Mechanism and management of atrial fibrillation in the patients with obstructive sleep apnea

Abstract Obstructive sleep apnea (OSA) is a highly prevalent disorder in patients with atrial fibrillation (AF). Although there has been an increase in the incidence of AF due to the aging population, it has been reported that OSA is still underdiagnosed because many patients remain asymptomatic or unaware of the symptoms associated with OSA, such as daytime sleepiness. Untreated OSA reduces the effectiveness of AF treatment, regardless of pharmacological or non‐pharmacological modes of therapy, such as catheter ablation. Experimental and clinical studies have shown that OSA pathophysiology is multifactorial, comprising of hypoxemia, hypercapnia, autonomic dysfunction, negative intrathoracic pressure changes, and arousals of OSA, and lead to AF. Both the acute and long‐term effects of obstructive apnea episodes are involved in the development of an arrhythmogenic substrate of AF. Undiagnosed OSA causes underutilized opportunities for more effective AF management. Therefore, it is important to screen for OSA in all patients being considered for rhythm control therapy. However, regardless of the growing evidence of the negative prognostic impact of OSA, there is a lack of awareness regarding this connection not only among patients but also among cardiologists and arrhythmia specialists. There is a barrier to performing a systemic screening for OSA in clinical practice. Therefore, it is important to establish a comprehensive OSA care team for the efficient diagnosis and treatment of OSA. This review provides the current understanding of OSA and its relationship to AF and the importance of the diagnosis and management of OSA in AF.


| INTRODUC TI ON
The prevalence of atrial fibrillation (AF) has increased with the aging population in Japan. 1 Hypertension, diabetes mellitus, heart failure, coronary artery disease, and chronic kidney disease are reported to be independent risk factors for the development of AF. 2,3 In a previous study, the prevalence of AF in patients with obstructive sleep apnea (OSA) was 4.8%, which was higher than that in the control group (1.9%). 4 The increased incidence of OSA was also related to the increase in new-onset AF. In contrast, the prevalence of OSA in patients with AF is reported to be 50-80%. [5][6][7] Notably, a cohort of patients who underwent catheter ablation for AF showed a high prevalence of sleep apnea. 8 Coexisting OSA reduced the maintenance rate of sinus rhythm after catheter ablation and electrical cardioversion in patients with AF. [9][10][11] In clinical practice, it is essential to identify the presence of concomitant OSA for the effective management of AF, in order to prevent its recurrence and associated comorbidities. Moreover, the number of catheter ablations performed to treat AF has been increasing over the last two decades 12,13 because of the advancement of 3D mapping systems and ablation catheter | 975 IWASAKI technology, including balloon ablation. International guidelines recommend catheter ablation for achieving rhythm control in the management of drug-refractory symptomatic AF. 2,13,14 Appropriate periprocedural management with a correct understanding of OSA is important to determine the long-term efficacy and safety of catheter ablation for AF. The present study reviews the current understanding of OSA and its relationship to AF and the importance of diagnosis and management of OSA as a part of the comprehensive treatment for patients with AF.

