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(Circulation. 1997;96:1537-1541.)
© 1997 American Heart Association, Inc.

Articles

Circadian Variation of Paroxysmal Atrial Fibrillation

Takeshi Yamashita, MD; Yuji Murakawa, MD; Kazunori Sezaki, MD; Masashi Inoue, MD; Noriyuki Hayami, MD; Yutaka Shuzui, MD; ; Masao Omata, MD

From The Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.

Correspondence to Takeshi Yamashita, MD, The Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113, Japan. E-mail yamt-tky{at}umin.u-tokyo.ac.jp

	Abstract

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Background Circadian variation in the incidence of acute cardiovascular events is well known but has not been extensively investigated in paroxysmal atrial fibrillation, although the significance of this arrhythmia is growing in our society with the increasing number of aged people.

Methods and Results We detected 150 patients with paroxysmal atrial fibrillation in a drug-free state from among 25 500 consecutive Holter recordings. To determine whether the onset, maintenance, and termination of paroxysmal atrial fibrillation were random events, we analyzed the total recorded duration of arrhythmia and the incidence of and number of patients with the onset, maintenance, and termination of this arrhythmia as hourly data and as hourly probabilities. A prominent circadian rhythm of the total duration of atrial fibrillation, 90% of which was well explained by a single cosinusoidal function, was detected with a nadir around 11 AM. Because the onset of the arrhythmia had little or no circadian rhythm, this finding was due to a diurnal pattern of maintenance and termination, both of which were well expressed by a double-harmonic density function. Maintenance showed a trough at 11 AM, and termination showed a peak at the same time, leading to the nonuniform duration of single episodes of atrial fibrillation throughout the 24-hour day.

Conclusions Paroxysmal atrial fibrillation showed a unique circadian variation that differed from the well-known pattern for acute cardiovascular events, a point that should be kept in mind when antiarrhythmic therapy is evaluated. Identification of factors that regulate the circadian pattern of the maintenance and termination of paroxysmal atrial fibrillation may lead to better chronotherapy for preventing perpetuation of this arrhythmia.

Key Words: circadian rhythm • fibrillation • arrhythmia

	Introduction

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Many variables within biophysical systems show peaks and troughs in the course of a 24-hour period. The onset of acute cardiovascular events does not occur randomly but rather shows a characteristic diurnal pattern.¹ Circadian variation, with prominent clustering of events in the morning between 6 AM and noon, has been demonstrated for acute myocardial infarction, sudden cardiac death, thrombotic stroke, and transient myocardial ischemia.^{1 2 3 4 5 6 7 8 9 10 11} This pattern not only provides a clue to the identification of rhythmic processes triggering these events, such as changes in catecholamine levels,^{12 13 14 15 16} but also supports the importance of time-oriented therapy.^{1 2 3 4 5 6 7 8 9 10 11}

Atrial fibrillation is a common and frustrating arrhythmia for patients and physicians because it produces symptoms in some patients and is the most frequent cardiogenic cause of stroke.^{17 18} The diurnal distribution of paroxysmal atrial fibrillation, a precursor of chronic atrial fibrillation, has not been extensively investigated, and only limited data regarding its onset are available.^{19 20 21 22} Unlike the acute cardiovascular events, paroxysmal atrial fibrillation persists for a prolonged period and then eventually terminates. If circadian variation exists in its maintenance and termination, the efficacy of antiarrhythmic therapy might be attenuated or augmented by such diurnal variation, as is the case for the anticoagulant effect of intravenous heparin.²³ However, the efficacy of most antiarrhythmic drugs for paroxysmal atrial fibrillation has been investigated without attention being given to these considerations.^{24 25 26 27 28 29 30 31 32 33 34} In the present study, we examined (1) whether paroxysmal atrial fibrillation shows circadian variation, (2) whether the components of paroxysmal atrial fibrillation (onset, maintenance, and termination) each have different circadian rhythms, and (3) whether circadian variation of maintenance and termination, if any, influences the clinical course of this arrhythmia.

