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(Circulation. 1995;92:1203-1208.)
© 1995 American Heart Association, Inc.

Articles

Morning Peak in Ventricular Tachyarrhythmias Detected by Time of Implantable Cardioverter/Defibrillator Therapy

Geoffrey H. Tofler, MD; Otavio C. E. Gebara, MD; Murray A. Mittleman, MD, DRPH; Peter Taylor, MD; William Siegel, MD; Ferdinand J. Venditti, Jr, MD; Carl A. Rasmussen, MD, PhD; James E. Muller, MD; for the CPI Investigators

From the Institute for Prevention of Cardiovascular Disease, Cardiovascular Division, Deaconess Hospital, Boston, and the Lahey Clinic, Burlington, Mass.

Correspondence to Geoffrey H. Tofler, MD, Institute for Prevention of Cardiovascular Disease, Deaconess Hospital, 1 Autumn St, Fifth Floor, Boston, MA 02215.

	Abstract

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Background A morning peak in occurrence of sudden cardiac death has been identified in epidemiological studies, but the studies are subject to selection bias, with the exclusion of unwitnessed deaths, which are more likely to occur at night. The recent availability of implantable cardioverter/defibrillators that record the time of ventricular tachyarrhythmias requiring either pacing or shock therapy provides an opportunity to clarify the timing of ventricular tachyarrhythmias predisposing to sudden cardiac death. Analysis of the timing of arrhythmias in different patient subgroups, such as patients with poor left ventricular function, may provide further insight into the mechanism of onset of sudden cardiac death.

Methods and Results We studied patients in whom a cardioverter/defibrillator (Ventak PRx) was implanted between September 1990 and September 1993 in US centers. Events that could be timed occurred in 483 patients. With an RR cycle length of 240 ms as a cutoff, corresponding to a heart rate of 250 beats per minute, episodes were categorized as rapid (n=1217) or less rapid (n=9266) ventricular tachyarrhythmias. A higher proportion of both rapid and less rapid ventricular tachyarrhythmias began in the late morning compared with other times of the day. The subgroup of patients with ejection fraction <20% at the time of implantation demonstrated a more uniform 24-hour distribution of tachycardias 250 beats per minute than patients with higher left ventricular ejection fraction.

Conclusions Further investigation of the late morning peak and of precipitants of ventricular tachyarrhythmias by use of data from the implantable cardioverter/defibrillator may provide insight into the pathophysiological mechanisms causing sudden cardiac death.

Key Words: defibrillation • tachycardia • circadian rhythm

	Introduction

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Sudden cardiac death is the leading cause of death in industrialized countries, with an estimated incidence of more than 300 000 cases per year in the United States.¹ Despite its frequency, the specific pathophysiological processes causing this catastrophic event remain unclear, in part because many of the episodes are unwitnessed. A clue to mechanism of onset has been provided by epidemiological reports of a significantly increased incidence of sudden cardiac death in the morning hours compared with other time periods.^{2 3} The morning peak, which has also been described for nonfatal myocardial infarction^{4 5} and transient myocardial ischemia,⁶ suggests that sudden cardiac death does not occur randomly but may be triggered by increases in adrenergic activity, systemic arterial pressure, heart rate, vascular tone, and coagulability that occur in the morning.⁷

Further insight into the mechanism of onset would be greatly advanced by identification of the exact timing and precipitants of the arrhythmia. Unfortunately, prior epidemiological studies of sudden cardiac death have been limited by their reliance on eyewitnesses to determine the timing of sudden cardiac death. Since the event often is unwitnessed and occurs without warning in an out-of-hospital setting, the data available from eyewitnesses are invariably incomplete. The implantable cardioverter/defibrillator (ICD) provides a new opportunity to firmly establish the timing of malignant ventricular tachyarrhythmias, the most common cause of sudden cardiac death. The effect of baseline characteristics on the timing of malignant arrhythmias can also be determined. For example, severe left ventricular dysfunction is associated with chronically increased sympathetic activity that may alter the circadian pattern of arrhythmia.

	Methods

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The study is based on data from 483 patients who had a Ventak PRx cardioverter/defibrillator (Cardiac Pacemaker, Inc) implanted between September 1990 and September 1993 and experienced ICD therapy on one or more occasions. Therapy history data were used to determine the time of occurrence of ventricular tachyarrhythmias. The Ventak PRx device provides retrievable data on date and time of pacing and shock therapy, cycle length of the RR interval preceding and following treatment, and the algorithm of the ICD response to each detected episode. The time assigned to the recorded events is referenced to time calibrations within the programs.

