Sleep Disordered Breathing and AFib: Emerging Data, Elucidating Mechanisms and Epidemiology
Sleep disordered breathing (SDB) can refer to either obstructive sleep apnea (OSA) or central sleep apnea (CSA). Both conditions have been reviewed in other articles in this series. For the purposes of this article on atrial fibrillation (AF), SDB refers primarily to OSA, but it should be noted that AF is also associated with CSA, both in those with and without heart failure.1,2
OSA is characterized by intermittent episodes of complete or partial upper airway collapse. These episodes of upper airway collapse are accompanied by an array of adverse physiologic consequences including intermittent hypoxia, ventilatory overshoot hyperoxia, hypercapnia, autonomic nervous system instability, sleep fragmentation and intrathoracic pressure alterations. In turn, these consequences lead to a state of enhanced thrombosis, cardiac structural alterations, endothelial dysfunction and up-regulation of pathways of systemic inflammation and oxidative stress which operate to bolster a pro-arrhythmogenic milieu resulting in increased risk of arrhythmias such as atrial fibrillation (AF). AF is projected to afflict up to 16 million individuals by the year 2050, costing over $6.7 billion annually. AF is not currently explained by known risk factors, underscoring the need to identify novel triggers. SDB is common in patients with cardiovascular disease and its attendant hypoxemia and autonomic dysfunction likely enhance AF propensity. Thus, SDB may represent a novel target for AF prevention and treatment strategies.
New Experimental Data
Exciting experimental data have recently emerged advancing our understanding of the pathophysiologic mechanisms connecting SDB and AF. The predominance of data has been focused on the role of the autonomic nervous system. Specifically, autonomic instability, which is a known AF risk,3,4 occurs in SDB via increased vagal activity during obstructive apneas and hypopneas in conjunction with post-apnea and hypopnea related hypercarbia or hypoxia-induced sympathoexcitation.5,6 Vagally mediated influences favor atrial macroreentry and reduce the effective refractory period, whereas sympathetic influences favor abnormal automaticity and triggered atrial activity.7 Compelling animal data support attenuation of apnea-mediated AF after autonomic blockade via ganglionated plexi neural ablation, thereby highlighting the importance of the role of the autonomic system in SDB and AF.8 Heart rate variability analyses have shown increased Standard Deviation of NN intervals (SDNN), increased high frequency (HF) and reduced low frequency (LF) preceding paroxysmal AF episodes suggesting that sympathovagal imbalances contribute to AF genesis. The role of autonomic imbalance in obstructive apnea-associated AF is further corroborated by atrial effective refractory period shortening subsequent to tracheal occlusion resulting in increased AF inducibility and the observation of inhibition of the post-apneic blood pressure rise by renal sympathetic denervation.9
Other SDB influences inceasing atrial arrhythmogensis include associated intermittent oxygen desaturation and phases of reoxygenation. AF is associated with activation of hypoxic factors including hypoxia inducible factor-1α (HIF-1α),10,11 a transcription factor which is also up-regulated in SDB.12 In an animal model, hypoxia has been noted to shorten the action potential in the left atrium, whereas reoxygenation induced pulmonary vein burst firing.13 Antioxidant administration attenuated the rate changes induced by hypoxia and reoxygenation, and also decreased the burst firing incidence. Linear stepwise changes in the atrial refractory period with the induction and resolution of hypercapnia, as occurs in SDB, have been identified, such that AF vulnerability is most prominent with return to eucapnia.14 Furthermore, obstructive apneas and hypopneas cause repetitive forced inspiration against a closed airway, which generates substantial negative pressures in the chest cavity (approaching -65mmHg).15
These cyclical increased intrathoracic pressures in SDB result in acute left atrial and pulmonary vein stretch15-18 thereby potentially resulting in stretch-mediated ion channel activation triggering AF. SDB leads to cardiac structural alteration including increased wall stress, increased afterload, increased atrial size17,18 and impaired diastolic function.17,19 Our published data demonstrate increased left ventricular mass index in SDB compared to those without SDB, mechanistically explained by the nocturnal degree of hypoxia.20 Known risks for AF include increased left atrial volume and strain, left ventricular hypertrophy and left atrial wall motion velocity.21 SDB markers include increased interleukin-6 (IL-6),22 soluble IL-6 receptor (sIL-6R)23 and high sensitivity C-Reactive Protein (hs-CRP)24 which represents potential pathways of increasing AF risk given increased hs-CRP levels are implicated in atrial structural and electrical remodeling25,26 and increased IL-6 levels have been associated with AF.27 Moreover, SDB-related intermittent hypoxia-reoxygenation results in oxidative stress28-31 which may alter myocyte ion channel function. Animal data show increased oxidized glutathione32 and NADPH oxidase levels in the left atrial appendage33 in persistent AF. Initiation and perpetuation of AF involves inflammation and oxidative stress, e.g. endothelin-1 has been increasingly implicated as a pathogenic factor in AF resulting in up-regulation of oxidative stress pathways.34-36
