
-
40
?
v-
r-
-*-
-
20 0-
Time of day
Figure 2 Bar graph of incidence of myocardial infarction of I741 patients of the ISAM (intravenous streptokinase in acute myocardial infarction) study. There is a marked circadian variation (p