Informed consent was obtained from all patients in whom the defibrillators were implanted. The ICD was programmed at each investigational center on the basis of indications for the device and test results. All devices were activated on the patient's discharge from the operating suite. Most centers used initial antitachycardia pacing therapy if the patient had presented with a ventricular tachycardia that caused no or minimal hemodynamic instability before device implantation. In addition to the 483 patients in whom device therapy occurred, an additional 410 patients had devices implanted but did not have device therapy.

Tachyarrhythmias that occurred during testing of the defibrillator were excluded from the analyses. To avoid counting a single episode more than once, episodes separated by <1 minute were considered to be a single episode. Since rapid ventricular tachyarrhythmias are more unstable than less rapid rhythms and may have different substrates and precipitants, the episodes were grouped on the basis of cycle length. Tachyarrhythmias with an RR cycle length <240 ms (heart rate, >250 beats per minute [bpm]) were prospectively classified as rapid tachyarrhythmias⁸ ; those with RR cycle lengths 240 ms (heart rate, 250 bpm) were classified as less rapid tachyarrythmias.

To avoid possible biasing of the data by a few individuals having multiple discharges within a relatively short period of time, an additional analysis was performed such that multiple discharges occurring within a 1-hour period were counted only once. The findings of the study were not materially altered by this second analysis.

Statistical Analysis
² goodness-of-fit testing was used to determine whether there was a nonuniform distribution of timing in the 24-hour period. Event distributions among the various subgroups were submitted to statistical analysis. The results of the analysis are contained in the tables. Differences between subgroups were determined from log-linear models.⁹ Statistical comparisons were made for the period from 6 AM to noon versus the average of the other time points. All significance tests are two-sided. Values are presented as mean±SD.

	Results

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Baseline Characteristics
The baseline characteristics of the 483 subjects are presented in Table 1. The majority of patients were male (82.7%), and patient mean age was 63.5±12.7 years. Coronary artery disease or ischemic cardiomyopathy was the primary cardiac disease in 81.4% of the patients.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics

Rapid Tachyarrhythmias (>250 bpm, Cycle Length <240 ms)
A total of 1217 separate episodes of rapid tachyarrhythmia were identified. The timing of these episodes is shown in Figs 1 and 2 and Table 2. A circadian pattern was demonstrated in the overall population, with a 3-hour peak between 9 AM and noon (21.8% of total episodes) and a 3-hour minimum between 3 and 6 AM (4.1% of episodes) (P<.001). When the patients were divided according to age, sex, left ventricular ejection fraction, New York Heart Association (NYHA) class, and primary cardiac disease, all groups had a trough period between midnight and 6 AM. However, the patients <50 years of age had a more prominent primary peak between 6 AM and noon than did older patients. The patients with nonischemic cardiac disease had a more prominent morning peak than did patients with underlying coronary artery disease.

View larger version (16K): [in this window] [in a new window]   Figure 1. Bar graph showing time of day of episodes of rapid ventricular tachyarrhythmias (heart rate, >250 beats per minute; cycle length, <240 ms). A circadian pattern is present with a peak frequency between 9 AM and noon.

View larger version (18K): [in this window] [in a new window]   Figure 2. Bar graphs showing time of day of episodes of rapid ventricular tachyarrhythmias (heart rate, >250 beats per minute; cycle length, <240 ms) based on left ventricular ejection fraction (EF).

View this table: [in this window] [in a new window]   Table 2. Effect of Baseline Characteristics on Time of Onset of Rapid Ventricular Tachyarrhythmias (Heart Rate, >250 bpm; Cycle Length, <240 ms)

Less Rapid Tachyarrhythmias (250 bpm, Cycle Length 240 ms)
A total of 9266 separate episodes of less rapid tachyarrhythmia were identified. The timing of these episodes is shown in Figs 3 and 4 and Table 3. A circadian pattern was demonstrated in the overall population, with a 3-hour peak between 9 AM and noon (21.3% of total episodes) and a 3-hour nadir between 3 and 6 AM (6.8% of episodes) (P<.001).