| PATHOPHYS I OLOGY OF AF IN OSA
OSA causes hypoxemia, hypercapnia, autonomic dysfunction, arousal, and substantial negative intrathoracic pressure changes ( Figure 1). The pathophysiology involved in OSA elicits inflammation, endothelial dysfunction, coagulation imbalance, hemodynamic alterations, electrical/structural remodeling of the atria/ventricle, and autonomic dysregulation. These factors are associated with AF initiation and perpetuation. Therefore, the pathophysiology of OSA is multifactorial and many unresolved complex mechanisms are involved in the development of AF, thereby causing both acute and long-term effects on its arrhythmogenic substrates.
The acute effects of OSA are mainly attributed to electrical remodeling (electrophysiological changes), and the long-term effects of OSA cause both electrical and structural remodeling. Several possible mechanisms associated with the electrical and structural remodeling leading to the occurrence of AF have been reported.
During upper airway obstruction, negative intrathoracic pressure becomes prominent, reaching pressures of less than −50 mm Hg. 15 Esophageal pressure during catheter ablation of AF with deep conscious sedation was −40 mm Hg without airway management. 16 Fluctuation of the negative intrathoracic pressure causes electrophysiological alterations through various mechanisms. Rostral fluid shift in the supine position also exacerbates upper airway obstruction. 17,18 Deeply negative intrathoracic pressure increases venous return, impairs left ventricular (LV) filling, and diminishes stroke volume. The redistribution of the circulating blood volume to the intrathoracic cavity causes dilatation of the atria. Acute atrial stretch causes shortening of the effective refractory period along with slowing of the conduction velocity across the pulmonary vein (PV)left atrium (LA) junction. 19 Moreover, strongly negative intrathoracic pressure activates intrathoracic baroreceptors, inducing autonomic reflex responses and causing refractory period shortening that also promotes AF. An animal model of sleep apnea showed effective refractory period shortening with increased AF inducibility during obstructive apnea. 20,21 In an obstructive apnea canine model, AF was induced reproducibly by turning off the respirator during end expiration for 2 min. The AF inducibility could be eliminated by ganglionated plexi ablation or pharmacological autonomic blockade. 22 Negative tracheal pressure in a pig model increased AF inducibility and shortened the atrial refractory period, which were prevented by the administration of atropine or vagotomy. 21 Atrial tachyarrhythmia could be induced by atrial burst pacing in obstructive apnea model using Zucker obese rat. Pretreatment with atropine and propranolol prevented AF induction in approximately 50% of rats. 20 Therefore, F I G U R E 1 Suggested mechanisms linking OSA pathophysiology and arrhythmogenic substrate of AF. Multiple and complex OSA pathophysiologies develop both acute and long-term arrhythmogenic substrates, leading to AF trigger and perpetuation. APD, action potential duration; Cx43, connexin-43; ERP, effective refractory period; LA, left atrium; LV, left ventricle; OSA, obstructive sleep apnea; PV, pulmonary vein; RA, right atrium. autonomic nervous activity, at least in part, plays a role in AF inducibility in the acute phase of OSA. While acute hypoxia might contribute to AF progression, hypoxia alone failed to induce AF in the rat model. An experimental study using rats with obstructive apnea showed repetitive premature atrial contractions during obstructive apnea with deep negative esophageal pressure. 23 It has been reported that AF is initiated during or just after the obstructive apnea episode, 24 implying acute episodes of OSA acutely enhance the triggering of premature atrial contractions, which can initiate AF.
Structural remodeling due to the long-term effects of OSA plays a crucial role in AF promotion. Substantial negative intrathoracic pressure also contributes to structural remodelling. Transmural pressure is one of the suggested mechanisms of cardiac remodelling in patients with OSA. Even in patients with normal systolic blood pressure (120 mm Hg), OSA with deep negative intrathoracic pressure of −60 mm Hg increased the transmural pressure to 180 mm Hg during the night, which is similar to the etiology in hypertensive patients ( Figure 2). Sustained repetitive episodes of OSA may elicit not only atrial remodeling but also ventricular remodeling (LV diastolic dysfunction and hypertrophy) through increased transmural pressure. 25,26 In addition, hypoxia-hypercapnia induces sympathetic activation, systemic inflammation, and oxidative stress, which cause LV remodeling. 26 Long-term OSA causes atrial fibrosis and reduced connexin-43 protein expression with the redistribution of lateral cell margins.
Optical mapping image analysis showed a reduction in the conduction velocity of the atrium in a long-term OSA rat model. 27 Indeed, a clinical study revealed an advanced LA low-voltage zone with extra-PV foci initiating AF in patients with AF and OSA. 28 A recent experimental study with a chronic rat OSA model showed transiently increased atrial exudative stress, which could recover within 24 h.
However, 3 weeks of intermittent negative upper airway pressure induced AF promotion by transesophageal atrial burst pacing and caused structural remodeling, including atrial fibrosis, cardiomyocyte hypertrophy, interstitial expansion, and reduced connexin-43 expressions. These observations were confirmed even in mild-to-moderate OSA with high night-to-night variability. 29 Animal studies have shown that chronic intermittent hypoxia increases atrial fibrosis, shortens the refractory period, and increases AF inducibility. 30 Hypercapnia also contributes to AF vulnerability via slowing of the conduction velocity. 31 Clinical studies have shown that nocturnal hypoxemia and pulse rate variability are independent predictors of AF. 32 The progressive nature of atrial structural remodeling along with electrophysiological remodeling associated with repetitive OSA episodes every night promotes AF in the absence of appropriate therapy.  37 The STOP-Bang questionnaire, consisting of eight questions, is often used to screen for OSA ( Table 1). The sensitivity and specificity of STOP-Bang for the diagnosis of moderate-to-severe OSA were 92.9% and 43.0%, respectively. 34    B. Polysomnography (PSG) or out-of-center sleep testing (OCST) demonstrates Five or more predominantly obstructive respiratory events (obstructive apnea, hypopnea, or respiratory effort-related arousals) per hour of sleep during PSG or per hour of monitoring (OCST).

