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Contemporary Reviews in Sleep Medicine |

OSA and Cardiac Arrhythmogenesis: Mechanistic Insights FREE TO VIEW

Anna M. May, MD; David R. Van Wagoner, PhD; Reena Mehra, MD
Author and Funding Information

FUNDING/SUPPORT: This study was supported by NIH funding through the National Heart, Lung, and Blood Institute under the following grant numbers: R21 HL108226 and R01 HL109493.

aDivision of Pulmonary, Critical Care, and Sleep Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH

bDepartment of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

cNeurologic Institute, Respiratory Institute, Heart and Vascular Institute and Molecular Cardiology Department, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

CORRESPONDENCE TO: Anna M. May, MD, University Hospitals Cleveland Medical Center, 11100 Euclid Ave, Bolwell 6th floor, Cleveland, OH 44106


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2017;151(1):225-241. doi:10.1016/j.chest.2016.09.014
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A surge of data has reproducibly identified strong associations of OSA with cardiac arrhythmias. As an extension of epidemiologic and clinic-based findings, experimental investigations have made strides in advancing our understanding of the putative OSA and cardiac arrhythmogenesis mechanistic underpinnings. Although most studies have focused on the links between OSA and atrial fibrillation (AF), relationships with ventricular arrhythmias have also been characterized. Key findings implicate OSA-related autonomic nervous system fluctuations typified by enhanced parasympathetic activation during respiratory events and sympathetic surges subsequent to respiratory events, which contribute to augmented arrhythmic propensity. Other more immediate pathophysiologic influences of OSA-enhancing arrhythmogenesis include intermittent hypoxia, intrathoracic pressure swings leading to atrial stretch, and hypercapnia. Intermediate pathways by which OSA may trigger arrhythmia include increased systemic inflammation, oxidative stress, enhanced prothrombotic state, and vascular dysfunction. Long-term OSA-associated sequelae such as hypertension, atrial enlargement and fibrosis, ventricular hypertrophy, and coronary artery disease also predispose to cardiac arrhythmia. These factors can lead to a reduction in atrial effective refractory period, triggered and abnormal automaticity, and promote slowed and heterogeneous conduction; all of these mechanisms increase the persistence of reentrant arrhythmias and prolong the QT interval. Cardiac electrical and structural remodeling observed in OSA animal models can progress the arrhythmogenic substrate to further enhance arrhythmia generation. Future investigations clarifying the contribution of specific OSA-related mechanistic pathways to arrhythmia generation may allow targeted preventative therapies to mitigate OSA-induced arrhythmogenicity. Furthermore, interventional studies are needed to clarify the impact of OSA pathophysiology reversal on cardiac arrhythmogenesis and related adverse outcomes.

Figures in this Article

OSA consists of repetitive episodes of complete or partial cessation of breathing: apneas and hypopneas, respectively. OSA is a common condition with progressively rising prevalence, largely attributable to the increasingly aged population and the ongoing obesity epidemic. In parallel to the increasing prevalence of OSA, atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is projected to affect 16 million people by 2050. AF is not fully explained by established risk factors, which underscores the need to definitively identify novel triggers such as OSA. Although causality between OSA and arrhythmia has yet to be established, emerging data have identified a range of mechanistic pathways that may increase the propensity of cardiac arrhythmogenesis in OSA. These pathways are complex, multidirectional, and potentially synergistic. OSA and AF have shared risk factors and consequences (ie, increasing age, obesity, hypertension) that may act together to increase cardiovascular risk.

Epidemiologic studies have shown that sleep-disordered breathing approximately doubles the risk of AF; in patients with OSA and heart failure, the risk is twofold to fourfold higher compared with those without either condition.,,,,,,,,, In addition, studies of circadian rhythm and sudden cardiac death have shown a predisposition of fatal events in those with obstructive apnea to the nocturnal period, a period of relative cardioprotection for individuals without obstructive apnea. Apneas and hypopneas characterizing OSA are frequently accompanied by oxygen desaturation and microarousals from sleep, the latter leading to sleep fragmentation. Autonomic nervous system imbalance characterized by vagal cardiac activation during, and unopposed sympathetic activation after, OSA events can precipitate arrhythmias., In addition, there are prominent intrathoracic pressure fluctuations in OSA secondary to attempts to breathe against an obstructed upper airway. These OSA-related pathophysiologic events lead to increased arrhythmia rates observed in patients with OSA., Overall, we can consider a conceptual model of repeated acute physiologic insults (ie, repetitive hemodynamic, hypoxemic, and autonomic surges) resulting in cardiac structural and electrical remodeling, which operate to create an altered arrhythmogenic substrate in apnea-induced arrhythmia (Fig 1, Tables 1 and 2).

Figure Jump LinkFigure 1 Overview of putative sleep apnea pathophysiologic pathways with varying levels of evidence potentially predisposing to cardiac arrhythmogenesis. O2 = oxygen.Grahic Jump Location

Table Graphic Jump Location
Table 1 Overview of Clinical or Epidemiologic Studies Characterizing Sleep-disordered Breathing and Cardiac Structural and Electrophysiologic Indices

AF = atrial fibrillation; AHI = apnea-hypoapnea index; CIH = chronic intermittent hypoxia; ERP = effective refractory period; HTN = hypertension; LV = left ventricular; PSG = polysomnography; QTc = corrected QT interval; RCT = randomized controlled trial; RV = right ventricular; Tp/Te = interval between the ECG T-wave peak and end.

Table Graphic Jump Location
Table 2 Overview of Animal Experimental Studies Characterizing Sleep-disordered Breathing and Cardiac Structural and Electrophysiologic Indices

HIF = hypoxia-inducible factor; LLVS = low-level vagosympathetic trunk stimulation; NTP = negative tracheal pressure; ROS = reactive oxygen species. See Table 1 legend for expansion of other abbreviations.

Although the present review focuses on the interrelationships of OSA and cardiac arrhythmia, it is important to recognize emerging epidemiologic data that implicate the possible role of central sleep-disordered breathing in the development of AF. Furthermore, in heart failure, central sleep-disordered breathing and Cheyne-Stokes respirations entrain the ventricular response to AF by inducing rhythmic oscillations in atrioventricular node refractoriness.

Cardiac arrhythmias incur heavy societal and personal burden, including lost productivity, increased health-care expenses, and raised risk of stroke., There is an urgency to perform studies that can better elucidate causal pathways and enhance our understanding of mechanistic pathways involved in OSA and cardiac arrhythmogenesis. By understanding and acting on these immediate and intermediate time frame pathways, it may be possible for OSA-focused treatments to optimize prevention and mitigation of arrhythmia-related morbidity and mortality.

A variety of electrophysiologic parameters encompassing abnormal automaticity, triggered automaticity, shortening of the atrial effective refractory period (ERP), QT interval prolongation, and reentrant mechanisms may be induced by OSA pathophysiology. Abnormal cardiac impulse formation can result in abnormal automaticity (spontaneous activity in normally quiescent cardiac cells) or triggered activity. Enhanced arrhythmogenesis occurs when automaticity is either reduced (resulting in bradycardia) or increased (resulting in tachycardia). Abnormal automaticity is oftentimes generated in response to potassium dysregulation,, which is observed during the hyperpneic phase of periodic central sleep apnea as a result of hypokalemia due to transcellular ion shifts and reduced renal absorption, hypocapnia,, and beta-adrenergic stimulation.

Triggered activity occurs when early or delayed afterdepolarizations reach a membrane potential threshold resulting in a spontaneous action potential (ie, triggered response). Triggered responses can result in extrasystoles that can precipitate tachyarrhythmias. Established triggered activity precipitants via early after-depolarizations include hypoxia, acidosis, and ventricular hypertrophy, all intrinsic characteristics of OSA pathophysiology. Alternatively, delayed afterdepolarizations resulting in triggered activity often occur in response to increased catecholamine levels, which are also inherent to OSA.,

The interval between the ECG T-wave peak and end has been studied as a measure of cardiac dispersion and repolarization; increases in this interval are associated with ventricular arrhythmogenesis and sudden cardiac death.,, Comparisons of patients with OSA vs control subjects identified increased ECG T-wave peak and end and QT dispersion in those with OSA,, and improvement in these measures with CPAP treatment., Because increased heterogeneity in ventricular recovery time and repolarization time are correlated with ventricular arrhythmias, these studies provide a mechanistic basis for OSA as a predisposing factor for nocturnal sudden cardiac death.