SDB and AF Relationships
Compelling data have been generated from clinic-based studies focused on SDB and AF relationships. One well referenced study found a significantly higher SDB prevalence of approximately 50% (ascertained by questionnaire) in AF patients, many with established structural heart disease, than in age-matched controls.37 In contrast, another study found a similar prevalence of SDB in AF patients and controls;38 close reading suggests that this study was likely under-powered with a control sample potentially biased towards having SDB.38 A case control study matched for age and sex and excluding those with left ventricular ejection fraction <50% demonstrated a three-fold increased adjusted odds of AF in those with moderate to severe SDB.39 Effectively treated SDB in compliant patients has been noted to reduce AF recurrence after cardioversion during a 12-month follow-up compared to SDB patients who elected not to undergo treatment with continuous positive airway pressure and compared to controls with SDB.40 These data suggest the role of reversal of SDB adverse physiologic effects in improving AF recurrence. Of note, those with untreated SDB and experienced recurrence of AF had a higher level of hypoxia defined by a mean nocturnal reduction in oxygen saturation compared to those without recurrence. The role of hypoxia in AF has also been supported by the observation of a reduction in post-operative AF with the use of supplemental oxygen in those with hypoxia.41 Retrospective clinical data also implicate nocturnal hypoxia as a risk of incident AF.1 Untreated SDB appears to influence the effectiveness of other standard AF therapies as well such as ablation and use of anti-arrhythmic medication. Results of a meta-analysis concluded that those with obstructive sleep apnea have a 25% greater risk of AF recurrence after catheter ablation compared to those without obstructive sleep apnea.42 Reduction in the effectiveness of anti-arrhythmic medication therapy in severe OSA compared to those with milder forms of obstructive sleep apnea has also been recently reported.43
We have performed epidemiologic observational studies which have demonstrated statistically significant associations of SDB and AF (odds ratio point estimates of two to four) even after taking into account a host of potential confounding factors such as age, sex, race, body mass index, and self-reported co-morbidities such as hypertension, diabetes mellitus, cardiovascular disease and heart failure.44,45 Specifically, among participants in the Sleep Heart Health Study, moderate to severe SDB, as compared to absence of SDB, was associated with a four-fold increase adjusted odds of AF on overnight polysomnography.44 Among elderly individuals, stronger associations have been reported between AF and central compared to obstructive sleep apnea even after consideration of confounding factors.45 In this study, a threshold effect was noted such that a moderate to severe degree of SDB (Apnea Hypopnea Index >24) conferred the greatest increased odds of AF independent of self-reported heart failure and cardiovascular disease. In those with a central apnea index >three, there was a three-fold higher odds of AF and an almost five-fold higher odds of AF was noted in those with Cheyne Stokes Respirations compared to those without.45
A causal association between SDB and arrhythmias is suggested by the findings from a case-cross over study, which examined the temporal distributions of AF paroxysms in association with the occurrence of apneas and hypopneas on polysomnography with a 17-fold higher odds of an episode of AF in the 90 seconds immediately following an apnea or hypopnea compared to a time period following non-obstructed breathing.46
Future of AF Treatment and Prevention Strategies
Overall, AF is an independent predictor of mortality47 and increased stroke, implicated in ~75,000 strokes per year.48 Annual costs for AF treatment have been estimated at $6.7 billion, including $2.9 billion for hospitalizations49 Therefore, improved AF disease management strategies are needed to reduce hospitalizations and costs.50 Furthermore, AF treatments such as ablation and anti-arrhythmic medications are fraught with inconsistent results and pro-arrhythmic side effects and successful treatment appears to be impaired without consideration of SDB treatment.51 Therefore, there is a critical need to identify alternative AF treatment and prevention strategies such as those targeting SDB. Research studies including clinical trials performed in AF should take SDB into consideration. Although compelling data has accumulated regarding the SDB-AF relationship, future clinical and epidemiologic research should focus on clinical trial investigating the effects of SDB treatment on AF burden and outcomes. Furthermore, future efforts should focus on the collection of objective cardiac function data as well as measurement and consideration of markers of autonomic function, systemic inflammation, oxidative stress and examination of daytime as well as nocturnal ECG in an effort to further elucidate pathophysiologic underpinnings.
