Nocturnal Peak in Atrial Tachyarrhythmia Occurrence
Nocturnal Peak in Atrial Tachyarrhythmia Occurrence
In patients with rare arrhythmias (<4 AT/AF episodes over the follow-up period), the events are distributed randomly over a 24-hour period. However, a nocturnal peak emerges in patients with more frequent AT/AF episodes and grows as a function of the total number of arrhythmias. This strong relationship between the nighttime peak of AT/AF initiation and total arrhythmia burden is present in both absolute and patient-normalized units. It is observed in patients of different age groups, genders, irrespective of the level of LVEF, presence of coronary artery disease and pharmacological treatment (including beta-blockers), as well as in the subsets of AT/AF of different duration.
The relationship between a nocturnal pattern of AT/AF and total arrhythmia burden was confirmed by the comparative analysis of the subgroups of patients with <4, 4–9 and 10–50 arrhythmias (Fig. 2A). Because the sample size of all 3 subgroups was similar (69–72 patients), the absence of a circadian pattern of arrhythmia initiation in those with <4 events, in contrast to those with 4–9 and 10–50 arrhythmias, could not be explained by the smaller sample size. In addition, the strong relationship between circadian pattern and the total arrhythmia burden was confirmed by the analysis of individual patient data (Fig. 5).
To explain the differences in the circadian patterns of AT/AF reported in different populations, Gillis et al. have suggested that the 24-hour distributions are modulated by the disease burden (i.e., the frequency and duration of arrhythmias as well as the presence of structural heart disease). Our analysis supports and further extends this notion by showing that the most important determinant of the circadian pattern of AT/AF initiation (among all studied clinical and demographic characteristics) is the total frequency of arrhythmic events.
Interestingly, the nocturnal pattern of AT/AF events has been observed not only in humans, but also in nonprimate mammals. In particular, a similar pattern of AT/AF (with a 12-hour shift due to the nocturnal activity pattern in mice) has been also reported in a genetic mouse model of heart failure and arrhythmias. This suggests that the predominance of AT/AF events during the period of rest (inactivity) involves the physiological mechanisms that have been evolutionally "conserved" and independent of species specifics.
A major role of the ANS in the initiation of AT/AF has long been recognized and supported by a number of experimental and clinical studies. However, despite its long history, the specific contributions of vagal and sympathetic ANS effects to the arrhythmogenesis, as well as the accuracy of estimating those effects in a clinical setting, are still being debated. Coumel has proposed to classify all AT/AF episodes as "vagal" or "sympathetic," depending on the relative balance between the 2 systems. However, a recent large-scale clinical study, which included 5,333 patients with AF from 35 European countries, has demonstrated that a majority of arrhythmic events cannot be classified as purely sympathetic or vagal; only 6% and 15% had vagal and adrenergic trigger patterns, respectively. Nevertheless, this large-scale multicenter investigation has confirmed the most important clinical implication of Coumel's theory that β-blockers applied in patients with the vagal type of AT/AF may promote arrhythmogenesis and increase the frequency of arrhythmic events.
A link between morbid obesity and obstructive sleep apnea has been well documented, although the exact physiological mechanisms remain debated. In our study, however, the nocturnal pattern of AT/AF was similar in all patients, regardless of their BMI. This does not support the notion that obstructive sleep apnea is a primary factor determining a nocturnal pattern of arrhythmias, although we cannot rule out the potential role of central apnea, which is highly prevalent in this population. Further research is necessary to delineate the impact of various forms of sleep-disordered breathing (SDB) on the nocturnal occurrence of arrhythmias. The central and obstructive SDB have been frequently observed in patients with nocturnal, paroxysmal, and chronic atrial fibrillation, although the temporal and causal links between the disordered breathing and arrhythmias remain to be determined. SDB is common in patients with low LVEF (<40%), who also have chronically elevated sympathetic and limited vagal activity.
The potential role of short-term surges of parasympathetic activity that may occur during nighttime also requires further investigation.
