Atrial fibrillation (AF) is a common arrhythmia with rising incidence. Obstructive sleep apnea (OSA) is prevalent among patients with AF. This observation has prompted significant research in understanding the relationship between OSA and AF. Multiple studies support a role of OSA in the initiation and progression of AF. This association has been independent of obesity, body mass index and hypertension. Instability of autonomic tone and wide swings in intrathoracic pressure are seen in OSA. These have been mechanistically linked to initiation of AF in OSA patients by lowering atrial effective refractory period, promoting pulmonary vein discharges and atrial dilation. OSA not only promotes initiation of AF but also makes management of AF difficult. Drug therapy and electrical cardioversion for AF are less successful in presence of OSA. There has been higher rate of early and overall recurrence after catheter ablation of AF in patients with OSA. Treatment of OSA with continuous positive airway pressure has been shown to improve control of AF. However, additional studies are needed to establish a stronger relationship between OSA treatment and success of AF therapies. There should be heightened suspicion of OSA in patients with AF. There is a need for guidelines to screen for OSA as a part of AF management.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and its prevalence has increased significantly in past three decades[1-3]. Hypertension, thyroid disease, coronary artery disease, cardiomyopathy and structural heart diseases are conventionally associated with high risk of AF[2,3]. Recently, a high prevalence of obstructive sleep apnea (OSA) has been noted among patients with AF indicating that OSA might be contributing to initiation and progression of AF[4,5].

OSA is a relatively common disorder and the prevalence of sleep apnea has been noted to be as high as 16% among men and 5% among women between 30 and 65 years of age[6]. Five percent of adults have undiagnosed sleep apnea[7]. OSA is even more common among patients with cardiovascular disorders and is associated with multiple autonomic and metabolic derangements. Sleep apnea has been implicated in pathogenesis of multiple cardiovascular disorders including arrhythmias, hypertension, heart failure and stroke[4-9]. Its modifiable nature and high prevalence makes it a potential therapeutic target. In this article, we review and discuss the available data explaining the potential pathophysiological mechanisms linking OSA and AF, as well as the therapeutic and prognostic implications of the presence of OSA in AF patients.

OSA is characterized by episodes of nocturnal hypoxemia secondary to diminished and/or interrupted airflow during sleep. Apneic episodes are defined by complete cessation of airflow for ≥ 10 s, while hypopnea episodes are characterized by either ≥ 30% reduction in airflow and ≥ 4% reduction in blood oxygen saturation from baseline for at least 10 s or 50% reduction in air flow and ≥ 3% reduction in oxygen saturation from baseline for at least 10 s or arousal from sleep. It can be categorized as central (absence of inspiratory effort), obstructive (intermittent airway obstruction with preserved/increased respiratory efforts) or mixed sleep apnea (combination of central and OSA). Several easy to use questionnaires have been developed to screen patients for sleep apnea including the Epworth Sleepiness scale[10], the Berlin Questionnaire[11], the STOP and STOP-BANG Questionnaires[12]. Overnight polysomnography is the gold standard test to diagnose and stratify sleep apnea based on the apnea/hypopnea index (AHI)[13,14]. OSA is defined as five or more episodes of apnea and hypopnea per hour of sleep (AHI ≥ 5) and can be classified as mild (AHI 5-15), moderate (AHI 16-30), or severe (AHI > 30)[13,15].

Obesity, OSA and AF have a multifaceted relationship. Obesity increases risk of OSA and is also an independent risk factor for development of AF. The risk of AF increases by 4% for every one-unit increase in body mass index (BMI)[16-18]. This association is stronger for patients aged < 65 years[19]. Sleep apnea (both central and OSA) is more common in patients with congestive heart failure (CHF), and CHF itself is associated with high risk of AF[20-23]. Hence, several confounders must be taken into consideration while analyzing the multidimensional relationship between AF and OSA.

The first insight into a potential link between OSA and AF came from an observational study which reported episodes of AF seen on ambulatory electrocardiographic monitoring among 3% of subjects with OSA[24]. This association was supported by the complete resolution of paroxysmal AF episodes among those who were successfully treated for OSA[24]. Higher prevalence of cardiac arrhythmias among patients with OSA has been confirmed in subsequent studies[25]. The Sleep Heart Health Study reported four times higher prevalence of AF in patients with sleep apnea vs those without sleep apnea (4.8% vs 0.9%)[26]. High frequency paroxysmal AF and persistent AF are both associated with presence of OSA[27]. The episodes of AF and nonsustained ventricular tachycardia have been noted to be significantly higher during the night after apneic episodes, an observation that further supports the temporal association between AF and sleep apnea[28]. Sleep apnea is also an independent predictor for occurrence of postoperative AF among coronary artery bypass surgery patients. In a study by Mooe et al[29], the rate of postoperative AF was significantly higher (32% vs 18%) among patients with OSA (AHI ≥ 5) compared to those without OSA.

