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(Circulation. 1997;96:3321-3327.)
© 1997 American Heart Association, Inc.

Articles

Nonuniform Nighttime Distribution of Acute Cardiac Events

A Possible Effect of Sleep States

Cynthia E. Lavery, MS; Murray A. Mittleman, MD, DrPH; Mylan C. Cohen, MD, MPH; James E. Muller, MD; ; Richard L. Verrier, PhD

From the Institute for Prevention of Cardiovascular Disease, Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Mass (C.E.L., M.AM, M.C.C., R.L.V.); Department of Epidemiology, Harvard School of Public Health, Boston, Mass (M.AM); and Division of Cardiovascular Medicine, Department of Internal Medicine, University of Kentucky Medical Center (Lexington) (J.E.M.).

	Abstract

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Background Although 250 000 myocardial infarctions and 38 000 sudden cardiac deaths occur at night annually, this public health problem is underappreciated and poorly understood. We examined whether the incidence of myocardial infarction, sudden cardiac death, and automatic implantable cardioverter-defibrillator (AICD) discharge was nonuniform, a result that may implicate physiological triggers such as sleep-state dependent changes in autonomic nervous system activity.

Methods and Results We conducted a review of the circadian pattern of the onset of myocardial infarction (n=19), sudden cardiac death (n=12), and AICD discharge (n=7). The nighttime period was chosen a priori as midnight to 5:59 AM. These reports documented 11 633 nocturnal myocardial infarctions (20% of the total myocardial infarctions), 1981 nocturnal sudden cardiac deaths (14.6% of the total sudden cardiac deaths), and 1200 nocturnal AICD discharges (15.0% of the total discharges). The distributions of myocardial infarction, sudden cardiac death, and AICD discharge were each significantly nonuniform (P<.001). The peak incidence of myocardial infarction and AICD discharge occurred between midnight and 0:59 AM, whereas the peak incidence of sudden cardiac death was between 1:00 and 1:59 AM. The trough in incidence occurred between 4:00 and 4:59 AM for sudden cardiac death and between 3:00 and 3:59 AM for myocardial infarction and AICD discharge.

Conclusions Nocturnal myocardial infarction, sudden cardiac death, and AICD discharge exhibit nonuniform distributions. This finding is consistent with the hypothesis that sleep-state dependent fluctuations in autonomic nervous system activity may trigger the onset of major cardiovascular events and provides further impetus for more directly testing this hypothesis at population, individual, and mechanistic levels. A better understanding of nocturnal triggers may make it possible to reduce the incidence of myocardial infarction, ventricular tachyarrhythmias, and sudden cardiac death during the nocturnal period.

Key Words: sleep • nervous system, autonomic • meta-analysis • circadian rhythm

	Introduction

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Acute cardiovascular events are known to exhibit a circadian pattern of onset with the peak incidence in the morning hours and the nadir during the night hours.^1,2 This nighttime trough in incidence has been assumed to be related to relative physiological quiescence during sleep. Despite this lower incidence at night, >250 000 myocardial infarctions and >38 000 sudden cardiac deaths occur annually at night in the United States. Whether these events are random or are triggered by specific physiological processes remains unknown.

Sleep is not a physiologically uniform state. Changes in brain state trigger surges in autonomic nervous system activity.³ Rapid eye movement (REM) sleep, which occurs at 90-minute intervals during sleep, is characterized by sharp surges of sympathetic nervous system activity reaching levels observed during wakefulness.⁴ This physiological process may be analogous to the surges in sympathetic nervous system activity thought to be responsible in part for triggering of myocardial infarction and sudden cardiac death associated with anger, heavy exertion, and sexual intercourse.^5-9 We hypothesized that the physiological processes associated with normal sleep could precipitate acute cardiovascular events. If this hypothesis were correct, then the distribution of acute cardiovascular events would be nonuniform throughout the night. We therefore conducted a review of published reports of the hourly incidence of acute myocardial infarction, sudden cardiac death, and discharge of automatic implantable cardioverter-defibrillators (AICDs) to evaluate whether the nocturnal incidence of these cardiac events is inhomogeneous. If this proved to be the case, the finding would provide further impetus for more directly testing this hypothesis at population, individual, and mechanistic levels.