	Methods

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Subjects
Recordings of paroxysmal atrial fibrillation in patients in a drug-free state were detected by screening 25 500 consecutive Holter recordings obtained for clinical reasons in our hospital and branch hospitals from January 1991 through November 1996. Paroxysmal atrial fibrillation was defined as an arrhythmia of supraventricular origin associated with a grossly irregular ventricular rhythm and no visible P or flutter waves that lasted for >1 minute and did not persist for 24 hours. Screening identified 181 patients with paroxysmal atrial fibrillation on their Holter recordings. Among them, 31 patients with a diagnosis of ischemic heart disease, valvular heart disease, or sick sinus syndrome were excluded; the remaining 150 patients were assessed in the present study. They included 120 men and 30 women who were 61.6±12.8 years of age. Thirty-eight patients had essential hypertension.

Data Analysis
To evaluate the overall circadian variation of paroxysmal atrial fibrillation, we first determined the total recorded duration of atrial fibrillation, the sum of the duration of each episode in the 150 patients, over 1-hour intervals in the 150 Holter recordings. The overall circadian variation of an arrhythmia depends on the variation of its onset, maintenance, and termination, so the incidence of each of these parameters was also determined over 1-hour intervals. Maintenance of the arrhythmia was defined as atrial fibrillation that existed at N o'clock that was sustained for another 1 hour to (N+1) o'clock. Because the patients showed marked variability in the number of episodes (eg, one patient had 6 episodes in an hour), analysis was also performed on the basis of the number of patients. By definition, the onset of atrial fibrillation requires the existence of normal sinus rhythm beforehand, whereas maintenance and termination require prior onset of the arrhythmia. Accordingly, the frequencies of onset, maintenance, and termination were normalized, and probabilities were calculated for each 1-hour interval by use of the following equations: probability of onset at N o'clock equals the number of patients developing atrial fibrillation between N and (N+1) o'clock divided by the number of patients in sinus rhythm at N o'clock; probability of maintenance at N o'clock equals the number of patients with sustained atrial fibrillation from N to (N+1) o'clock divided by the number of patients with atrial fibrillation at N o'clock; and probability of termination at N o'clock equals the number of patients in whom atrial fibrillation terminated between N and (N+1) o'clock divided by the number of patients who had atrial fibrillation at N o'clock or developed it between N and (N+1) o'clock.

It should be noted that the probability of termination does not equal (1-probability of maintenance). If there is circadian variation in the maintenance and termination of paroxysmal atrial fibrillation, the duration of an episode should depend on the time of onset. To test this hypothesis, we compared the duration of paroxysmal atrial fibrillation among 12 subgroups obtained by dividing the time of onset into 2-hour intervals.

Statistical Analysis
We used a ² test for goodness of fit to determine whether there was a nonuniform distribution across the 24-hour period in (1) the total recorded duration of paroxysmal atrial fibrillation; (2) the incidence of onset, maintenance, and termination of the arrhythmia; and (3) the number of patients with onset, maintenance, and termination. A single- or double-harmonic model with the hour of the day as the independent variable was fitted to the hourly data on the recorded duration of atrial fibrillation and the data on the probabilities of onset, maintenance, and termination. The model was evaluated by a t test (two-tailed) for the estimated coefficients, by F test on the overall significance, and by R² statistics. The effect of the time of onset on the duration of arrhythmia was analyzed by ANOVA. Statistical significance was set at P<.05.

	Results

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In the 150 Holter recordings, a total of 407 episodes of paroxysmal atrial fibrillation were available for analysis. Among them, 118 episodes (29%) were accompanied by such symptoms as palpitation, chest discomfort, and shortness of breath. However, in 25 episodes, the time of onset of symptoms differed from the time of onset of arrhythmia by >30 minutes and instead corresponded to the time of rapid ventricular response during atrial fibrillation.