Obstructive sleep apnea is more prevalent among patients with AF than the general population. Gami et al[4] reported significantly higher prevalence (49% vs 32%) and a strong association (adjusted odds ratio of 2.19) between sleep apnea and AF in patients undergoing electrical cardioversion as compared patients without AF. This association was independent of age, sex, body mass index, hypertension and heart failure. High rates of sleep apnea are seen among patients with chronic persistent and permanent AF even after matching for age, sex and other relevant co morbid conditions[5]. The association between AF and sleep apnea may be underestimated, as most studies have reported a strong association between AF and sleep apnea despite using higher (AHI > 15) than standard (AHI > 5) threshold to diagnose OSA.

The association between AF and sleep apnea could be attributed to a higher prevalence of traditional risk factors for AF (especially obesity and hypertension) among OSA patients[30,31]. However, the association between AF and sleep apnea is found to be stronger than that of sleep apnea and traditional risk factors for AF[4]. OSA is more prevalent even among younger AF patients with normal left ventricular function[27]. This association remains statistically significant even after adjustment for covariates including hypertension, body mass index, and neck circumference. These findings highlight OSA as an independent risk factor for AF.

The suspected role of OSA in the pathogenesis of AF is based on sound physiological observations (Figure 1). OSA is characterized by repeated episodes of nocturnal hypoxemia. Intermittent hypoxemia causes mitochondrial dysfunction by altering redox state of cytochrome oxidase and results in repetitive oxidative stress[32,33]. Hypoxemic episodes induce transcription factors like nuclear factor kappa-B leading to increased production of inflammatory cytokines such as tumor necrosis factor α and interleukin 6. These cytokines, in concert with increased oxidative stress, lead to endothelial dysfunction, insulin resistance, hypercoagulability, and adverse myocardial remodeling[34-37].

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Figure 1 Schematic illustration of multiple pathophysiological mechanisms contributing to atrial fibrillation in obstructive sleep apnea. AERP: Atrial effective refractory period; AF: Atrial fibrillation.

Hypoxemic episodes induce sympathetic surges leading to vasoconstriction, hypertension and tachycardia[38,39], and ultimately increased myocardial oxygen demand. This increased stress on myocardium results in adverse myocardial remodeling, which is a substrate for cardiac arrhythmias[40,41].

Autonomic tone instability seen in OSA also contributes to pathogenesis of AF. Increases in parasympathetic and sympathetic tone are known to trigger AF[42]. During normal sleep afferent inputs from stretch receptors in lung tissue inhibit the paroxysmal parasympathetic discharges that occur during rapid eye movement sleep[43,44]. These receptors are activated due to lung expansion during normal ventilation. However, in apneic patients this response is attenuated due to pauses in breathing. Uninhibited paroxysmal parasympathetic discharges lead to marked paroxysmal bradycardia. Bradycardia is associated with decrease in atrial effective refractory period (AERP). The reduction in AERP promotes rapid electrical firing from atrial tissue in pulmonary vein ostia, thereby leading to AF[42,45,46]. Hypoxemia and hypercapnea associated with apneic episodes promote chronically heightened sympathetic activity[38,47,48]. Heightened sympathetic tone induces focal discharges from pulmonary veins, which have high concentration of adrenergic and vagal nerve endings[49-51]. Hypoxemia may exert an effect on cardiac arrhythmias that is independent and additive of sleep apnea. This hypothesis is supported by increased rates of ventricular ectopy among chronic obstructive pulmonary disease patients who have nocturnal hypoxemia without sleep apnea[52-54].

OSA is also associated with sudden and frequent changes in intrathoracic pressures, which are transmitted to thin walled atria and cause atrial stretch. Repetitive stretch may result in atrial enlargement and structural changes in pulmonary vein ostia, predisposing to development of AF[42,45].

AF patients with OSA respond poorly to both pharmacological and non-pharmacological therapy (cardioversion or ablation) with high rate of recurrence[55-58].

Several observational studies have indicated a high prevalence of OSA among patients with AF. Concomitant OSA is associated with poor response to treatment for AF. Limited data indicate that treatment of OSA results in a lower rate of AF recurrence. Patients with AF may be screened for OSA with a simple tool such as Berlin questionnaire, and high-risk patients should be considered for formal sleep study. The educational, behavioral and therapeutic interventions for sleep apnea should be offered to AF patients with OSA.