	Methods

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We searched the medical literature for January 1, 1985, through June 30, 1996, using MEDLINE and reviewed the bibliographies of reports retrieved from the MEDLINE search to identify 19 published studies that included detailed data on the circadian pattern of acute nonfatal myocardial infarction in 1-hour intervals.^2,10-27 Data were available for 57 759 patients with myocardial infarction. We also identified 12 published studies that included detailed data on the circadian pattern of sudden cardiac death for a total of 13 591 patients^28-39 and 7 studies with data on the circadian pattern of AICD discharge in 1197 patients with a total of 8006 documented discharges.^40-46 The method of data abstraction is reported elsewhere.¹ In brief, data were abstracted from figures and tables independently by two reviewers. Discrepancies were resolved by conference and consensus. In the event of continued disagreement, one of the other investigators adjudicated.

The studies that were included for the nonfatal myocardial infarction analysis used the standard definition of myocardial infarction; to be included, at least two of the three following criteria were present: chest discomfort and/or symptoms suggestive of myocardial infarction for 20 minutes, ECG changes suggestive of evolving myocardial infarction according to the Minnesota coding system, and typical elevation of at least one of three cardiac enzymes to at least twice the upper limit of normal.

The definitions of sudden cardiac death were heterogeneous among the 12 studies but were clinically strict. Buff and coworkers²⁸ included in-hospital general medical ward cardiopulmonary arrests, defined as physician-documented circulatory collapse that required resuscitation efforts. Aronow and coworkers³³ studied a population at a long-term health care facility. The other 10 studies included only out-of-hospital deaths.^29-32,34-39 The majority of the out-of-hospital studies and the Aronow study defined sudden cardiac death as unexpected nontraumatic death within 1 hour of symptom onset in adults where the death could not be attributed to a disease other than coronary artery disease.^29-34,36 Moser and coworkers³⁹ defined sudden death as unexpected cardiac arrest that occurred outside the hospital within 15 minutes of a change in symptoms or during sleep in a previously ambulatory patient in stable condition. The remaining studies reported subjects who were found in cardiac arrest, developed cardiac arrest in the presence of emergency personnel,³⁵ or were witnessed collapsing or found in ventricular fibrillation, pulseless ventricular tachycardia, or asystole.^37,38 Willich and coworkers²⁹ were the only investigators to discriminate between definite and possible sudden cardiac deaths; both were included in our review.

Documentation of the timing of sudden cardiac death onset was based on the arrival time of the rescue squad³⁶; receipt of the emergency call by the dispatch^28,35,37,38; retrospective telephone interviews with witnesses, friends, or relatives^29,32,39; or death certificate.³¹ In three studies, the method of timing of the sudden cardiac death was not disclosed.^30,33,34

For the circadian pattern of AICD discharges, the time of each discharge was taken from the device at clinic visits. The devices used in each of the seven studies recorded time and date of the event. Some studies diagnosed ventricular tachyarrhythmias via RR intervals,^41,42,44,45 whereas others used devices that had the capability to store intracardiac ECGs before each event.^43,46 One study⁴⁰ involved the use of some devices with cycle length determination of arrhythmias and others with intracardiac ECG capability. Each discharge was analyzed for appropriateness of therapy for sustained ventricular tachyarrhythmia based on information available from the device. Excluded from our review were the less rapid tachyarrhythmias referred to by Tofler and collegues.⁴⁴ Only the rapid ventricular tachyarrhythmias (heart rate, >250 bpm; cycle length, <240 ms) were included. The other six studies did not distinguish between rapid and less rapid ventricular tachyarrhythmias.

We defined the time period of 12:00 to 5:59 AM, a priori, as the nocturnal period, according to current practice.^29,38 Analyses of the circadian pattern of onset of acute myocardial infarction, sudden cardiac death, and AICD discharge were carried out using simple proportions. The data were then combined, and the hourly intervals were tested by the ² test for goodness-of-fit. A significant nonuniform distribution was considered present if uniformity could be rejected. In addition, a sensitivity analysis was conducted by omitting the data from 5:00 to 5:59 AM. A two-sided value of P<.05 was considered statistically significant.