Discussion
In patients with rare arrhythmias (<4 AT/AF episodes over the follow-up period), the events are distributed randomly over a 24-hour period. However, a nocturnal peak emerges in patients with more frequent AT/AF episodes and grows as a function of the total number of arrhythmias. This strong relationship between the nighttime peak of AT/AF initiation and total arrhythmia burden is present in both absolute and patient-normalized units. It is observed in patients of different age groups, genders, irrespective of the level of LVEF, presence of coronary artery disease and pharmacological treatment (including beta-blockers), as well as in the subsets of AT/AF of different duration.
The relationship between a nocturnal pattern of AT/AF and total arrhythmia burden was confirmed by the comparative analysis of the subgroups of patients with <4, 4–9 and 10–50 arrhythmias (Fig. 2A). Because the sample size of all 3 subgroups was similar (69–72 patients), the absence of a circadian pattern of arrhythmia initiation in those with <4 events, in contrast to those with 4–9 and 10–50 arrhythmias, could not be explained by the smaller sample size. In addition, the strong relationship between circadian pattern and the total arrhythmia burden was confirmed by the analysis of individual patient data (Fig. 5).
Previous Studies
To explain the differences in the circadian patterns of AT/AF reported in different populations, Gillis et al. have suggested that the 24-hour distributions are modulated by the disease burden (i.e., the frequency and duration of arrhythmias as well as the presence of structural heart disease). Our analysis supports and further extends this notion by showing that the most important determinant of the circadian pattern of AT/AF initiation (among all studied clinical and demographic characteristics) is the total frequency of arrhythmic events.
Interestingly, the nocturnal pattern of AT/AF events has been observed not only in humans, but also in nonprimate mammals. In particular, a similar pattern of AT/AF (with a 12-hour shift due to the nocturnal activity pattern in mice) has been also reported in a genetic mouse model of heart failure and arrhythmias. This suggests that the predominance of AT/AF events during the period of rest (inactivity) involves the physiological mechanisms that have been evolutionally "conserved" and independent of species specifics.
Autonomic Nervous System Activity and Circadian Patterns of the AT/AF Initiation
A major role of the ANS in the initiation of AT/AF has long been recognized and supported by a number of experimental and clinical studies. However, despite its long history, the specific contributions of vagal and sympathetic ANS effects to the arrhythmogenesis, as well as the accuracy of estimating those effects in a clinical setting, are still being debated. Coumel has proposed to classify all AT/AF episodes as "vagal" or "sympathetic," depending on the relative balance between the 2 systems. However, a recent large-scale clinical study, which included 5,333 patients with AF from 35 European countries, has demonstrated that a majority of arrhythmic events cannot be classified as purely sympathetic or vagal; only 6% and 15% had vagal and adrenergic trigger patterns, respectively. Nevertheless, this large-scale multicenter investigation has confirmed the most important clinical implication of Coumel's theory that β-blockers applied in patients with the vagal type of AT/AF may promote arrhythmogenesis and increase the frequency of arrhythmic events.
Body Mass Index and Sleep-disordered Breathing
A link between morbid obesity and obstructive sleep apnea has been well documented, although the exact physiological mechanisms remain debated. In our study, however, the nocturnal pattern of AT/AF was similar in all patients, regardless of their BMI. This does not support the notion that obstructive sleep apnea is a primary factor determining a nocturnal pattern of arrhythmias, although we cannot rule out the potential role of central apnea, which is highly prevalent in this population. Further research is necessary to delineate the impact of various forms of sleep-disordered breathing (SDB) on the nocturnal occurrence of arrhythmias. The central and obstructive SDB have been frequently observed in patients with nocturnal, paroxysmal, and chronic atrial fibrillation, although the temporal and causal links between the disordered breathing and arrhythmias remain to be determined. SDB is common in patients with low LVEF (<40%), who also have chronically elevated sympathetic and limited vagal activity.
The potential role of short-term surges of parasympathetic activity that may occur during nighttime also requires further investigation.
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