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Time of Day

Fig. 6. Meta-analysis of time of sudden cardiac death in over 19,000 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 the excess incidence of sudden deaths occurring during the 6 am to noon segment. Reprinted with permission from ref. 36.

events) (36). The relative risk of sudden cardiac death was 1.29X greater (95% confidence interval 1.26-1.32) in the morning period compared to the rest of the day. The morning excess of sudden cardiac deaths accounted for 22.5% of morning sudden deaths and 6.8% (95% confidence interval 6.4-7.1%) of all sudden deaths (Fig. 6). Ventricular tachycardia and ventricular fibrillation are the most frequent arrhythmias causing sudden cardiac death. Several studies of patients with automatic implantible cardioverter-defibrillators (AICD) capable of documenting the time of arrhythmias (56-61) and a study of the arrival time in the emergency room of patients with ventricular fibrillation (62), demonstrated a morning peak and a nighttime nadir of the frequency of these events (Fig. 7).

The relationship between morning and myocardial infarction has prompted consideration that the time of awakening, rather than the time of day per se, may better explain the variation in the time of onset of acute coronary syndromes. In one study of 224 patients, the relative risk of acute myocardial infarction onset between 6 and 9 am was 1.8 (95% confidence interval 1.3-2.4) (63). After adjustment for individual wake times, the relative risk of infarction onset in the first 3 h after awakening increased to 2.4 (95% confidence interval 1.8-3.1). Another study of 137 patients found 23% of patients to report the onset of symptoms of myocardial infarction within 1 h of awakening (64). In the CAST experience of 3309 patients with a history of myocardial infarction, 24% experienced symptom onset within 4 h of awakening (65). In patients with sudden cardiac death, the relative risk for the first 3 h after awakening was 2.6 (95% confidence interval 1.6-4.2) compared to other times of the day (66). Studies of ambulatory patients undergoing Holter monitoring to detect myocardial ischemic episodes found that ischemic time increased significantly for the 2 h after awakening (42,46). This increase was observed even after correction for the greater level of physical and mental activity, which independently influenced ambulatory ischemia (42). The multicenter European

Fig. 7. Cireadian variation in frequency of ventricular tachyarrhythmic events in 32 patients with automatic implantable defibrillators capable of recording the time of occurrence of arrhythmias. The Y-axis represents the number of events vs time of day. The predominance of events during the 6 am to noon time period is statistically significant by analysis of variance (ANOVA) (p = 0.007). The curve is a fourth-order harmonic regression curve, demonstrating a significant periodicity in the frequency of events over time (R2 = 0.91, p < 0.001). Reprinted with permission from ref. 57.

Fig. 7. Cireadian variation in frequency of ventricular tachyarrhythmic events in 32 patients with automatic implantable defibrillators capable of recording the time of occurrence of arrhythmias. The Y-axis represents the number of events vs time of day. The predominance of events during the 6 am to noon time period is statistically significant by analysis of variance (ANOVA) (p = 0.007). The curve is a fourth-order harmonic regression curve, demonstrating a significant periodicity in the frequency of events over time (R2 = 0.91, p < 0.001). Reprinted with permission from ref. 57.

angina study cited above found 50% of anginal attacks to occur within 6 h of awakening (48). While the hours of sleep (generally midnight to 6 am) have been shown to encompass the lowest frequency of the onset of acute coronary syndromes, one study found that in patients with stable coronary disease, arising at night was strongly associated with the occurrence of transient myocardial ischemia detectable by ambulatory monitoring (67).

Other Patterns in the Timing of Acute Cardiac Events

In addition to variation in frequency of acute cardiac events over the course of a typical 24-h sleep-wake cycle, other temporal and environmental cycles have been shown to affect the timing of these events. Several studies have shown that myocardial infarctions are more likely to occur on Monday (26,68-70). One group demonstrated that this pattern was present only in a working, as opposed to a nonworking, population (68), although this was not confirmed in another study (34). One interesting observation has been made concerning 148 sudden cardiac deaths over a 10-yr period on the Hawaiian Island of Kauai (71). While the occurrence of sudden death in local residents demonstrated the typical 6 am to noon peak, sudden death in visitors coming from 2500 to 5400 miles distant (3-6 time zones) showed a peak in the 6 pm to midnight time period. This may reflect altered sleep-wake cycles induced by "jet lag."

A seasonal variation, with a peak in wintertime admissions for acute myocardial infarction and a summertime trough, has also been reported (28,34,69). One group studied the daily frequency of myocardial infarction over a 10-yr period and found correlations to varying weather patterns from year-to-year; higher incidence correlated with lower temperature and higher humidity (72). A study of vital statistics from five Minneapolis-St. Paul winters found no statistical relation between air temperature and cardiovascular mortality (73). However, this study found that snowfall influenced mortality on the day of occurrence and for 2 d following snowfall. The combination of rain and snow was found to produce a dramatic increase in mortality from acute myocardial infarction. Similar observations were made in Toronto, Ontario, Canada (74). On the other hand, a large multicenter study did find a significant increase in cardiovascular disease event rates with decreasing air temperatures (75). A recent study in patients with event-recording implantable cardioverter-defibrillators (ICD) found that the frequency of ventricular tachyarrhythmias correlated with the temperature calculated to be "felt" by the individual. "Felt-temperatures" in the range considered to represent thermal stress were associated with higher frequencies of arrhythmia (76). The role that climate, as opposed to nonmete-orological features of seasonal transitions, may play as a modifier of susceptibility to acute coronary disease onset is unclear. While the seasonal distribution of myocardial infarction existed without regard to climate in a multicenter, 259,891-patient U.S. study (77), a study of540 acute MI patients in Taiwan, a country with a year-round uniform subtropical climate found no such seasonal variation (78).-

Many of the studies examining the circadian variation of acute myocardial infarction have performed analyses in subgroups of patients, with the goal of gaining insights into triggering mechanisms by identifying differences in circadian rhythms between groups with different characteristics. In most studies, age, sex, cigarette smoking, prior myocar-dial infarction, or angina pectoris have not affected circadian patterns. The findings for diabetic patients have been less consistent, with some studies showing attenuation of cir-cadian variation of myocardial infarction onset in diabetics (26,27,69,79), and others showing preserved circadian variation (24,31,80). One study found circadian variation to be present in treated diabetic subjects, and abolished in untreated patients (81).

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