	Results

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Nonfatal Myocardial Infarction
During the 24-hour period, 11 633 patients (20.1%) experienced onset of myocardial infarction between midnight and 5:59 AM of a total of 57 759 patients. Results from the 19 studies of nonfatal myocardial infarction are shown in Table 1. The incidence of nonfatal myocardial infarction during the nighttime hours reported in the 19 studies ranged from 15.5% to 26.7% of all myocardial infarctions in the 24-hour period, for an average of 20.1%. The distribution of nonfatal myocardial infarction was significantly nonuniform throughout the night with ² goodness-of-fit, P<.001 (Fig 1). The incidence was elevated between midnight and 1:59 AM and between 5:00 and 5:59 AM, with a trough between 3:00 and 3:59 AM. Because of the possibilities that the peak in the incidence reported between 5:00 and 5:59 AM either was due to subjects' waking with symptoms of infarction, ischemia, or electrical instability that had begun earlier or occurred in patients who were already awake and active, we conducted a sensitivity analysis by excluding the period from 5:00 to 5:59 AM to eliminate a possible effect from awakening before 6:00 AM. This analysis resulted again in a significantly nonuniform distribution of myocardial infarction for the 5-hour period from midnight to 4:59 AM (P<.001).

View this table: [in this window] [in a new window]   Table 1. The 24-Hour Incidence, Nighttime Incidence, and Nighttime Percent of Myocardial Infarction for 19 Studies

View larger version (54K): [in this window] [in a new window]   Figure 1. Pooled data showing the hourly incidence of myocardial infarction onset between midnight and 5:59 AM from 19 studies involving 11 633 patients. The number of myocardial infarctions observed each hour appears above each bar.

Sudden Cardiac Death
In the 24-hour period, 1981 of a total of 13 591 patients (14.6%) experienced onset of sudden cardiac death between midnight and 5:59 AM. Results from the 12 studies of sudden cardiac death are shown in Table 2. The incidence of sudden cardiac death during the nighttime hours reported in the 12 studies ranged from 6.4% to 19.6% of all sudden cardiac deaths in the 24-hour period, for an average of 14.6%. Fig 2 shows that the distribution of sudden cardiac death onset was significantly nonuniform throughout the night (P<.001). The peak incidence of sudden cardiac death during the night hours occurred between 12:00 and 1:59 AM, with the nadir between 4:00 and 4:59 AM. A statistically significant nonuniform distribution of sudden cardiac death for the period from midnight to 4:59 AM (P<.001) remained after the period from 5:00 to 5:59 AM was excluded.

View this table: [in this window] [in a new window]   Table 2. The 24-Hour Incidence, Nighttime Incidence, and Nighttime Percent of Sudden Cardiac Death for 12 Studies

View larger version (52K): [in this window] [in a new window]   Figure 2. The hourly incidence of sudden cardiac death (SCD) onset from 12 studies involving 1981 patients with onset between midnight and 5:59 AM. The number above each bar indicates the number of sudden cardiac deaths observed each hour.

AICD Discharge
A total of 7 studies were identified that included data on the hourly incidence of AICD discharge in 1197 patients. These 1197 patients experienced 8006 defibrillator discharges, 1200 (15.0%) of which occurred between midnight and 5:59 AM. Results from the 7 studies of AICD discharge are shown in Table 3. The incidence of AICD discharge during the nighttime hours reported in the 7 studies ranged from 10.3% to 19.8% of all AICD discharges in the 24-hour period, for an average of 15.0%. Fig 3 shows that the distribution of these AICD discharges was nonuniform over the 6-hour nocturnal period (P<.001). The peak incidence during the nighttime hours occurred between midnight and 0:59 AM and sloped down to the nadir between 3:00 and 3:59 AM. After the period from 5:00 to 5:59 AM was excluded, a statistically significant nonuniform distribution of AICD discharge persisted (P<.001).

View this table: [in this window] [in a new window]   Table 3. The 24-Hour Incidence, Nighttime Incidence, and Nighttime Percent of AICD Discharge for 7 Studies

View larger version (53K): [in this window] [in a new window]   Figure 3. The hourly incidence of AICD discharge during the nocturnal period from 7 studies involving 1197 patients experiencing 1200 discharges between midnight and 5:59 AM. The number of discharges observed each hour is indicated over each bar.