Overall Circadian Variation of Paroxysmal Atrial Fibrillation
If the onset, maintenance, and termination of paroxysmal atrial fibrillation occurred randomly throughout the day, the total recorded duration of atrial fibrillation in the Holter monitorings would have been uniformly distributed throughout the recorded period. However, the total recorded duration of fibrillation did not show a uniform distribution (P<.001; Fig 1) but increased during the night, with a peak at about midnight, and decreased in the morning, with a nadir at about 11. This variation implied that the chance of the arrhythmia existing was not random. The total recorded duration of paroxysmal atrial fibrillation fitted a single-harmonic curve [f(t)=2110+817 cos (t-0.267), where t is the time of day in hours; r=.947, P<.01 by F test, and each coefficient was significant by t test]. It was noteworthy that 90% of the observed variation was explained by a single cosinusoidal density function. Moreover, this circadian variation did not correspond to that reported previously for onset of paroxysmal atrial fibrillation,^{19 20 21 22} suggesting that maintenance or termination of the arrhythmia had a different circadian variation from its onset.

View larger version (87K): [in this window] [in a new window]   Figure 1. Hourly total duration of paroxysmal atrial fibrillation accumulated in the total 150 patients. A single-harmonic fit is represented by curved line. A prominent circadian rhythm is present, with a peak at midnight and a nadir at 11 AM.

Circadian Variation of Onset, Maintenance, and Termination
The incidence of onset was not uniformly distributed throughout the 24-hour period (P<.05; Fig 2A) because it showed a double peak with increases after lunch and at midnight. In contrast, the number of patients developing the arrhythmia at each time showed a uniform distribution (P=.47). Also, the probability of onset could not be fitted to a single- or double-harmonic curve [eg, double harmonic: f(t)=0.098+0.016 cos (t+0.995)+0.012 cos (2t+0.81); r=.57, P=.18 by F test; Fig 2A]. These findings indicated that the onset of paroxysmal atrial fibrillation did not show cosinusoidal circadian variation like the total duration of the arrhythmia, although the incidence had a weak double-peaked diurnal rhythm.

View larger version (57K): [in this window] [in a new window]   Figure 2. Hourly frequency of paroxysmal atrial fibrillation episodes and hourly number of patients with episodes (left) and hourly probability (right; A, onset; B, maintenance; and C, termination). The left panels reveal that all parameters except the number of patients with onset showed a significant nonuniform distribution. In the right panels, the probabilities of maintenance and termination show a good fit to double-harmonic curves.

In contrast to the onset, we found novel circadian variations of both the maintenance and termination of paroxysmal atrial fibrillation. The incidence of maintenance of the arrhythmia for 1 hour was equal to the number of patients with sustaining arrhythmia, and the incidence showed significant nonuniformity throughout the 24-hour period (P<.001; Fig 2B). It showed a sharp decline in the morning to a nadir about 10 AM and then a gradual increase after lunch. Because maintenance requires the prior onset of arrhythmia, the data were normalized. The normalized probability of maintenance also showed a nadir at 10 AM and fitted well to a double-harmonic curve with acrophases at 3 to 4 AM and 5 to 6 PM [f(t)=0.81+0.091 cos (t+0.29)-0.064 cos (2t+1.05); r=.74, P<.05 by F test, and all coefficients were significant by t test; Fig 2B]. There was a 47% improvement in R² compared with the single-harmonic fitting of the same data.

