The autonomic nervous system as a piece of the mechanistic puzzle linking sleep and atrial fibrillation

autonomic nervous system

The autonomic nervous system is well known to play an integral role in the development and progression of atrial fibrillation (AF) as well as in sleep and circadian rhythm pathophysiology [1]. More than a century ago, vagal stimulation was found to be an adequate method for obtaining AF [2]. Following the pioneering clinical observations by Coumel et al. [3] in the 1970s, alteration of autonomic tone assessed by heart rate variability (HRV) immediately before the onset of paroxysmal AF (PAF) has been described [4].
Obstructive sleep apnea (OSA) is the most common sleep disorder observed in about 34% and 17% of middle-aged men and women [5]. It is well known that OSA and AF share common risk factors such as obesity, increasing age, male sex, hypertension, and heart failure. Screening for the often underdiagnosed OSA in patients with recurrent AF after either cardioversion or ablation is recommended by the American Heart Association [5]. However, even though OSA and AF often coexist, their relationship has been frequently discussed, with several potential underlying mechanisms being suggested [1]. Chronic recurrence of intermittent hypoxia with acute alteration in intrathoracic pressure may lead to long-term atrial remodeling altering atrial electrophysiology [5]. Long pauses and bradycardia are common in patients with OSA, and those episodes might be related to increased parasympathetic activity [1].
Vagal effects of shortening the action potential and refractory period are further recognized to be nonhomogeneous in the atrial wall. At the same time, sympathetic activation in patients with OSA is well known. This is important since experimental [6] and first clinical evidence [7] suggests that autonomic coactivation proceeds the onset of AF. These effects of the sympathetic and parasympathetic autonomic nervous system potentially resulting in a predisposition to AF may be assessed by analysis of HRV [4] and autonomic bedside testing [7,8].
In this issue of JICE, Mohammadieh et al. [9] present first evidence on cardiac autonomic function measured by HRV in PAF patients with and without OSA. A total of 101 patients with a history of AF were enrolled in this prospective dual-center study and underwent in-laboratory polysomnography including Holter analysis. Overall, HRV parameters did not differ between PAF patients with and without OSA. As indicated by frequency-domain analysis of HRV, during non-rapid eye movement sleep, PAF patients with OSA showed increased cardiac parasympathetic activity (increased high-frequency power) and reduced cardiac sympathetic activity (reduced low-frequency power and ratio of low-/high-frequency power) compared to patients without OSA. There were no differences during rapid eye movement sleep. Interestingly, Mohammadieh et al. found an increase in parasympathetic activity in PAF patients with OSA, suggesting vagal predominance as the main contributor to AF induction in this population. Although puzzling, these findings highlight the importance of the autonomic nervous system linking sleep and atrial fibrillation.
We congratulate the authors on the first study of HRV in PAF patients with and without OSA providing interesting findings on cardiac autonomic function in this population. The authors present relevant hypothesis-generating data. The present investigations also highlight some challenges which are related to such study designs and the still somehow limited methods to evaluate the activity of the autonomic nervous system in clinical scenarios.   In the past, the autonomic mechanisms preceding the onset of AF have been widely studied by HRV in various patient cohorts leading to partly diverging results (Table 1). Whereas some groups described predominance of either the sympathetic or parasympathetic nervous system, more recently, others found evidence for autonomic coactivation linked to heart rate dynamics in patients with PAF [7]. In a greater detail, observation of selected time points before AF onset indicated consecutive autonomic changes, with an initial increase in sympathetic followed by parasympathetic activity. Classification of AF episodes into those occurring at day-or nighttime has demonstrated that especially nocturnal AF might be associated with an increase in parasympathetic activity without any change in sympathetic tone ( Table 1). In the here presented work [9], besides the noted parasympathetic predominance, reduced sympathetic activity during non-rapid eye movement sleep has been reported in patients with OSA compared to those without. This observation might be explained and further reinforced by a ceiling effect driven by a higher intrinsic sympathetic tone based on recurrent apneic events in this population.
Despite the here introduced promising approach providing for the first time insights into cardiac autonomic function by HRV analysis in patients with PAF and OSA, certain methodological challenges should be kept in mind. First, HRV reflects "global" cardiac autonomic control by quantifying sinus nodal activity/ control. To which extent these data are related to "local" intracardiac neural control on the atrial and ventricular level is not well understood. Furthermore, considering inclusion of unselected patients, sinus node dysfunction, which is often associated with AF, might have been a confounder in the here presented study. Despite recent developments in terms of additional nonlinear analyses, HRV remains a scientifically well studied but indirect measure of the cardiac autonomic nervous system, still leaving some questions unanswered.
Time-and frequency-domain HRV has recently demonstrated reliability across stable stage-2, slow-wave, and rapid eye movement sleep, while still remaining reliable during disrupted sleep [10]. In the here presented study, HRV analysis was performed during "steady-state" sinus rhythm excluding all OSA events and the immediate post-apneic period in order to compare chronic, but not acute, autonomic changes. However, these excluded time periods might give additional mechanistic insights into the underlying autonomic activation potentially explaining the oftentimes observed coexistence of AF and OSA.
In line with previous work suggesting OSA as an independent risk factor for AF [1], Mohammadieh et al. describe that PAF patients with severe OSA (apnea hypopnea index ≥ 30/h) had more AF beats than those without severe OSA as well as a higher AF burden than patients with moderate or without OSA. This observation confirms prior analyses indicating a strong association between OSA and AF and therefore suggesting a combined treatment of both comorbidities. Patients with OSA average deviation of the plot data away from the axis perpendicular to the long axis (axis 2); SD/RR, variation index; VLF, very low frequency have a 1.7-fold increased risk of recurrent AF after catheter ablation compared to those without, and effective treatment of OSA using continuous positive airway pressure has been correlated with prolonged maintenance of sinus rhythm, with a 70% risk reduction of recurrent AF after catheter ablation [11]. Taken together, considering the present data, additional mechanistic studies as well as prospectively, randomized controlled trials are warranted to understand therapeutical options of interference with the autonomic nervous system as a fascinating piece of the mechanistic puzzle linking sleep and AF.
Funding Open Access funding enabled and organized by Projekt DEAL.

Conflict of interest
The authors declare no competing interests.
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