	Discussion

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We found that the incidence of nonfatal myocardial infarction, sudden cardiac death, and AICD discharge is remarkably nonuniform throughout the night. This review of 57 759 patients with nonfatal myocardial infarction, 13 591 patients with sudden cardiac death, and 1197 patients with AICD discharges revealed that 20.1% of myocardial infarctions, 14.6% of sudden cardiac deaths, and 15.0% of AICD discharges occurred during the nighttime period between midnight and 5:59 AM. The peak incidence of myocardial infarction and AICD discharge occurred between midnight and 0:59 AM, whereas the peak incidence of sudden cardiac death was between 1:00 and 1:59 AM. The trough in incidence occurred between 4:00 and 4:59 AM for sudden cardiac death and between 3:00 and 3:59 AM for myocardial infarction and AICD discharge.

The mechanisms accounting for the nonuniform nighttime distribution of acute cardiovascular events are unknown. Despite the common belief that sleep is a time of relative protection from cardiac events, presumably because of the absence of triggering activities that occur during wakefulness, in fact, normal sleep is a dynamic process that involves complex regulation of the autonomic nervous system.³ Slow-wave sleep is associated with increased baroreceptor sensitivity, increased parasympathetic tone, and decreased heart rate. Conversely, REM sleep, which occurs four to six times per night for a total of 90 minutes, or 20% to 25% of total sleep time, is characterized by surges in sympathetic activity and decreased baroreceptor regulation and control.^47-49

A possible mechanism underlying the nonuniform distribution of cardiovascular events during the nighttime hours is that nocturnal surges in sympathetic activity that occur during REM sleep could precipitate myocardial ischemia⁵⁰ and infarction by stimulating thrombotic processes²¹ and increasing fibrinolytic aggregability⁵¹ or by increasing hemodynamic stress on vessel walls via increased heart rate, blood pressure, and myocardial demand. REM sleep is associated with sympathetic activity, which may cause plaque rupture, increased platelet aggregability, and coronary vasospasm.⁴ REM-induced surges in sympathetic and parasympathetic nervous system activity can lead to surges or pauses in heart rhythm, increased electrical instability, and ventricular tachyarrhythmias.^47-49,52 Under pathological conditions such as myocardial infarction, impairment in the ability to activate the vagus nerve may contribute to a documented overshoot in unbridled sympathetic nervous system activity during both REM and non-REM sleep.⁵³ REM bouts also increase in intensity and duration toward the morning, which may explain the increased incidence of cardiac events between 5:00 and 5:59 AM.

Deep sleep, or slow-wave sleep, may also play a role in triggering cardiovascular events. Decreased cardiac output and blood pressure due to increased vagal tone have been documented during normal deep sleep. In patients with stenotic coronary artery lesions, the decrease in blood pressure associated with deep sleep⁵⁴ may reduce the volume and velocity of blood flow, leading to ischemia, thrombi, and possibly evoking emboli either before or after arousal from sleep.⁵⁵ Electrical instability secondary to poor myocardial perfusion may lead to potentially fatal arrhythmias.

Alternatively, it is possible that the nonuniform distribution observed here reflects many unknown and uncontrolled variables in our pooled data. This ecological comparison is problematic due to limitations inherent in the design. Many alternate explanations may be responsible for the nonuniform distribution. Unfortunately, the pooled data did not include age, gender, individual variation in timing of the sleep/wake cycle, and cultural variation in sleep patterns for the individual subjects. The reviewed studies include a diverse international population. It is impossible to ascertain the effect of cultural patterns, weekday versus weekend variation, and individual variations. The studies also likely included shift workers, who may have a different circadian rhythm and certainly have altered sleep/wake cycles. Data on sleep state and nocturnal or morning arousal are not available for the individual patients. Specifically, it is not known whether the individuals awoke from sleep and arose before the onset of the cardiovascular symptoms, thus omitting sleep state–dependent surges as a trigger. As Barry and coworkers⁴¹ have shown, for patients with extensive coronary artery disease, rising at night often is associated with episodes of myocardial ischemia. Finally, and most importantly, it is possible that some, if not all, of the nonuniformity observed in this study is attributable to events during wakefulness because some patients may have retired after midnight and others may have awakened before 6:00 AM. Despite this, in such a large population, it is likely that the majority of these subjects were in bed, sleeping, before the onset of their cardiac symptoms.

