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CK-M8 estimated hour of onset 24 h period replotted

Fig. 2. Cireadian variation in myocardial infarction onset. The number of infarctions/h is plotted on the Y-axis vs the time of onset on the X-axis (24-h clock) for 849 patients experiencing acute myocardial infarction. The hour of onset of infarction is determined from extrapolated from creatine phos-phokinase MB fraction levels. There is a significant excess of infarctions between the hours of 6 am and noon, with a small secondary peak at 7 to 8 pm. Reprinted with permission from ref. 24.

849 patients (24). Serial cardiac muscle enzyme levels were used to estimate the time of the onset of infarction. These investigators identified a prominent morning increase in the incidence of infarction onset, peaking from 9 AM to noon, with a smaller peak in the early evening. A nadir in the incidence of infarction onset was observed at night (Fig. 2). Similar findings were reported from the Intravenous Streptokinase in Acute Myocardial Infarction (ISAM) trial of 1741 patients, with infarction occurring 1.8 X more frequently between 6 am and noon, compared to the other quarters of the day (25). This pattern, with a predominance of infarctions beginning in the morning hours, and a relative paucity beginning during what would be considered hours of sleep (midnight to 6 am), has been confirmed in many other studies (26-35). Some but not all investigators have also reported a second, smaller peak in the incidence of infarction onset during the late afternoon or evening hours. A meta-analysis of 30 studies encompassing 66,635 patients found a relative risk for myocardial onset between 6 am and noon of 1.38 (95% confidence interval 1.37-1.40) (36). This study calculated that 27.7% of morning nonfatal infarctions and 8.8% (95% confidence interval 8.5-9.0%) of all nonfatal myocar-dial infarctions could be attributed to the excess morning risk of acute myocardial infarction (Fig. 3).

A similar pattern of circadian variation occurs in acute coronary and vascular events other than nonfatal myocardial infarction. The onset of chest pain at rest in patients hospitalized with unstable angina pectoris also shows a statistically significant morning peak (37-41). In the Thrombolysis in Myocardial Infarction (TIMI) III study of unstable angina and non-Q wave myocardial infarction, 31.4% of 7730 patients entered into

Morning Excess Angina Pectoris

Fig. 3. Meta-analysis of time of onset of acute myocardial infarction in over 66,000 patients. In these studies the 24-h period is divided into 6-h segments, beginning at midnight. The dotted line shows the expected number of infarctions for each 6-h time period, and the black shaded area shows the excess incidence of infarctions occurring during the 6 AM to noon segment. Reprinted with permission from ref. 36.

Fig. 3. Meta-analysis of time of onset of acute myocardial infarction in over 66,000 patients. In these studies the 24-h period is divided into 6-h segments, beginning at midnight. The dotted line shows the expected number of infarctions for each 6-h time period, and the black shaded area shows the excess incidence of infarctions occurring during the 6 AM to noon segment. Reprinted with permission from ref. 36.

the registry roster had onset of pain between 6 am and noon (37) (Fig. 4). One study of 1167 patients with non-Q wave myocardial infarction failed to show a significant diurnal variation in time of onset of symptoms (41). However, the larger TIMI III study demonstrated a significant morning excess of events in both the unstable angina and non-Q wave myocardial infarction subgroups (37).

Ambulatory monitoring of patients with stable coronary artery disease and myocar-dial ischemia also demonstrates an increase in the number of episodes of transient myocardial ischemia occurring during the morning hours, between 6 AM and noon, again sometimes with a secondary peak in the late afternoon (42-47) (Fig. 5). A multicenter European study of over 1087 stable angina patients found both early morning (9 am to noon) and afternoon (3 pm to 6 pm) peaks in anginal attack frequency (48). Another study of transient myocardial ischemia in the early posthospital phase of acute myocardial infarction demonstrated the peak incidence of ischemic episodes to be in the early evening hours rather than in the morning (49). This suggests that circadian patterns may be altered transiently by an event such as acute myocardial infarction.

Ischemic stroke represents another vascular catastrophe with pathogenesis similar to that of myocardial ischemic events. A significant variation in the time of onset of stroke symptoms, with a dominant peak in the 6 am to noon time frame, has been demonstrated (50,51). Even when accounting for stroke patients awakening with symptoms, when the time of onset may not be known, over 50% of strokes in one study (50) and 38% in another (51) were thought to have had their onset between 6 am and noon.

The timing of sudden cardiac death also appears to have a similar circadian variation, demonstrated in two studies of the Massachusetts population (52,53), a group of patients with advanced heart failure dying suddenly (54), and in patients receiving antiarrhythmic agents during the Cardiac Arrhythmia Supression Trail (CAST) (55). A meta-analy-sis also reviewed 19 published studies of the time of onset of sudden cardiac death (5834

Fig. 4. The circadian variation in the timing of the onset of unstable angina pectoris and non-Q wave myocardial infarction, from the TIMI III Registry. The percent of patients with onset of symptoms in each 2-h time period (X-axis) is shown. The _p-values are the result of the chi-square goodness-of-fit test for a uniform distribution, indicating a highly significant nonuniformity. Reprinted with permission from ref. 37.

Fig. 4. The circadian variation in the timing of the onset of unstable angina pectoris and non-Q wave myocardial infarction, from the TIMI III Registry. The percent of patients with onset of symptoms in each 2-h time period (X-axis) is shown. The _p-values are the result of the chi-square goodness-of-fit test for a uniform distribution, indicating a highly significant nonuniformity. Reprinted with permission from ref. 37.

Fig. 5. Circadian variation in myocardial ischemic burden in patients undergoing 24-hourly ambulatory monitoring. The solid lines indicate the level of physical and mental activity (Y-axis on left) throughout the 24-h cycle (X-axis). These levels increase in the morning, remain elevated throughout the day, and decrease at night. The dotted line plots the total duration of myocardial ischemia per hour (Y-axis on right). There is a prominent morning peak in ischemic time, paralleling the rise in the level of physical and mental activity. However, ischemic time decreases after the morning hours despite maintenance of high physical and mental activity levels. Reprinted with permission from ref. 42.

Fig. 5. Circadian variation in myocardial ischemic burden in patients undergoing 24-hourly ambulatory monitoring. The solid lines indicate the level of physical and mental activity (Y-axis on left) throughout the 24-h cycle (X-axis). These levels increase in the morning, remain elevated throughout the day, and decrease at night. The dotted line plots the total duration of myocardial ischemia per hour (Y-axis on right). There is a prominent morning peak in ischemic time, paralleling the rise in the level of physical and mental activity. However, ischemic time decreases after the morning hours despite maintenance of high physical and mental activity levels. Reprinted with permission from ref. 42.

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