After myocytes produce an action potential, there is a period of time when the activated cells are recovering and unable to produce another action potential; this interval is referred to as the ERP. The ERP typically halts further activations to prevent arrhythmias. Perturbations that shorten the atrial ERP predispose the heart to arrhythmias such as AF. Simulated by intermittent hypoxia and hypercapnia, obstructive apnea has been shown in canine models to decrease atrial ERP. ERP shortens with negative tracheal pressure during simulated obstructive apnea via increased vagal tone; this effect was mitigated by administration of atropine. Taken in toto, shortening of the atrial ERP during obstructive events may predispose to AF generation.

Autonomic Nervous System Alterations

Although there are unequivocal synergies among the OSA pathophysiologic sequelae, data suggest that the OSA-related sympathovagal imbalance may be the primary trigger in cardiac arrhythmogenesis. Increasing respiratory efforts of progressive magnitude to achieve restoration of airway patency are intrinsic to obstructive respiratory event physiology. Enhanced vagal efferent outflow to the heart leads to the bradycardia observed during the apneic event (ie, the diving reflex). These vagal influences shorten the atrial ERP and, hence, enhance vulnerability to excitatory stimuli. After upper airway patency restoration, strong sympathetic nervous system responses are elicited secondary to the interacting effects of central respiratory sympathetic coupling, hypoxia, hypercapnia, and absence of sympathoinhibition from normal lung initiation reflexes. These sequential autonomic alterations lead to enhanced arrhythmia susceptibility.

Further support for the role of autonomic influences in OSA comes from a canine model in which ablation of the right ganglionated plexus resulted in inhibition of apnea-induced AF. Autonomic dysfunction has been further corroborated by observations in a porcine model in response to tracheal occlusion causing increasing AF inducibility (ie, reduction of the atrial ERP) that was mitigated by renal sympathetic denervation and low-level baroreceptor stimulation, an intervention to suppress both sympathetic and parasympathetic activity., OSA-induced intermittent hypoxemic bouts serve as recurrent instigators of sympathetic discharges, thereby favoring triggered atrial activity and abnormal automaticity, a mechanism bolstered by data demonstrating the importance of the sympathetically enriched ganglionated plexus in apnea-induced AF. Although shortened refractoriness may play a role in atrial arrhythmogenesis, conduction slowing secondary to OSA-induced cardiac structural remodeling (fibrosis and connexin dysregulation) is likely also an important mechanism contributing to arrhythmia persistence.

Hypoxia and Hypercapnia

Apneas and hypopneas impair gas exchange and lead to oxygen desaturation, particularly in individuals with underlying pulmonary or cardiovascular disease. Termination of upper airway obstruction subsequent to a respiratory event may lead to re-oxygenation and formation of hazardous reactive oxygen species (ROS).,, Oxidative stress is implicated in myocardial hypertrophy, injury, and apoptosis leading to structural changes in animal models of the heart.,, ROS generation has been linked to arrhythmogenesis both in animals and humans as a result of changes in calcium channel activity and by promotion of microvascular ischemia., Hypoxemia directly stimulates chemoreceptors in the carotid body, precipitating increased ventilation and sympathetic discharges.,, In addition, hypoxia leads to peripheral vasoconstriction, which increases both preload and afterload, thereby causing increased cardiac workload. Oxidative stress secondary to hypoxia uncouples endothelial nitric oxide synthase, and thus increases superoxide generation and decreasing nitric oxide production. This chain of events leads to endothelial dysfunction, which has bidirectional relationships with AF. Oxidative stress promotes activation of fibroblasts to myofibroblasts, leading to deposition of perivascular and interstitial fibrosis that promotes slowed and heterogeneous conduction.

Although the evidence is not entirely consistent, some data support intermittent hypoxia as a potential factor enhancing arrhythmogenesis. For instance, hypoxia and hypercapnia altered measures of AF inducibility in a canine model (ie, reduced the ERP and increased the window of vulnerability). In this study, 1 h of intermittent hypoxia (10 s of apnea for every 30 s of breathing) in a canine model altered heart rate variability markers of sympathovagal balance. The immediacy of the effects of intermittent hypoxia is underscored by resolution of these changes within 1 h of re-ventilation. Challenges encountered with this study and others include the limited ability to examine the isolated influences of the various facets of OSA (ie, hypoxia, hypercapnia, acidosis). Although data describing the specific relationship of hypercapnia and AF inducibility are sparse, one study was designed to examine differential effects of episodic hypercapnia relative to hypoxemia on electrophysiologic parameters in a sheep model. Hypercapnia in the setting of autonomic blockade lengthened the atrial ERP, increased right atrial conduction time and functional conduction delay, and caused a significant rise in extracellular potassium. In this study, although hypercapnia exerted a protective effect on measures of AF inducibility, return to eucapnia enhanced AF vulnerability secondary to the differential between atrial ERP shortening to below baseline levels and normalization of functional conduction delay.

Intrathoracic Pressure Alterations

Upper airway occlusion generates negative intrathoracic pressures, resulting in augmented cardiac transmural pressures. These large oscillations pressure (up to –65 mm Hg) lead to increased left ventricular afterload and compromise the thin-walled, compliant atria by causing acute distension. This atrial distension then leads to acute shortening of the atrial ERP via vagal activation., In addition, these acute changes lead to increased central venous volume. These mechanical cardiac influences may lead to activation of stretch-mediated ion channels and can lead to cardiac remodeling, hence enhancing arrhythmogenic propensity. Even in healthy control subjects, simulated obstructive apnea via the Müller maneuver increased premature beats and prolonged the corrected QT interval, a measure of delayed ventricular repolarization. In patients with paroxysmal AF, simulated obstructive hypopneas and apneas lead to progressive increases in atrial premature beat frequency and corrected QT interval prolongation, which have been implicated as precursors to AF and ventricular arrhythmia/sudden cardiac death, respectively.

Moreover, the large shifts in intrathoracic pressure during obstructive apneas seem to be sufficient to cause ventricular remodeling. Healthy subjects who underwent the Müller maneuver, simulating increased intrathoracic pressures, were found to have an acute increase in left ventricular afterload. In addition, upper airway occlusion was found to have deleterious effects on myocardial mechanics characterized by decreased left and right ventricular deformation during systolic cardiac contraction. These ventricular perturbations in response to repeated insults of negative intrathoracic pressure alterations over time can lead to fluctuations in afterload burden, left ventricular hypertrophy, and increased risk of arrhythmogenesis., Overall, studies suggest that OSA promotes atrial and ventricular structural remodeling as well as alterations in cardiac electrophysiology predisposing to arrhythmogenesis.

Systemic Inflammation and Oxidative Stress

A cardinal feature of OSA is the repetitive hypoxia/re-oxygenation that causes activation of a proinflammatory cascade, cellular adenosine 5′-triphosphate depletion, and xanthine oxidase activation, all factors that drive ROS formation and reductions in nitric oxide, a key vasodilator., Sleep fragmentation and reduced sleep associated with OSA may represent an important factor, resulting in an enhanced state of systemic inflammation and oxidative stress as exhibited by increases in myeloperoxidase and oxidized low-density lipoprotein levels. OSA induces formation of harmful ROS and activation of proinflammatory cytokines while downregulating antiinflammatory mediators; this action leads to endothelial damage and predisposes to cardiovascular disease development and possibly an increased arrhythmia propensity, although this theory is speculative.

In many studies, an array of systemic inflammatory markers has been associated with OSA. For instance, in a meta-analysis, C-reactive protein, tumor necrosis factor-α, IL-8, intercellular adhesion molecule, selectin, and vascular cellular adhesion molecule were all found to be higher with apparent monotonic relationships in those with OSA compared with control subjects. Other biochemical mediators such as increasing soluble IL-6 receptor levels, considered to operate by more expansive trans-signaling pathways than IL-6, is associated with increasing severity of OSA with diurnal patterning independent of obesity. In addition, recent randomized controlled trial data suggest reduction in these levels with OSA treatment. Systemic inflammation has also been implicated in AF. For instance, C-reactive protein levels are elevated in patients with AF corresponding to the AF burden level and may contribute to AF persistence. Both plasma C-reactive protein and IL-6 levels are associated with left atrial dilation and endothelial dysfunction, which are recognized AF contributors., Specific studies, however, are needed to examine upregulation of systemic inflammation and oxidative stress in those with OSA and AF.