As with all reviews of the literature, there is a potential for publication and data extraction bias. Multiple observers were used to reduce mismeasurement. Initial measurement error may be present in the original studies of myocardial infarction because investigators relied on patient self-report. However, Muller and colleagues conducted a validation study using data from the Multicenter Investigation of Limitation of Infarct Size Study² and found that the time of myocardial infarction onset as estimated by serial creatine kinase measurements correlated well with self-reported time of myocardial infarction symptom onset. There also is a potential problem of misclassification of the time of reported sudden cardiac death onset because not all sudden cardiac deaths are witnessed. The differing definitions of sudden cardiac death and various differences in data handling may also have an impact on the nighttime distribution of sudden cardiac death. Random misclassification tends to make the distribution of events appear more uniform throughout the night. On the other hand, if more subjects were likely to be found early in the night (ie, midnight to 12:59 AM) or early in the morning hours (ie, 5:00 to 5:59 AM) rather than during other nocturnal hours, nonuniformity of the sudden cardiac death distribution may be false due to differential misclassification. Martens and coworkers³⁸ found in their registry of 4719 subjects that the number of unwitnessed cardiac arrests was not significantly higher during the nighttime hours compared with the daytime hours. Willich and coworkers,²⁹ in their study of sudden cardiac deaths occurring in the Framingham cohort, distributed the hourly probability of death equally over the time interval in which the death was known to have occurred when the hour of onset of sudden cardiac death could not be determined accurately. In addition, Maron and coworkers excluded six subjects for whom it was impossible to determine the nocturnal time of death.³² The nonfatal myocardial infarction distribution may also been affected by differential misclassification. Subjects may not experience symptoms of acute myocardial infarction, even if the pathophysiological processes are present during sleep, until after waking. This fact may artificially inflate the number of myocardial infarctions during the 5:00-to-5:59 AM time period. It is impossible to estimate the effect of differential misclassification in the sudden cardiac death and nonfatal myocardial infarction data sets. The AICD discharge data are not plagued with this problem because each discharge was recorded directly from the device. However, the mechanisms underlying the arrhythmias in the patients with AICDs may not be representative of the pathophysiology involved in other clinical situations involving life-threatening ventricular arrhythmias. As mentioned previously, 6 of the 7 studies of AICD discharge did not differentiate between rapid and less rapid ventricular tachyarrhythmias.

In conclusion, nocturnal myocardial infarction, sudden cardiac death, and AICD discharge exhibit a nonuniform distribution. This finding is consistent with the hypothesis that sleep state–dependent fluctuations in autonomic nervous system activity may trigger the onset of major cardiac events and provides further impetus for more directly testing this hypothesis at population, individual, and mechanistic levels. Definitive elucidation of this mechanism will be aided by simultaneous monitoring of sleep state and ECG, which is now practical with home-based technology,⁵⁶ by determining time of myocardial infarction and sudden cardiac death in relation to time of onset of sleep, time of awakening, and nocturnal arousal from sleep. A better understanding of nocturnal triggers may make it possible to reduce the incidence of myocardial infarction, ventricular arrhythmias, and sudden cardiac death during the nocturnal period.

	Acknowledgments

 
This work was supported by grant R01-HL-50078 from the National Heart, Lung, and Blood Institute of the National Institutes of Health and the Pharmacoeconomics Division of G.D. Searle and Co. The authors are indebted to Sandra Verrier for her editorial contributions.

	Footnotes

 
Reprint requests to Murray A. Mittleman, MD, DrPH, Institute for Prevention of Cardiovascular Disease, Beth Israel Deaconess Medical Center, One Autumn St, 5th Floor, Boston MA 02215.

Received May 6, 1997; revision received July 29, 1997; accepted August 2, 1997.

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