| E VALUATI ON AND D IAG NOS IS OF OSA SYNDROME IN THE PATIENTS WITH AF
C. PSG or OCST demonstrates Fifteen or more predominantly obstructive respiratory events (apneas, hypopneas, or respiratory effort-related arousals) per hour of sleep during PSG or per hour of monitoring (OCST).

| During catheter ablation procedure
Airway management to prevent obstructive apnea is essential to ensure the efficacy and safety of catheter ablation procedures.
Catheter ablation with deep sedation has the potential risk of obstructive apnea due to glossoptosis. Obstructive apnea can lead to instability in the effects of sedation and analgesia, and may cause unexpected motion in patients, leading to inaccurate 3-dimensional electroanatomic mapping. In addition, the shift in the position of the heart associated with dynamic diaphragmatic movements during and after an obstructive apnea episode might cause unstable catheter manipulation and the risk of cardiac tamponade. 45 The substantial deep negative intrathoracic pressure during obstructive apnea may lead to air embolization through the blood access sheath. 46 Although the effectiveness of catheter ablation under general anesthesia has been reported, 47 general anesthesia is not widely performed in Japan because of the total time, cost, and insurance concerns associated with the procedure. 48 The J-CARAF study revealed that only 2.9% of the total 10,795 ablation procedures were performed under general anesthesia. 49

| FUTURE D IREC TI ON OF OSA SCREENING AND MANAG EMENT A S A COMPREHEN S IVE TRE ATMENT OF AF
Cardiologists and arrhythmia specialists have many opportunities to care for patients with AF; however, there is a barrier to performing PSG in some hospitals, and systematic screening for OSA has not yet been established. In addition, some physicians as well as patients are less aware of the negative prognostic impact of OSA. Although the importance of comprehensive treatment of AF has been proposed, undiagnosed OSA is a modifiable risk factor, and appropriate therapeutic intervention is expected to enhance the effectiveness of AF treatments, including catheter ablation. 58 Recently, various smartphone applications or mobile devices for self-screening of OSA have been available and reported to be useful tool as a screening for moderate to severe OSA. 59 Although physician should be cautions for making clinical diagnosis of OSA based on these devices, the novel technology will be able to facilitate screening of OSA. Moreover, establishing a comprehensive OSA care team for efficient diagnosis and treatment through close interdisciplinary collaboration between sleep-disorder specialists and cardiologists is desired. OSA is one of the most expensive risk factors for both the screening and treatment of AF. Prospective clinical trials are needed to clarify the impact of OSA on the burden and outcome of AF, the benefit of OSA treatment, and the cost-effectiveness of routine OSA screening.

FU N D I N G I N FO R M ATI O N
None.

CO N FLI C T O F I NTE R E S T
Author has no conflict of interest related to this review.