Prothrombotic State

OSA has also been associated with increased levels of prothrombotic markers. Although the identification of AF as an activator of blood coagulation markers is well recognized, emerging data implicate hypercoagulability as a potential cause or promoter of AF via induction of atrial fibrosis (ie, bidirectional pathways have been characterized). The enhanced prothrombotic milieu in AF has been attributed not only to left atrial abnormalities but also to activation of coagulation factors, platelet activation, and increased fibrinolytic activity. The extent of hypoxic burden and intermittent hypoxia in OSA has been associated with measures of platelet activation, elevations of fibrinogen, and platelet aggregation and thrombus formation response to hypobaric hypoxia in experimental models. Interestingly, even at modest levels of sleep-disordered breathing, a hypercoagulable state has been observed with increases in plasminogen activator inhibitor-1 and fibrinogen independent of obesity. Subjects with an incremental rise in the apnea-hypopnea index exhibit diurnal patterning characterized by an enhanced prothrombotic state in the morning vs evening. Although further study is needed, it is possible that OSA-induced hypercoagulability may result in atrial remodeling and represent a pathway contributing to AF pathogenesis.

Cardiac Structural and Electrical Remodeling

Large shifts in transmural pressure, intermittent hypoxia, and upregulation of systemic inflammation and oxidative stress due to OSA over the long term can cause cardiac structural and electrical remodeling. Structural remodeling characterized by ventricular and atrial hypertrophy and increased interstitial fibrosis is a key feature of heart failure. It is unclear if increased arrhythmogenicity from heart failure and OSA is a function of a shared risk factor profile or the combined effects of these disorders causing accelerated cardiac structural change. Despite lack of difference in background risk, atrial remodeling characterized by atrial enlargement has been observed in patients with OSA compared with control subjects and is significantly associated with measures of arterial stiffness. Animal models of sleep apnea rapidly develop atrial remodeling., Electrical remodeling measures captured by multipolar catheters were abnormal in patients with OSA compared with control subjects as highlighted by decreased atrial voltage, slower atrial conduction velocity, and more widespread complex electrograms. Chronic apnea over 12 weeks in a canine and rat model resulted in electrical conduction prolongation, which led to increased AF inducibility., In moderate to severe OSA, echocardiographic evidence of inter- and intra-atrial electromechanical delay in conjunction with P-wave dispersion on ECG was observed. Furthermore, increased left ventricular mass and hypertrophy, the latter of which predisposes to ventricular arrhythmias and conduction delay, have been observed to be particularly accentuated in individuals with both sleep apnea and hypertension., Taken together, these studies indicate that OSA is associated with atrial remodeling and dilation as well as left ventricular hypertrophy leading to electrophysiologic alterations predisposing to arrhythmogenesis.

OSA results in intermittent hypoxia, hypercapnia, pronounced intrathoracic pressure swings, and autonomic nervous system dysfunction. Over time, these direct factors can cause left atrial and ventricular remodeling, exacerbate coronary artery disease, and produce metabolic dysregulation. This dysfunctional milieu sets up the substrate for increased atrial and ventricular arrhythmogenicity. This outcome has been observed most starkly in studies of AF and sudden cardiac death in those with OSA. Although increased systemic inflammation, oxidative stress, and a prothrombotic state have been identified in OSA and separately in AF, further study is needed to investigate the mediation and modulation of these pathways in the OSA and arrhythmia relationship.

To better identify preventative therapeutic targets, future research should focus on the acute compared with chronic OSA-related changes that result in cardiac structural and electrical remodeling. Scant data are focused on the investigation of hypercapnia in OSA as a culprit in arrhythmogenesis. Furthermore, evaluation of the reproducibility of existing findings in alternate experimental models is required. Specifically, organ-specific tissue and molecular experimental studies are needed to examine the direct effects of intermittent hypoxia and hypercapnia on cardiac myocyte and fibroblast voltage-gated ion channels.

Vulnerability of certain areas of the myocardium to OSA-related influences should be clarified (eg, nonpulmonary vein triggers) to inform optimal AF therapeutic approaches such as high-priority anatomical target mapping. Because phenotypic progression of paroxysmal AF to persistent AF occurs, understanding the facets of OSA pathophysiology that are responsible for this progression is important for developing effective preventative strategies. In this era of precision medicine, identifying patient subgroup susceptibilities to OSA-related consequences (eg, intermittent hypoxia or autonomic instability) that would facilitate targeted treatment approaches represents another priority area. The effect of OSA, AF, and heart failure progression as well as ischemic stroke also warrants future research.

Finally, although intriguing data seem to implicate untreated sleep-disordered breathing in the development of recurrent AF after cardioversion or ablation, our field is ripe for the conduct of rigorously performed randomized controlled trials with well-phenotyped participants followed up closely for intervention adherence to examine the effect of OSA treatment on priority AF outcomes. Thus, future investigations should focus on the characterization of the OSA-specific mechanistic pathways because preferentially targeting OSA-related pathophysiologic consequences may reduce arrhythmia-associated morbidity and mortality.

Financial/nonfinancial disclosures: None declared.

Role of sponsors: The sponsor had no role in the preparation of the manuscript.

Peppard P.E. .Young T. .Barnet J.H. .Palta M. .Hagen E.W. .Hla K.M. . Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol. 2013;177:1006-1014 [PubMed]journal. [PubMed]
 
Go A.S. .Hylek E.M. .Phillips K.A. .et al Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001;285:2370-2375 [PubMed]journal. [CrossRef] [PubMed]
 
Benjamin E.J. .Wolf P.A. .D’Agostino R.B. .Silbershatz H. .Kannel W.B. .Levy D. . Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation. 1998;98:946-952 [PubMed]journal. [CrossRef] [PubMed]
 
Mehra R. .Stone K.L. .Varosy P.D. .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;169:1147-1155 [PubMed]journal. [CrossRef] [PubMed]
 
Mehra R. .Benjamin E.J. .Shahar E. .et al Association of nocturnal arrhythmias with sleep-disordered breathing: the Sleep Heart Health Study. Am J Respir Crit Care Med. 2006;173:910-916 [PubMed]journal. [CrossRef] [PubMed]
 
Ng C.Y. .Liu T. .Shehata M. .Stevens S. .Chugh S.S. .Wang X. . Meta-analysis of obstructive sleep apnea as predictor of atrial fibrillation recurrence after catheter ablation. Am J Cardiol. 2011;108:47-51 [PubMed]journal. [CrossRef] [PubMed]
 
Goyal S.K. .Sharma A. . Atrial fibrillation in obstructive sleep apnea. World J Cardiol. 2013;5:157-163 [PubMed]journal. [CrossRef] [PubMed]
 
Holmqvist F. .Guan N. .Zhu Z. .et al Impact of obstructive sleep apnea and continuous positive airway pressure therapy on outcomes in patients with atrial fibrillation—results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Am Heart J. 2015;169:647-654.e2 [PubMed]journal. [CrossRef] [PubMed]
 
Kanagala R. .Murali N.S. .Friedman P.A. .et al Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation. 2003;107:2589-2594 [PubMed]journal. [PubMed]
 
Cadby G. .McArdle N. .Briffa T. .et al Severity of obstructive sleep apnea is an independent predictor of incident atrial fibrillation hospitalization in a large sleep-clinic cohort. Chest. 2015;148:945-952 [PubMed]journal. [CrossRef] [PubMed]
 
Mooe T. .Gullsby S. .Rabben T. .Eriksson P. . Sleep-disordered breathing: a novel predictor of atrial fibrillation after coronary artery bypass surgery. Coron Artery Dis. 1996;7:475-478 [PubMed]journal. [CrossRef] [PubMed]
 
Gami A.S. .Hodge D.O. .Herges R.M. .et al Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation. J Am Coll Cardiol. 2007;49:565-571 [PubMed]journal. [CrossRef] [PubMed]
 
Gami A.S. .Howard D.E. .Olson E.J. .Somers V.K. . Day-night pattern of sudden death in obstructive sleep apnea. N Engl J Med. 2005;352:1206-1214 [PubMed]journal. [CrossRef] [PubMed]
 