The maintenance and termination of an arrhythmia are naturally related to each other. In the present study, however, maintenance of atrial fibrillation was defined as an episode lasting for >1 hour and thus was not directly related to the incidence of termination, including the termination of brief episodes persisting for <1 hour. Thus, we also analyzed the incidence and number of patients with termination. Both parameters were nonuniform and showed a peak from 9 AM to 1 PM (P<.001 for the incidence and P<.05 for the number of patients; Fig 2C), with an inverse trend to that of maintenance as expected. The discordance between the peaks for incidence and the number of patients with termination resulted because some patients had many episodes of atrial fibrillation occurring at 1 PM (the most likely time of occurrence) and terminating rapidly. As with the maintenance of atrial fibrillation, termination requires prior onset of the arrhythmia, so the data were normalized. The probability of termination also fitted well to a double-harmonic curve with acrophases at 11 to 12 AM and 10 to 11 PM [f(t)=0.295-0.129 cos (t-0.019)+0.081 cos (2t+0.58); r=.865, P<.05 by F test, and all coefficients were significant by t test; Fig 2C]. There was a 39% improvement in R² compared with the single-harmonic fit. These findings indicated that the maintenance and termination of atrial fibrillation showed different and more marked cosinusoidal circadian variations compared with the onset.

Duration of Paroxysmal Atrial Fibrillation in Relation to the Time of Onset
To examine the effects of the circadian variation of maintenance and termination on the course of atrial fibrillation, we analyzed the duration of paroxysmal atrial fibrillation in relation to the time of onset (Fig 3). When all episodes were included, they tended to show a nonuniform distribution throughout 24 hours, but the difference did not reach statistical significance (P=.067). Because brief episodes have little significance compared with longer ones, we also analyzed the data for episodes >2 minutes (227 episodes) and for episodes >10 minutes (151 episodes). These analyses revealed that the duration of fibrillation varied significantly according to the time of onset when the arrhythmia lasted for >2 minutes or for >10 minutes (both P<.05).

View larger version (26K): [in this window] [in a new window]   Figure 3. Differences in the duration of paroxysmal atrial fibrillation (Paf) depending on the time of onset. Data are expressed as mean±SE. indicates the duration of all episodes; , duration of episodes lasting >2 minutes; and , duration of episodes lasting >10 minutes.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The present study clearly demonstrated circadian periodicity of the maintenance and termination of paroxysmal atrial fibrillation. The circadian variation of the maintenance, which had a inverse relationship to that of termination, was unique in being completely different from the well-known circadian pattern of acute cardiovascular events. These circadian variations led to differences in the duration of the arrhythmia, depending on the time of onset.

In contrast to the extensively investigated circadian variation of acute cardiovascular events (myocardial ischemia/infarction, sudden death, and stroke), little attention has been paid to paroxysmal atrial fibrillation. Although atrial fibrillation is not fatal in itself, it is a common arrhythmia that increases in incidence with age and places the patient at a high risk of having a stroke.^{17 18} Therefore, its clinical significance is growing in societies with a rapidly increasing elderly population like Japan. However, the pathophysiology of paroxysmal atrial fibrillation remains incompletely understood.

In the past, paroxysmal atrial fibrillation has been a difficult disorder to investigate because of its intermittent and sometimes asymptomatic nature. Even the limited data previously published regarding the circadian variation of its onset are controversial.^{19 20 21 22} One study found no circadian variation,²² whereas another found a double peak in the incidence of fibrillation onset.^{20 21} A common weakness of these studies is that they addressed only the variation of onset of symptomatic episodes causing admission to the emergency room, attendance of a mobile coronary care unit, or telephone transmission of ECGs.^{19 20 21 22} Therefore, they have the inherent limitations that the data described only symptomatic episodes and based the time of onset on the patient's symptoms rather than the actual onset of arrhythmia. These problems might have introduced some uncertainties into the data.

Our data, however, demonstrated that paroxysmal atrial fibrillation actually shows circadian variation, 90% of which was explained by a single cosinusoidal density function as expressed by its total recorded duration. This is a surprisingly high coefficient compared with that for acute cardiovascular events (eg, acute myocardial infarction: R²=.53 for single-harmonic regression and R²=.58 for double-harmonic regression).³ We found no significant nonuniform distribution in the number of patients with onset of the arrhythmia and no cosinusoidal variation in the probability of onset, but we did find only a nonuniform distribution of its incidence, similar to previous reports.^{19 20 21 22} These contradictory results suggested that circadian variation of the arrhythmia was regulated mainly by its maintenance and termination.