View larger version (21K): [in this window] [in a new window]   Figure 3. Bar graph showing time of day of episodes of less rapid ventricular tachyarrhythmias (heart rate, 250 beats per minute; cycle length, 240 ms). A statistically significant (P<.001) circadian rhythm is present with an hourly peak between 9 and 10 AM, a 3-hour peak between 9 AM and noon (21.3% of total episodes), and a 3-hour minimum between 3 and 6 AM (6.8% of episodes).

View larger version (20K): [in this window] [in a new window]   Figure 4. Bar graphs showing time of day of episodes of slower ventricular tachyarrhythmias (heart rate, 250 beats per minute; cycle length, 240 ms) based on left ventricular ejection fraction (EF). A delayed peak frequency and more uniform 24-hour pattern are seen among patients with ejection fraction <20%.

View this table: [in this window] [in a new window]   Table 3. Effect of Baseline Characteristics on Time of Onset of Less Rapid Ventricular Tachyarrhythmia (Heart Rate, 250 bpm; Cycle Length, 240 ms)

The circadian pattern observed among patients with either low ejection fraction (<20%) (Fig 4) or NYHA class IV symptoms of congestive heart failure at time of implantation was significantly different from that of patients with higher ejection fraction or less severe heart failure. The pattern in the patients with poor function was characterized by an attenuated nighttime fall in frequency of arrhythmia and a blunted 6 AM–to–noon peak.

	Discussion

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These data obtained from 483 patients with ICDs demonstrate a prominent circadian rhythm in the frequency of ventricular tachyarrhythmias, with a peak frequency between 9 AM and noon and a nadir at night. This pattern, which was present for both rapid and less rapid ventricular tachyarrhythmias, is similar to that previously described for sudden cardiac death in epidemiological studies.^{2 3} A morning peak of device therapy was also observed in a recent analysis of 32 patients with ICDs.¹⁰ In this analysis by Lampert et al,¹⁰ episodes with a rate >240 bpm were excluded from analysis, as were patients with a diagnosis other than coronary artery disease.

The first large study to demonstrate a circadian pattern of sudden cardiac death was a retrospective analysis of mortality records.² In this population, the time of out-of-hospital cardiac deaths occurring 1 hour after onset of symptoms showed a significant circadian variation, with a nadir during the night, a primary peak in the late morning (from 9 to 11 AM), and a smaller secondary peak from 5 to 6 PM. These data were subject to the criticism that the exclusion of unwitnessed deaths, which were more likely to occur at night, created an artifactual circadian rhythm. A subsequent analysis of the Framingham Heart Study Population, which yielded similar findings, used methods to compensate for the problem of selective exclusion of unwitnessed deaths during the night.³ More recently, Levine and coworkers¹¹ identified a similar morning peak of sudden cardiac death among patients with out-of-hospital cardiac arrests seen by the City of Houston Emergency Medical Services during a 1-year period, but again, biases in case selection could not be excluded. Using documentation from semiautomated defibrillators in the Berlin, Germany, emergency care system, Arntz et al¹² found a primary peak of frequency of ventricular fibrillation between 6 AM and noon. Asystolic episodes were more evenly distributed throughout the day.

Because population-based studies have an inherent selection bias resulting from exclusion of unwitnessed deaths, data from other sources are needed to firmly establish the timing of sudden cardiac death. While not all sudden cardiac death is caused by ventricular tachyarrhythmias, such arrhythmias are the final cause of most cases, and their timing can help resolve the issue of the timing of sudden cardiac death. Devices such as the Ventak PRx offer an invaluable tool for timing of tachyarrhythmias because they provide uninterrupted 24-hour surveillance and precise time recording.

Prior Studies of Ventricular Arrhythmias
Most studies of ventricular ectopy indicate a prominent peak during daytime hours and a trough during the night.^{13 14} In 164 ambulatory patients studied over 3 consecutive days by 24-hour Holter monitoring, Canada et al¹³ showed that a circadian pattern of ventricular premature beats with a morning peak was consistently present for each day of observation. Twidale et al¹⁵ observed that the peak incidence of sustained, symptomatic ventricular tachycardic episodes in 68 patients occurred between 10 AM and noon.