Narkiewicz K. .Somers V.K. . The sympathetic nervous system and obstructive sleep apnea: implications for hypertension. J Hypertens. 1997;15:1613-1619 [PubMed]journal. [CrossRef] [PubMed]
 
Narkiewicz K. .Somers V.K. . Sympathetic nerve activity in obstructive sleep apnoea. Acta Physiol Scand. 2003;177:385-390 [PubMed]journal. [CrossRef] [PubMed]
 
Camen G. .Clarenbach C.F. .Stöwhas A.C. .et al The effects of simulated obstructive apnea and hypopnea on arrhythmic potential in healthy subjects. Eur J Appl Physiol. 2013;113:489-496 [PubMed]journal. [CrossRef] [PubMed]
 
Mansukhani M.P. .Wang S. .Somers V.K. . Chemoreflex physiology and implications for sleep apnoea: insights from studies in humans. Exp Physiol. 2015;100:130-135 [PubMed]journal. [CrossRef] [PubMed]
 
May A.M. .Blackwell T. .Stone P.H. .et al Central sleep-disordered breathing predicts incident atrial fibrillation in older men. Am J Respir Crit Care Med. 2016;193:783-791 [PubMed]journal. [CrossRef] [PubMed]
 
Leung R.S.T. .Bowman M.E. .Diep T.M. .Lorenzi-Filho G. .Floras J.S. .Bradley T.D. . Influence of Cheyne-Stokes respiration on ventricular response to atrial fibrillation in heart failure. J Appl Physiol (1985). 2005;99:1689-1696 [PubMed]journal. [CrossRef] [PubMed]
 
Coyne K.S. .Paramore C. .Grandy S. .Mercader M. .Reynolds M. .Zimetbaum P. . Assessing the direct costs of treating nonvalvular atrial fibrillation in the United States. Value Health J Int Soc Pharmacoeconomics Outcomes Res. 2006;9:348-356 [PubMed]journal. [CrossRef]
 
Kim M.H. .Lin J. .Hussein M. .Kreilick C. .Battleman D. . Cost of atrial fibrillation in United States managed care organizations. Adv Ther. 2009;26:847-857 [PubMed]journal. [CrossRef] [PubMed]
 
Roden D.M. .Iansmith D.H. . Effects of low potassium or magnesium concentrations on isolated cardiac tissue. Am J Med. 1987;82:18-23 [PubMed]journal
 
Goodfriend T.L. . Obesity, sleep apnea, aldosterone, and hypertension. Curr Hypertens Rep. 2008;10:222-226 [PubMed]journal. [CrossRef] [PubMed]
 
Berger K.I. .Ayappa I. .Sorkin I.B. .Norman R.G. .Rapoport D.M. .Goldring R.M. . CO(2) homeostasis during periodic breathing in obstructive sleep apnea. J Appl Physiol (1985). 2000;88:257-264 [PubMed]journal. [PubMed]
 
Joung B. .Chen P.S. . Function and dysfunction of human sinoatrial node. Korean Circ J. 2015;45:184-191 [PubMed]journal. [CrossRef] [PubMed]
 
Antzelevitch C. .Burashnikov A. . Overview of basic mechanisms of cardiac arrhythmia. Card Electrophysiol Clin. 2011;3:23-45 [PubMed]journal. [CrossRef] [PubMed]
 
Gupta P. .Patel C. .Patel H. .et al T(p-e)/QT ratio as an index of arrhythmogenesis. J Electrocardiol. 2008;41:567-574 [PubMed]journal. [CrossRef] [PubMed]
 
Panikkath R. .Reinier K. .Uy-Evanado A. .et al Prolonged Tpeak-to-tend interval on the resting ECG is associated with increased risk of sudden cardiac death. Circ Arrhythm Electrophysiol. 2011;4:441-447 [PubMed]journal. [CrossRef] [PubMed]
 
Yamaguchi M. .Shimizu M. .Ino H. .et al T wave peak-to-end interval and QT dispersion in acquired long QT syndrome: a new index for arrhythmogenicity. Clin Sci. 2003;105:671-676 [PubMed]journal. [CrossRef] [PubMed]
 
Kilicaslan F. .Tokatli A. .Ozdag F. .et al Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio are prolonged in patients with moderate and severe obstructive sleep apnea. Pacing Clin Electrophysiol. 2012;35:966-972 [PubMed]journal. [CrossRef] [PubMed]
 
Voigt L. .Haq S.A. .Mitre C.A. .Lombardo G. .Kassotis J. . Effect of obstructive sleep apnea on QT dispersion: a potential mechanism of sudden cardiac death. Cardiology. 2011;118:68-73 [PubMed]journal. [CrossRef] [PubMed]
 
Roche F. .Gaspoz J.M. .Court-Fortune I. .et al Alteration of QT rate dependence reflects cardiac autonomic imbalance in patients with obstructive sleep apnea syndrome. Pacing Clin Electrophysiol. 2003;26:1446-1453 [PubMed]journal. [CrossRef] [PubMed]
 
Roche F. .Barthélémy J.C. .Garet M. .Duverney D. .Pichot V. .Sforza E. . Continuous positive airway pressure treatment improves the QT rate dependence adaptation of obstructive sleep apnea patients. Pacing Clin Electrophysiol. 2005;28:819-825 [PubMed]journal. [CrossRef] [PubMed]
 
Gillis A.M. .Stoohs R. .Guilleminault C. . Changes in the QT interval during obstructive sleep apnea. Sleep. 1991;14:346-350 [PubMed]journal. [PubMed]
 
Lu Z. .Nie L. .He B. .et al Increase in vulnerability of atrial fibrillation in an acute intermittent hypoxia model: importance of autonomic imbalance. Auton Neurosci Basic Clin. 2013;177:148-153 [PubMed]journal. [CrossRef]
 
Linz D. .Schotten U. .Neuberger H.R. .Böhm M. .Wirth K. . Combined blockade of early and late activated atrial potassium currents suppresses atrial fibrillation in a pig model of obstructive apnea. Heart Rhythm Off J Heart Rhythm Soc. 2011;8:1933-1939 [PubMed]journal. [CrossRef]
 
Leung R.S. . Sleep-disordered breathing: autonomic mechanisms and arrhythmias. Prog Cardiovasc Dis. 2009;51:324-338 [PubMed]journal. [CrossRef] [PubMed]
 
Ghias M. .Scherlag B.J. .Lu Z. .et al The role of ganglionated plexi in apnea-related atrial fibrillation. J Am Coll Cardiol. 2009;54:2075-2083 [PubMed]journal. [CrossRef] [PubMed]
 
Linz D. .Mahfoud F. .Schotten U. .et al Renal sympathetic denervation suppresses postapneic blood pressure rises and atrial fibrillation in a model for sleep apnea. Hypertension. 2012;60:172-178 [PubMed]journal. [CrossRef] [PubMed]
 
Linz D. .Hohl M. .Khoshkish S. .et al Low-level but not high-level baroreceptor stimulation inhibits atrial fibrillation in a pig model of sleep apnea. J Cardiovasc Electrophysiol. 2016;27:1086-1092 [PubMed]journal. [CrossRef] [PubMed]
 
Volders P.G. . Novel insights into the role of the sympathetic nervous system in cardiac arrhythmogenesis. Heart Rhythm. 2010;7:1900-1906 [PubMed]journal. [CrossRef] [PubMed]
 
Iwasaki Y.K. .Kato T. .Xiong F. .et al Atrial fibrillation promotion with long-term repetitive obstructive sleep apnea in a rat model. J Am Coll Cardiol. 2014;64:2013-2023 [PubMed]journal. [CrossRef] [PubMed]
 
Guggisberg A.G. .Hess C.W. .Mathis J. . The significance of the sympathetic nervous system in the pathophysiology of periodic leg movements in sleep. Sleep. 2007;30:755-766 [PubMed]journal. [PubMed]
 
Peng Y.J. .Yuan G. .Ramakrishnan D. .et al Heterozygous HIF-1alpha deficiency impairs carotid body-mediated systemic responses and reactive oxygen species generation in mice exposed to intermittent hypoxia. J Physiol. 2006;577:705-716 [PubMed]journal. [CrossRef] [PubMed]
 