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- Leung, R.S., et al., Association between atrial fibrillation and central sleep apnea. Sleep 2005; 28:1543-6.
- Lombardi, F., et al., Autonomic nervous system and paroxysmal atrial fibrillation: a study based on the analysis of RR interval changes before, during and after paroxysmal atrial fibrillation. Eur Heart J 2004; 25:1242-8.
- Chen, Y.J., et al., Role of atrial electrophysiology and autonomic nervous system in patients with supraventricular tachycardia and paroxysmal atrial fibrillation. J Am Coll Cardiol 1998; 32:732-8.
- Leuenberger, U., et al., Surges of muscle sympathetic nerve activity during obstructive apnea are linked to hypoxemia. J Appl Physiol 1995; 79:581-8.
- Smith, M.L., et al., Role of hypoxemia in sleep apnea-induced sympathoexcitation. J Auton Nerv Syst 1996; 56:184-90.
- Volders, P.G., Novel insights into the role of the sympathetic nervous system in cardiac arrhythmogenesis. Heart Rhythm 2010; 7:1900-6.
- Ghias, M., et al., The role of ganglionated plexi in apnea-related atrial fibrillation. J Am Coll Cardiol 2009; 54:2075-83.
- Linz, D., et al., Renal sympathetic denervation suppresses postapneic blood pressure rises and atrial fibrillation in a model for sleep apnea. Hypertension 2012; 60:172-8.
- Gramley, F., et al., Atrial fibrillation is associated with cardiac hypoxia. Cardiovasc Pathol 2010;19:102-11.
- Ogi, H., et al., Is structural remodeling of fibrillated atria the consequence of tissue hypoxia? Circ J 2010; 74:1815-21.
- Yuan, G., et al., Induction of HIF-1alpha expression by intermittent hypoxia: involvement of NADPH oxidase, Ca2+ signaling, prolyl hydroxylases, and mTOR. J Cell Physiol 2008; 217:674-85.
- Lin, Y.K., et al., Hypoxia and reoxygenation modulate the arrhythmogenic activity of the pulmonary vein and atrium. Clin Sci (Lond) 2012; 122:121-32.
- Stevenson, I.H., et al., Atrial electrophysiology is altered by acute hypercapnia but not hypoxemia: implications for promotion of atrial fibrillation in pulmonary disease and sleep apnea. Heart Rhythm 2010; 7:1263-70.
- Somers, V.K., M.E. Dyken, and J.L. Skinner, Autonomic and hemodynamic responses and interactions during the Mueller maneuver in humans. J Auton Nerv Syst 1993; 44:253-9.
- Haissaguerre, M., et al., Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998; 339:659-66.
- Otto, M.E., et al., Comparison of cardiac structural and functional changes in obese otherwise healthy adults with versus without obstructive sleep apnea. Am J Cardiol 2007; 99:1298-302.
- Romero-Corral, A., et al., Decreased right and left ventricular myocardial performance in obstructive sleep apnea. Chest 2007; 132:1863-70.
- Arias, M.A., et al., Obstructive sleep apnea syndrome affects left ventricular diastolic function: effects of nasal continuous positive airway pressure in men. Circulation 2005; 112:375-83.
- Chami, H.A., et al., Left ventricular morphology and systolic function in sleep-disordered breathing: the Sleep Heart Health Study. Circulation 2008; 117:2599-607.
- Antonielli, E., et al., Clinical value of left atrial appendage flow for prediction of long-term sinus rhythm maintenance in patients with nonvalvular atrial fibrillation. J Am Coll Cardiol 2002; 39:1443-9.
- Shearer, W.T., et al., Soluble TNF-alpha receptor 1 and IL-6 plasma levels in humans subjected to the sleep deprivation model of spaceflight. J Allergy Clin Immunol 2001; 107:165-70.
- Mehra, R., et al., Soluble interleukin 6 receptor: A novel marker of moderate to severe sleep-related breathing disorder. Arch Intern Med 2006; 166:1725-31.
- Meier-Ewert, H.K., et al., Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. J Am Coll Cardiol 2004; 43:678-83.
- Conen, D., et al., A multimarker approach to assess the influence of inflammation on the incidence of atrial fibrillation in women. Eur Heart J 2010; 31:1730-6.
- Kurotobi, T., et al., A pre-existent elevated C-reactive protein is associated with the recurrence of atrial tachyarrhythmias after catheter ablation in patients with atrial fibrillation. Europace 2010; 12:1213-8.
- Marcus, G.M., et al., Interleukin-6 and atrial fibrillation in patients with coronary artery disease: data from the Heart and Soul Study. Am Heart J 2008; 155:303-9.