Effect of Left Ventricular Function on Timing of Ventricular Arrhythmias
Gillis and coworkers¹⁶ reported that among patients with prior myocardial infarction, the circadian pattern of ventricular premature beats was absent in those with left ventricular dysfunction (ejection fraction <30%). Studies also indicate a reduced heart rate variability in patients with congestive heart failure compared with normal subjects.¹⁷ Patients with a prior history of congestive heart failure have been shown to have a less prominent primary morning peak of nonfatal myocardial infarction than those without congestive heart failure.¹⁸ This altered timing has been postulated to be due to persistent elevated levels of catecholamine activity during the night among individuals with poor left ventricular function.¹⁹ However, a recent analysis of the timing of sudden cardiac death by Moser et al²⁰ found a preserved morning peak of sudden cardiac death among patients with advanced heart failure, defined as NYHA class III or IV with a reduced ejection fraction (mean, 20±8%) at time of referral to their center. In the present study, patients with poor left ventricular systolic function had a preserved morning peak of rapid ventricular tachyarrhythmias, although the morning peak of less rapid tachyarrhythmias was attenuated. These data suggest that faster unstable ventricular tachycardic episodes may have different precipitants than do slower, potentially more stable ventricular tachycardia episodes. On subgroup analysis, younger patients (<50 years old) had a more prominent morning peak of rapid tachyarrhythmias than did older patients. Patients whose primary cardiac disease was not ischemic also had a more prominent morning peak in rapid tachyarrhythmia than those with coronary artery disease. These observations were not the result of a priori hypotheses and therefore require confirmation in other databases. Moser et al²⁰ found that the time of sudden death peaked in the morning for patients with both ischemic and nonischemic causes of heart failure.

Limitations
Since individual confirmation of each tachyarrhythmic episode was not performed in this study and electrograms of the arrhythmia leading to ICD discharge were not available from the device, we cannot exclude the possibility that some arrhythmias were supraventricular in origin. Supraventricular arrhythmias have been found to have an evening trough in frequency.²² In some cases, artifact may have been incorrectly diagnosed as a ventricular tachyarrhythmia. The true incidence of appropriate therapy with the device is difficult to estimate, although inappropriate discharges were estimated in one study to occur in 24% of cases.²² The future use of ICD devices with more specific recognition algorithms that provide electrograms of the rhythm leading to the device discharge, as well as devices that provide a record of arrhythmias not leading to discharge, will further advance knowledge of the timing and triggers of tachyarrhythmia.²³ The generalizability of the present findings can be questioned, because patients with implanted defibrillators are not representative of the majority of patients at risk for sudden cardiac death. However, the population with defibrillators has an incidence of atherosclerotic coronary artery disease similar to that of the general population that suffers sudden cardiac death.¹ Wake-time data were not available for this analysis. If the circadian patterns are related more to activity-inactivity cycles than to time of day, as previously reported for sudden cardiac death,²⁴ nonfatal myocardial infarction,²⁵ and transient myocardial ischemia,²⁶ adjustment for time of awakening would provide a more accurate assessment of the relation between onset of the arrhythmias and activity. Complete data on medication such as ß-blockers and antiarrhythmics were not available; hence, medication history was not used for subset analysis. ß-Blocking therapy would be expected to blunt circadian patterns.²⁷

Conclusions
Recognition of the morning peak in onset of ventricular tachyarrhythmias may provide an impetus to the design of drug regimens that emphasize pharmacological protection during the expected hours of higher risk. However, even complete elimination of the morning increase in sudden cardiac death by effective therapy would prevent only a small fraction of the total number of events.

Since primary prevention requires a broader approach, the major benefit of the recognition of the morning peak in ventricular tachyarrhythmia is the support it provides for the broader concept that sudden cardiac death at any time of the day is frequently triggered by activities of the subject.^{7 28 29} The advent of implantable cardioverter technology provides an opportunity to gain new understanding into the physical and emotional triggers of sudden cardiac death and to evaluate pharmacological and other modalities of treatment to interrupt the link between external stressors and catastrophic cardiac events. Several studies have demonstrated that both physical^{30 31} and psychological stress^{32 33} may lead to arrhythmia, but this link requires further exploration. By use of the case-crossover method recently developed by Maclure³⁴ and Mittleman et al,³⁵ it will be possible to investigate the relation between potential triggers and sudden cardiac death. A more complete understanding of circadian variation and triggering mechanisms should permit progress in the prevention of sudden cardiac death.

	Acknowledgments

 
We wish to thank the staff of Cardiac Pacemaker, Inc for their assistance in data collection and analysis and Kathy Carney for preparation of the manuscript.

	Footnotes

 
Dr Venditti is a consultant to Cardiac Pacemaker, Inc, manufacturer of the device described in this study.

Received December 5, 1994; revision received March 13, 1995; accepted March 19, 1995.

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