Peng Y. .Yuan G. .Overholt J.L. .Kumar G.K. .Prabhakar N.R. . Systemic and cellular responses to intermittent hypoxia: evidence for oxidative stress and mitochondrial dysfunction. Adv Exp Med Biol. 2003;536:559-564 [PubMed]journal. [PubMed]
 
Prabhakar N.R. .Kumar G.K. . Oxidative stress in the systemic and cellular responses to intermittent hypoxia. Biol Chem. 2004;385:217-221 [PubMed]journal. [PubMed]
 
Chen L. .Zhang J. .Gan T.X. .et al Left ventricular dysfunction and associated cellular injury in rats exposed to chronic intermittent hypoxia. J Appl Physiol. 2008;104:218-223 [PubMed]journal. [PubMed]
 
Chen L. .Einbinder E. .Zhang Q. .Hasday J. .Balke C.W. .Scharf S.M. . Oxidative stress and left ventricular function with chronic intermittent hypoxia in rats. Am J Respir Crit Care Med. 2005;172:915-920 [PubMed]journal. [CrossRef] [PubMed]
 
Park A.M. .Suzuki Y.J. . Effects of intermittent hypoxia on oxidative stress-induced myocardial damage in mice. J Appl Physiol. 2007;102:1806-1814 [PubMed]journal. [CrossRef] [PubMed]
 
Brown D.A. .O’Rourke B. . Cardiac mitochondria and arrhythmias. Cardiovasc Res. 2010;88:241-249 [PubMed]journal. [CrossRef] [PubMed]
 
Jeong E.M. .Liu M. .Sturdy M. .et al Metabolic stress, reactive oxygen species, and arrhythmia. J Mol Cell Cardiol. 2012;52:454-463 [PubMed]journal. [CrossRef] [PubMed]
 
Daly M.D. .Scott M.J. . The cardiovascular responses to stimulation of the carotid body chemoreceptors in the dog. J Physiol. 1963;165:179-197 [PubMed]journal. [CrossRef] [PubMed]
 
De Daly M.B. .Scott M.J. . The effects of stimulation of the carotid body chemoreceptors on heart rate in the dog. J Physiol. 1958;144:148-166 [PubMed]journal. [CrossRef] [PubMed]
 
Souvannakitti D. .Kumar G.K. .Fox A. .Prabhakar N.R. . Contrasting effects of intermittent and continuous hypoxia on low O(2) evoked catecholamine secretion from neonatal rat chromaffin cells. Adv Exp Med Biol. 2009;648:345-349 [PubMed]journal. [PubMed]
 
Khayat R. .Patt B. .Hayes D. . Obstructive sleep apnea: the new cardiovascular disease. Part I: obstructive sleep apnea and the pathogenesis of vascular disease. Heart Fail Rev. 2009;14:143-153 [PubMed]journal. [CrossRef] [PubMed]
 
Gutierrez A. .Van Wagoner D.R. . Oxidant and inflammatory mechanisms and targeted therapy in atrial fibrillation: an update. J Cardiovasc Pharmacol. 2015;66:523-529 [PubMed]journal. [CrossRef] [PubMed]
 
Stevenson I.H. .Roberts-Thomson K.C. .Kistler P.M. .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;7:1263-1270 [PubMed]journal. [CrossRef] [PubMed]
 
Parish J.M. .Somers V.K. . Obstructive sleep apnea and cardiovascular disease. Mayo Clin Proc. 2004;79:1036-1046 [PubMed]journal. [CrossRef] [PubMed]
 
Dewland T.A. .Vittinghoff E. .Mandyam M.C. .et al Atrial ectopy as a predictor of incident atrial fibrillation: a cohort study. Ann Intern Med. 2013;159:721-728 [PubMed]journal. [CrossRef] [PubMed]
 
Straus S.M. .Kors J.A. .De Bruin M.L. .et al Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am Coll Cardiol. 2006;47:362-367 [PubMed]journal. [CrossRef] [PubMed]
 
Orban M. .Bruce C.J. .Pressman G.S. .et al Dynamic changes of left ventricular performance and left atrial volume induced by the Mueller maneuver in healthy young adults and implications for obstructive sleep apnea, atrial fibrillation, and heart failure. Am J Cardiol. 2008;102:1557-1561 [PubMed]journal. [CrossRef] [PubMed]
 
Koshino Y. .Villarraga H.R. .Orban M. .et al Changes in left and right ventricular mechanics during the Mueller maneuver in healthy adults: a possible mechanism for abnormal cardiac function in patients with obstructive sleep apnea. Circ Cardiovasc Imaging. 2010;3:282-289 [PubMed]journal. [CrossRef] [PubMed]
 
Drager L.F. .Bortolotto L.A. .Figueiredo A.C. .Silva B.C. .Krieger E.M. .Lorenzi-Filho G. . Obstructive sleep apnea, hypertension, and their interaction on arterial stiffness and heart remodeling. Chest. 2007;131:1379-1386 [PubMed]journal. [CrossRef] [PubMed]
 
Cioffi G. .Russo T.E. .Stefenelli C. .et al Severe obstructive sleep apnea elicits concentric left ventricular geometry. J Hypertens. 2010;28:1074-1082 [PubMed]journal. [CrossRef] [PubMed]
 
Nanduri J. .Vaddi D.R. .Khan S.A. .Wang N. .Makerenko V. .Prabhakar N.R. . Xanthine oxidase mediates hypoxia-inducible factor-2α degradation by intermittent hypoxia. PloS One. 2013;8:e75838- [PubMed]journal. [CrossRef] [PubMed]
 
Eisele H.J. .Markart P. .Schulz R. . Obstructive sleep apnea, oxidative stress, and cardiovascular disease: evidence from human studies. Oxid Med Cell Longev. 2015;2015:608438- [PubMed]journal. [PubMed]
 
DeMartino T. .El Ghoul R. .Wang L. .et al Oxidative stress and inflammation differentially elevated in objective versus habitual subjective reduced sleep duration in obstructive sleep apnea. Sleep. 2016;39:1361-1369 [PubMed]journal. [CrossRef] [PubMed]
 
Nadeem R. .Molnar J. .Madbouly E.M. .et al Serum inflammatory markers in obstructive sleep apnea: a meta-analysis. J Clin Sleep Med. 2013;9:1003-1012 [PubMed]journal. [PubMed]
 
Chung M.K. .Martin D.O. .Sprecher D. .et al C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation. Circulation. 2001;104:2886-2891 [PubMed]journal. [CrossRef] [PubMed]
 
Kaski J.C. .Arrebola-Moreno A.L. . Inflammation and thrombosis in atrial fibrillation [in Spanish]. Rev Esp Cardiol. 2011;64:551-553 [PubMed]journal. [CrossRef] [PubMed]
 
Tousoulis D. .Zisimos K. .Antoniades C. .et al Oxidative stress and inflammatory process in patients with atrial fibrillation: the role of left atrium distension. Int J Cardiol. 2009;136:258-262 [PubMed]journal. [CrossRef] [PubMed]
 
Liak C. .Fitzpatrick M. . Coagulability in obstructive sleep apnea. Can Respir J. 2011;18:338-348 [PubMed]journal. [CrossRef] [PubMed]
 
Spronk HM, De Jong AM, Verheule S, et al. Hypercoagulability causes atrial fibrosis and promotes atrial fibrillation [published online ahead of print April 12, 2016].Eur Heart J.
 