- Ichikawa, H., et al., Molecular mechanisms of anoxia/reoxygenation-induced neutrophil adherence to cultured endothelial cells. Circ Res 1997; 81:922-31.
- Dyugovskaya, L., P. Lavie, and L. Lavie, Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med 2002; 165:934-9.
- Prabhakar, N.R., Sleep apneas: an oxidative stress? Am J Respir Crit Care Med 2002; 165:859-60.
- Schulz, R., et al., Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. Impact of continuous positive airway pressure therapy. Am J Respir Crit Care Med 2000; 162:566-70.
- Neuman, R.B., et al., Oxidative stress markers are associated with persistent atrial fibrillation. Clin Chem 2007; 53:1652-7.
- Dudley, S.C., Jr., et al., Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage: role of the NADPH and xanthine oxidases. Circulation 2005; 112:1266-73.
- Mayyas, F., et al., Association of left atrial endothelin-1 with atrial rhythm, size, and fibrosis in patients with structural heart disease. Circ Arrhythm Electrophysiol 2010; 3:369-79.
- Nakazawa, Y., et al., Endothelin-1 as a predictor of atrial fibrillation recurrence after pulmonary vein isolation. Heart Rhythm 2009; 6:725-30.
- Piechota, A., A. Polanczyk, and A. Goraca, Role of endothelin-1 receptor blockers on hemodynamic parameters and oxidative stress. Pharmacol Rep 2010; 62:28-34.
- Gami, A.S., et al., Association of atrial fibrillation and obstructive sleep apnea. Circulation 2004;110:364-7.
- Porthan, K.M., et al., Prevalence of sleep apnea syndrome in lone atrial fibrillation: a case-control study. Chest 2004; 125:879-85.
- Stevenson, I.H., et al., Prevalence of sleep disordered breathing in paroxysmal and persistent atrial fibrillation patients with normal left ventricular function. Eur Heart J 2008; 29:1662-9.
- Kanagala, R., et al., Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation 2003; 107:2589-94.
- Kisner, D., et al., Reduced incidence of atrial fibrillation after cardiac surgery by continuous wireless monitoring of oxygen saturation on the normal ward and resultant oxygen therapy for hypoxia. Eur J Cardiothorac Surg 2009; 35:111-5.
- Ng, C.Y., et al., Meta-analysis of obstructive sleep apnea as predictor of atrial fibrillation recurrence after catheter ablation. Am J Cardiol 2011; 108:47-51.
- Monahan, K., et al., Relation of the severity of obstructive sleep apnea in response to anti-arrhythmic drugs in patients with atrial fibrillation or atrial flutter. Am J Cardiol 2012; 110:369-72.
- Mehra, R., et al., Association of nocturnal arrhythmias with sleep-disordered breathing: The Sleep Heart Health Study. Am J Respir Crit Care Med 2006; 173:910-6.
- Mehra, R., et al., Nocturnal Arrhythmias across a spectrum of obstructive and central sleep-disordered breathing in older men: outcomes of sleep disorders in older men (MrOS sleep) study. Arch Intern Med 2009; 169:1147-55.
- Monahan, K., et al., Triggering of nocturnal arrhythmias by sleep-disordered breathing events. J Am Coll Cardiol 2009; 54:1797-804.
- Benjamin, E.J., et al., Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998; 98:946-52.
- Wolf, P.A., et al., Probability of stroke: a risk profile from the Framingham Study. Stroke 1991; 22:312-8.
- Coyne, K.S., et al., Assessing the direct costs of treating nonvalvular atrial fibrillation in the United States. Value Health 2006; 9:348-56.
- Kim, M.H., et al., Cost of atrial fibrillation in United States managed care organizations. Adv Ther 2009; 26:847-57.
- McNamara, R.L., et al., Management of atrial fibrillation: review of the evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography. Ann Intern Med 2003; 139:1018-33.
Keywords: Action Potentials, Anti-Arrhythmia Agents, Arrhythmias, Cardiac, Atrial Fibrillation, Autonomic Nervous System, C-Reactive Protein, Cheyne-Stokes Respiration, Electrocardiography, Heart Atria, Heart Failure, Heart Rate, Hypercapnia, Hypercapnia, Inflammation, Ion Channels, Pulmonary Veins, Risk Factors, Sleep Apnea Syndromes, Sleep Deprivation, Stroke Volume, Thrombosis, Interleukin-6, Catheter Ablation, Cost of Illness, Polysomnography, Hypertrophy, Left Ventricular, Oxidative Stress, Oxidative Stress, Hyperoxia, Hyperoxia, NADPH Oxidases, Receptors, Interleukin-6, Stroke, Models, Animal, Continuous Positive Airway Pressure
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