In contrast to the onset of paroxysmal atrial fibrillation, there was a clear cosinusoidal circadian variation of its maintenance and termination. The diurnal variation of maintenance differed from (or was inverse to) that of acute cardiovascular events (morning increase), whereas the variation of termination mimicked the pattern for acute cardiovascular events. These findings suggest two possibilities: (1) physiological processes totally different from those triggering acute cardiovascular events underlie the maintenance of paroxysmal atrial fibrillation, and (2) physiological processes that trigger acute cardiac events facilitate the termination of atrial fibrillation. There are numerous exogenous and endogenous daily rhythms for which the relationship to the peak of acute cardiovascular events requires further study. The exogenous variables are physical and mental stress after wakening or habitual morning activities.¹ Among the endogenous variables, blood pressure, heart rate, plasma epinephrine, plasma cortisol level, platelet aggregability, and fibrinolytic activity have been reported to be important.^{12 13 14 15 16} Although these variables, alone or in combination, may account for part of the circadian rhythm of acute cardiovascular events, some inconsistencies remain to be resolved. Similarly, the physiological processes underlying the maintenance and termination of atrial fibrillation remain unknown. One possible mechanism is that vagal tone increases at night and facilitates maintenance of the arrhythmia because experimental atrial fibrillation can be induced and maintained through shortening of the atrial refractory period by administration of acetylcholine.³⁵ However, the circadian variation of heart rate variability representing vagal tones does not exactly correspond to the diurnal pattern of arrhythmia maintenance clarified in the present study.^{36 37} The variation of termination was similar to that of strokes, which is interesting because thrombus formation during atrial fibrillation is one of the important causes of stroke.^{10 12 38}

Clinically, it is important that atrial fibrillation did not persist uniformly throughout the day and that its spontaneous duration varied according to the time of onset. This raises two points with regard to antiarrhythmic therapy. The first concerns interpretation of the results of clinical trials. Numerous studies have assessed drugs for terminating atrial fibrillation, and the efficacy has varied markedly between reports. Among class Ia drugs, procainamide has been reported to be effective in 9% to 65% of patients.^{32 33} Among class Ic drugs, flecainide was reported to terminate the arrhythmia in 22% to 92% of patients.^{33 34} These differences were due to patient selection or arrhythmia duration but may have arisen in part from circadian variability of the spontaneous course of paroxysmal atrial fibrillation in relation to the time of drug administration. Thus, future clinical trials involving patients with recent-onset paroxysmal atrial fibrillation should take these considerations into account. The second point concerns the timing of antiarrhythmic therapy. Treatment for paroxysmal atrial fibrillation can be aimed at prevention of the onset, prevention of long-term persistence after onset, and termination of the arrhythmia. The present study suggested that these three objectives would require differently timed therapy. The first objective (prevention of onset) would require a high drug level throughout the day with a peak after lunch; the second (prevention of maintenance) would need higher drug concentrations at night; and the third (termination) would be met best with lower drug concentrations around noon. However, these clinical considerations are still hypothetical; therefore, the diurnal variation of drug efficacy needs further exploration as the effects of intravenous heparin.²³

The present study has several limitations. First, patients were selected on the basis of the chance recording of episodes of atrial fibrillation during Holter monitoring, and this may have resulted in some bias. However, any prospective study of paroxysmal atrial fibrillation is hampered by the difficulty of exactly documenting the onset and spontaneous termination of arrhythmic episodes because the relatively long periods between recurrences generally precludes the use of continuous ambulatory recording. Second, the circadian variation observed in the present study is best referred to as a " population rhythm," a problem that has been encountered but not solved by previous investigators. Although limited for these reasons, our results provided new perspective on paroxysmal atrial fibrillation and some clues to the timing of antiarrhythmic therapy.

Received December 17, 1996; revision received March 12, 1997; accepted March 30, 1997.

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