Watson T. .Shantsila E. .Lip G.Y. . Mechanisms of thrombogenesis in atrial fibrillation: Virchow’s triad revisited. Lancet. 2009;373:155-166 [PubMed]journal. [CrossRef] [PubMed]
 
Rahangdale S. .Yeh S.Y. .Novack V. .et al The influence of intermittent hypoxemia on platelet activation in obese patients with obstructive sleep apnea. J Clin Sleep Med. 2011;7:172-178 [PubMed]journal. [PubMed]
 
Wessendorf T.E. .Thilmann A.F. .Wang Y.M. .Schreiber A. .Konietzko N. .Teschler H. . Fibrinogen levels and obstructive sleep apnea in ischemic stroke. Am J Respir Crit Care Med. 2000;162:2039-2042 [PubMed]journal. [CrossRef] [PubMed]
 
Nakanishi K. .Tajima F. .Nakata Y. .et al Hypercoagulable state in a hypobaric, hypoxic environment causes non-bacterial thrombotic endocarditis in rats. J Pathol. 1997;181:338-346 [PubMed]journal. [CrossRef] [PubMed]
 
Mehra R. .Xu F. .Babineau D.C. .et al Sleep-disordered breathing and prothrombotic biomarkers: cross-sectional results of the Cleveland Family Study. Am J Respir Crit Care Med. 2010;182:826-833 [PubMed]journal. [CrossRef] [PubMed]
 
Yagmur J. .Yetkin O. .Cansel M. .et al Assessment of atrial electromechanical delay and influential factors in patients with obstructive sleep apnea. Sleep Breath. 2012;16:83-88 [PubMed]journal. [CrossRef] [PubMed]
 
Chatterjee S. .Bavishi C. .Sardar P. .et al Meta-analysis of left ventricular hypertrophy and sustained arrhythmias. Am J Cardiol. 2014;114:1049-1052 [PubMed]journal. [CrossRef] [PubMed]
 
Nalliah C.J. .Sanders P. .Kalman J.M. . Obstructive sleep apnea treatment and atrial fibrillation: a need for definitive evidence. J Cardiovasc Electrophysiol. 2016;27:1001-1010 [PubMed]journal. [CrossRef] [PubMed]
 
Bonsignore M.R. .Parati G. .Insalaco G. .et al Continuous positive airway pressure treatment improves baroreflex control of heart rate during sleep in severe obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 2002;166:279-286 [PubMed]journal. [CrossRef] [PubMed]
 
Smith J.H. .Baumert M. .Nalivaiko E. .McEvoy R.D. .Catcheside P.G. . Arousal in obstructive sleep apnoea patients is associated with ECG RR and QT interval shortening and PR interval lengthening. J Sleep Res. 2009;18:188-195 [PubMed]journal. [CrossRef] [PubMed]
 
Barta K. .Szabó Z. .Kun C. .et al The effect of sleep apnea on QT interval, QT dispersion, and arrhythmias. Clin Cardiol. 2010;33:E35-E39 [PubMed]journal
 
Dursunoglu D. .Dursunoglu N. .Evrengül H. .et al QT interval dispersion in obstructive sleep apnoea syndrome patients without hypertension. Eur Respir J. 2005;25:677-681 [PubMed]journal. [CrossRef] [PubMed]
 
Cagirci G. .Cay S. .Gulsoy K.G. .et al Tissue Doppler atrial conduction times and electrocardiogram interlead P-wave durations with varying severity of obstructive sleep apnea. J Electrocardiol. 2011;44:478-482 [PubMed]journal. [CrossRef] [PubMed]
 
Dimitri H. .Ng M. .Brooks A.G. .et al Atrial remodeling in obstructive sleep apnea: Implications for atrial fibrillation. Heart Rhythm. 2012;9:321-327 [PubMed]journal. [CrossRef] [PubMed]
 
Kim S.H. .Cho G.Y. .Shin C. .et al Impact of obstructive sleep apnea on left ventricular diastolic function. Am J Cardiol. 2008;101:1663-1668 [PubMed]journal. [CrossRef] [PubMed]
 
Drager L.F. .Bortolotto L.A. .Pedrosa R.P. .Krieger E.M. .Lorenzi-Filho G. . Left atrial diameter is independently associated with arterial stiffness in patients with obstructive sleep apnea: potential implications for atrial fibrillation. Int J Cardiol. 2010;144:257-259 [PubMed]journal. [CrossRef] [PubMed]
 
Matiello M. .Nadal M. .Tamborero D. .et al Low efficacy of atrial fibrillation ablation in severe obstructive sleep apnoea patients. Europace. 2010;12:1084-1089 [PubMed]journal. [CrossRef] [PubMed]
 
Fein A.S. .Shvilkin A. .Shah D. .et al Treatment of obstructive sleep apnea reduces the risk of atrial fibrillation recurrence after catheter ablation. J Am Coll Cardiol. 2013;62:300-305 [PubMed]journal. [CrossRef] [PubMed]
 
Naruse Y. .Tada H. .Satoh M. .et al Concomitant obstructive sleep apnea increases the recurrence of atrial fibrillation following radiofrequency catheter ablation of atrial fibrillation: clinical impact of continuous positive airway pressure therapy. Heart Rhythm. 2013;10:331-337 [PubMed]journal. [CrossRef] [PubMed]
 
Tkacova R. .Dajani H.R. .Rankin F. .Fitzgerald F.S. .Floras J.S. .Douglas Bradley T. . Continuous positive airway pressure improves nocturnal baroreflex sensitivity of patients with heart failure and obstructive sleep apnea. J Hypertens. 2000;18:1257-1262 [PubMed]journal. [CrossRef] [PubMed]
 
Bonsignore M.R. .Parati G. .Insalaco G. .et al Baroreflex control of heart rate during sleep in severe obstructive sleep apnoea: effects of acute CPAP. Eur Respir J. 2006;27:128-135 [PubMed]journal. [CrossRef] [PubMed]
 
Ruttanaumpawan P. .Gilman M.P. .Usui K. .Floras J.S. .Bradley T.D. . Sustained effect of continuous positive airway pressure on baroreflex sensitivity in congestive heart failure patients with obstructive sleep apnea. J Hypertens. 2008;26:1163-1168 [PubMed]journal. [CrossRef] [PubMed]
 
Tamisier R. .Pépin J.L. .Rémy J. .et al 14 nights of intermittent hypoxia elevate daytime blood pressure and sympathetic activity in healthy humans. Eur Respir J. 2011;37:119-128 [PubMed]journal. [CrossRef] [PubMed]
 
Tamisier R. .Nieto L. .Anand A. .Cunnington D. .Weiss J.W. . Sustained muscle sympathetic activity after hypercapnic but not hypocapnic hypoxia in normal humans. Respir Physiol Neurobiol. 2004;141:145-155 [PubMed]journal. [CrossRef] [PubMed]
 
Usui K. .Bradley T.D. .Spaak J. .et al Inhibition of awake sympathetic nerve activity of heart failure patients with obstructive sleep apnea by nocturnal continuous positive airway pressure. J Am Coll Cardiol. 2005;45:2008-2011 [PubMed]journal. [CrossRef] [PubMed]
 
Kohler M. .Stoewhas A.C. .Ayers L. .et al Effects of continuous positive airway pressure therapy withdrawal in patients with obstructive sleep apnea: a randomized controlled trial. Am J Respir Crit Care Med. 2011;184:1192-1199 [PubMed]journal. [CrossRef] [PubMed]
 
Phillips C.L. .Yang Q. .Williams A. .et al The effect of short-term withdrawal from continuous positive airway pressure therapy on sympathetic activity and markers of vascular inflammation in subjects with obstructive sleep apnoea. J Sleep Res. 2007;16:217-225 [PubMed]journal. [CrossRef] [PubMed]
 
Chrysostomakis S.I. .Simantirakis E.N. .Schiza S.E. .et al Continuous positive airway pressure therapy lowers vagal tone in patients with obstructive sleep apnoea-hypopnoea syndrome. Hell J Cardiol. 2006;47:13-20 [PubMed]journal
 
Dursunoglu D. .Dursunoglu N. . Effect of CPAP on QT interval dispersion in obstructive sleep apnea patients without hypertension. Sleep Med. 2007;8:478-483 [PubMed]journal. [CrossRef] [PubMed]
 
Rossi V.A. .Stoewhas A.C. .Camen G. .et al The effects of continuous positive airway pressure therapy withdrawal on cardiac repolarization: data from a randomized controlled trial. Eur Heart J. 2012;33:2206-2212 [PubMed]journal. [CrossRef] [PubMed]
 
Baranchuk A. .Pang H. .Seaborn G.E. .et al Reverse atrial electrical remodelling induced by continuous positive airway pressure in patients with severe obstructive sleep apnoea. J Interv Card Electrophysiol. 2013;36:247-253 [PubMed]journal. [CrossRef] [PubMed]
 
Maeno K. .Kasagi S. .Ueda A. .et al Effects of obstructive sleep apnea and its treatment on signal-averaged P-wave duration in men. Circ Arrhythm Electrophysiol. 2013;6:287-293 [PubMed]journal. [CrossRef] [PubMed]
 
Bayır P.T. .Demirkan B. .Bayır Ö. .et al Impact of continuous positive airway pressure therapy on atrial electromechanical delay and P-wave dispersion in patients with obstructive sleep apnea. Ann Noninvasive Electrocardiol. 2014;19:226-233 [PubMed]journal. [CrossRef] [PubMed]
 
Dursunoglu N. .Dursunoglu D. .Ozkurt S. .et al Effects of CPAP on left ventricular structure and myocardial performance index in male patients with obstructive sleep apnoea. Sleep Med. 2007;8:51-59 [PubMed]journal. [CrossRef] [PubMed]
 
Dursunoglu N. .Dursunoglu D. .Ozkurt S. .Gür S. .Ozalp G. .Evyapan F. . Effects of CPAP on right ventricular myocardial performance index in obstructive sleep apnea patients without hypertension. Respir Res. 2006;7:22- [PubMed]journal. [CrossRef] [PubMed]
 
Oliveira W. .Campos O. .Cintra F. .et al Impact of continuous positive airway pressure treatment on left atrial volume and function in patients with obstructive sleep apnoea assessed by real-time three-dimensional echocardiography. Heart. 2009;95:1872-1878 [PubMed]journal. [CrossRef] [PubMed]
 
Colish J. .Walker J.R. .Elmayergi N. .et al Obstructive sleep apnea: effects of continuous positive airway pressure on cardiac remodeling as assessed by cardiac biomarkers, echocardiography, and cardiac MRI. Chest. 2012;141:674-681 [PubMed]journal. [CrossRef] [PubMed]
 
Oliveira W. .Poyares D. .Cintra F. .et al Impact of continuous positive airway pressure treatment on right ventricle performance in patients with obstructive sleep apnoea, assessed by three-dimensional echocardiography. Sleep Med. 2012;13:510-516 [PubMed]journal. [CrossRef] [PubMed]
 
Vural M.G. .Cetin S. .Firat H. .Akdemir R. .Yeter E. . Impact of continuous positive airway pressure therapy on left atrial function in patients with obstructive sleep apnoea: assessment by conventional and two-dimensional speckle-tracking echocardiography. Acta Cardiol. 2014;69:175-184 [PubMed]journal. [PubMed]
 
Craig S. .Pepperell J.C. .Kohler M. .Crosthwaite N. .Davies R.J. .Stradling J.R. . Continuous positive airway pressure treatment for obstructive sleep apnoea reduces resting heart rate but does not affect dysrhythmias: a randomised controlled trial. J Sleep Res. 2009;18:329-336 [PubMed]journal. [CrossRef] [PubMed]
 
Campen M.J. .Shimoda L.A. .O’Donnell C.P. . Acute and chronic cardiovascular effects of intermittent hypoxia in C57BL/6J mice. J Appl Physiol. 2005;99:2028-2035 [PubMed]journal. [CrossRef] [PubMed]
 
Lesske J. .Fletcher E.C. .Bao G. .Unger T. . Hypertension caused by chronic intermittent hypoxia—influence of chemoreceptors and sympathetic nervous system. J Hypertens. 1997;15:1593-1603 [PubMed]journal. [CrossRef] [PubMed]
 
Linz D. .Hohl M. .Nickel A. .et al Effect of renal denervation on neurohumoral activation triggering atrial fibrillation in obstructive sleep apnea. Hypertension. 2013;62:767-774 [PubMed]journal. [CrossRef] [PubMed]
 
Fletcher E.C. .Lesske J. .Culman J. .Miller C.C. .Unger T. . Sympathetic denervation blocks blood pressure elevation in episodic hypoxia. Hypertension. 1992;20:612-619 [PubMed]journal. [CrossRef] [PubMed]
 
Bao G. .Randhawa P.M. .Fletcher E.C. . Acute blood pressure elevation during repetitive hypocapnic and eucapnic hypoxia in rats. J Appl Physiol. 1997;82:1071-1078 [PubMed]journal. [PubMed]
 
Gao M. .Zhang L. .Scherlag B.J. .et al Low-level vagosympathetic trunk stimulation inhibits atrial fibrillation in a rabbit model of obstructive sleep apnea. Heart Rhythm. 2015;12:818-824 [PubMed]journal. [CrossRef] [PubMed]
 
Ravelli F. .Allessie M. . Effects of atrial dilatation on refractory period and vulnerability to atrial fibrillation in the isolated Langendorff-perfused rabbit heart. Circulation. 1997;96:1686-1695 [PubMed]journal. [CrossRef] [PubMed]
 
Iwasaki Y. .Shi Y. .Benito B. .et al Determinants of atrial fibrillation in an animal model of obesity and acute obstructive sleep apnea. Heart Rhythm. 2012;9:1409-1416.e1 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 Overview of putative sleep apnea pathophysiologic pathways with varying levels of evidence potentially predisposing to cardiac arrhythmogenesis. O2 = oxygen.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Overview of Clinical or Epidemiologic Studies Characterizing Sleep-disordered Breathing and Cardiac Structural and Electrophysiologic Indices

AF = atrial fibrillation; AHI = apnea-hypoapnea index; CIH = chronic intermittent hypoxia; ERP = effective refractory period; HTN = hypertension; LV = left ventricular; PSG = polysomnography; QTc = corrected QT interval; RCT = randomized controlled trial; RV = right ventricular; Tp/Te = interval between the ECG T-wave peak and end.

Table Graphic Jump Location
Table 2 Overview of Animal Experimental Studies Characterizing Sleep-disordered Breathing and Cardiac Structural and Electrophysiologic Indices

HIF = hypoxia-inducible factor; LLVS = low-level vagosympathetic trunk stimulation; NTP = negative tracheal pressure; ROS = reactive oxygen species. See Table 1 legend for expansion of other abbreviations.

References

Peppard P.E. .Young T. .Barnet J.H. .Palta M. .Hagen E.W. .Hla K.M. . Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol. 2013;177:1006-1014 [PubMed]journal. [PubMed]
 
Go A.S. .Hylek E.M. .Phillips K.A. .et al Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001;285:2370-2375 [PubMed]journal. [CrossRef] [PubMed]
 
Benjamin E.J. .Wolf P.A. .D’Agostino R.B. .Silbershatz H. .Kannel W.B. .Levy D. . Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation. 1998;98:946-952 [PubMed]journal. [CrossRef] [PubMed]
 
Mehra R. .Stone K.L. .Varosy P.D. .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;169:1147-1155 [PubMed]journal. [CrossRef] [PubMed]
 
Mehra R. .Benjamin E.J. .Shahar E. .et al Association of nocturnal arrhythmias with sleep-disordered breathing: the Sleep Heart Health Study. Am J Respir Crit Care Med. 2006;173:910-916 [PubMed]journal. [CrossRef] [PubMed]
 
Ng C.Y. .Liu T. .Shehata M. .Stevens S. .Chugh S.S. .Wang X. . Meta-analysis of obstructive sleep apnea as predictor of atrial fibrillation recurrence after catheter ablation. Am J Cardiol. 2011;108:47-51 [PubMed]journal. [CrossRef] [PubMed]
 
Goyal S.K. .Sharma A. . Atrial fibrillation in obstructive sleep apnea. World J Cardiol. 2013;5:157-163 [PubMed]journal. [CrossRef] [PubMed]
 
Holmqvist F. .Guan N. .Zhu Z. .et al Impact of obstructive sleep apnea and continuous positive airway pressure therapy on outcomes in patients with atrial fibrillation—results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Am Heart J. 2015;169:647-654.e2 [PubMed]journal. [CrossRef] [PubMed]
 
Kanagala R. .Murali N.S. .Friedman P.A. .et al Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation. 2003;107:2589-2594 [PubMed]journal. [PubMed]
 
Cadby G. .McArdle N. .Briffa T. .et al Severity of obstructive sleep apnea is an independent predictor of incident atrial fibrillation hospitalization in a large sleep-clinic cohort. Chest. 2015;148:945-952 [PubMed]journal. [CrossRef] [PubMed]
 
Mooe T. .Gullsby S. .Rabben T. .Eriksson P. . Sleep-disordered breathing: a novel predictor of atrial fibrillation after coronary artery bypass surgery. Coron Artery Dis. 1996;7:475-478 [PubMed]journal. [CrossRef] [PubMed]
 
Gami A.S. .Hodge D.O. .Herges R.M. .et al Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation. J Am Coll Cardiol. 2007;49:565-571 [PubMed]journal. [CrossRef] [PubMed]
 
Gami A.S. .Howard D.E. .Olson E.J. .Somers V.K. . Day-night pattern of sudden death in obstructive sleep apnea. N Engl J Med. 2005;352:1206-1214 [PubMed]journal. [CrossRef] [PubMed]
 
Narkiewicz K. .Somers V.K. . The sympathetic nervous system and obstructive sleep apnea: implications for hypertension. J Hypertens. 1997;15:1613-1619 [PubMed]journal. [CrossRef] [PubMed]
 
Narkiewicz K. .Somers V.K. . Sympathetic nerve activity in obstructive sleep apnoea. Acta Physiol Scand. 2003;177:385-390 [PubMed]journal. [CrossRef] [PubMed]
 
Camen G. .Clarenbach C.F. .Stöwhas A.C. .et al The effects of simulated obstructive apnea and hypopnea on arrhythmic potential in healthy subjects. Eur J Appl Physiol. 2013;113:489-496 [PubMed]journal. [CrossRef] [PubMed]
 
Mansukhani M.P. .Wang S. .Somers V.K. . Chemoreflex physiology and implications for sleep apnoea: insights from studies in humans. Exp Physiol. 2015;100:130-135 [PubMed]journal. [CrossRef] [PubMed]
 
May A.M. .Blackwell T. .Stone P.H. .et al Central sleep-disordered breathing predicts incident atrial fibrillation in older men. Am J Respir Crit Care Med. 2016;193:783-791 [PubMed]journal. [CrossRef] [PubMed]
 
Leung R.S.T. .Bowman M.E. .Diep T.M. .Lorenzi-Filho G. .Floras J.S. .Bradley T.D. . Influence of Cheyne-Stokes respiration on ventricular response to atrial fibrillation in heart failure. J Appl Physiol (1985). 2005;99:1689-1696 [PubMed]journal. [CrossRef] [PubMed]
 
Coyne K.S. .Paramore C. .Grandy S. .Mercader M. .Reynolds M. .Zimetbaum P. . Assessing the direct costs of treating nonvalvular atrial fibrillation in the United States. Value Health J Int Soc Pharmacoeconomics Outcomes Res. 2006;9:348-356 [PubMed]journal. [CrossRef]
 
Kim M.H. .Lin J. .Hussein M. .Kreilick C. .Battleman D. . Cost of atrial fibrillation in United States managed care organizations. Adv Ther. 2009;26:847-857 [PubMed]journal. [CrossRef] [PubMed]
 
Roden D.M. .Iansmith D.H. . Effects of low potassium or magnesium concentrations on isolated cardiac tissue. Am J Med. 1987;82:18-23 [PubMed]journal
 
Goodfriend T.L. . Obesity, sleep apnea, aldosterone, and hypertension. Curr Hypertens Rep. 2008;10:222-226 [PubMed]journal. [CrossRef] [PubMed]
 
Berger K.I. .Ayappa I. .Sorkin I.B. .Norman R.G. .Rapoport D.M. .Goldring R.M. . CO(2) homeostasis during periodic breathing in obstructive sleep apnea. J Appl Physiol (1985). 2000;88:257-264 [PubMed]journal. [PubMed]
 
Joung B. .Chen P.S. . Function and dysfunction of human sinoatrial node. Korean Circ J. 2015;45:184-191 [PubMed]journal. [CrossRef] [PubMed]
 
Antzelevitch C. .Burashnikov A. . Overview of basic mechanisms of cardiac arrhythmia. Card Electrophysiol Clin. 2011;3:23-45 [PubMed]journal. [CrossRef] [PubMed]
 
Gupta P. .Patel C. .Patel H. .et al T(p-e)/QT ratio as an index of arrhythmogenesis. J Electrocardiol. 2008;41:567-574 [PubMed]journal. [CrossRef] [PubMed]
 
Panikkath R. .Reinier K. .Uy-Evanado A. .et al Prolonged Tpeak-to-tend interval on the resting ECG is associated with increased risk of sudden cardiac death. Circ Arrhythm Electrophysiol. 2011;4:441-447 [PubMed]journal. [CrossRef] [PubMed]
 
Yamaguchi M. .Shimizu M. .Ino H. .et al T wave peak-to-end interval and QT dispersion in acquired long QT syndrome: a new index for arrhythmogenicity. Clin Sci. 2003;105:671-676 [PubMed]journal. [CrossRef] [PubMed]
 
Kilicaslan F. .Tokatli A. .Ozdag F. .et al Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio are prolonged in patients with moderate and severe obstructive sleep apnea. Pacing Clin Electrophysiol. 2012;35:966-972 [PubMed]journal. [CrossRef] [PubMed]
 
Voigt L. .Haq S.A. .Mitre C.A. .Lombardo G. .Kassotis J. . Effect of obstructive sleep apnea on QT dispersion: a potential mechanism of sudden cardiac death. Cardiology. 2011;118:68-73 [PubMed]journal. [CrossRef] [PubMed]
 
Roche F. .Gaspoz J.M. .Court-Fortune I. .et al Alteration of QT rate dependence reflects cardiac autonomic imbalance in patients with obstructive sleep apnea syndrome. Pacing Clin Electrophysiol. 2003;26:1446-1453 [PubMed]journal. [CrossRef] [PubMed]
 
Roche F. .Barthélémy J.C. .Garet M. .Duverney D. .Pichot V. .Sforza E. . Continuous positive airway pressure treatment improves the QT rate dependence adaptation of obstructive sleep apnea patients. Pacing Clin Electrophysiol. 2005;28:819-825 [PubMed]journal. [CrossRef] [PubMed]
 
Gillis A.M. .Stoohs R. .Guilleminault C. . Changes in the QT interval during obstructive sleep apnea. Sleep. 1991;14:346-350 [PubMed]journal. [PubMed]
 
Lu Z. .Nie L. .He B. .et al Increase in vulnerability of atrial fibrillation in an acute intermittent hypoxia model: importance of autonomic imbalance. Auton Neurosci Basic Clin. 2013;177:148-153 [PubMed]journal. [CrossRef]
 
Linz D. .Schotten U. .Neuberger H.R. .Böhm M. .Wirth K. . Combined blockade of early and late activated atrial potassium currents suppresses atrial fibrillation in a pig model of obstructive apnea. Heart Rhythm Off J Heart Rhythm Soc. 2011;8:1933-1939 [PubMed]journal. [CrossRef]
 
Leung R.S. . Sleep-disordered breathing: autonomic mechanisms and arrhythmias. Prog Cardiovasc Dis. 2009;51:324-338 [PubMed]journal. [CrossRef] [PubMed]
 
Ghias M. .Scherlag B.J. .Lu Z. .et al The role of ganglionated plexi in apnea-related atrial fibrillation. J Am Coll Cardiol. 2009;54:2075-2083 [PubMed]journal. [CrossRef] [PubMed]
 
Linz D. .Mahfoud F. .Schotten U. .et al Renal sympathetic denervation suppresses postapneic blood pressure rises and atrial fibrillation in a model for sleep apnea. Hypertension. 2012;60:172-178 [PubMed]journal. [CrossRef] [PubMed]
 
Linz D. .Hohl M. .Khoshkish S. .et al Low-level but not high-level baroreceptor stimulation inhibits atrial fibrillation in a pig model of sleep apnea. J Cardiovasc Electrophysiol. 2016;27:1086-1092 [PubMed]journal. [CrossRef] [PubMed]
 
Volders P.G. . Novel insights into the role of the sympathetic nervous system in cardiac arrhythmogenesis. Heart Rhythm. 2010;7:1900-1906 [PubMed]journal. [CrossRef] [PubMed]
 
Iwasaki Y.K. .Kato T. .Xiong F. .et al Atrial fibrillation promotion with long-term repetitive obstructive sleep apnea in a rat model. J Am Coll Cardiol. 2014;64:2013-2023 [PubMed]journal. [CrossRef] [PubMed]
 
Guggisberg A.G. .Hess C.W. .Mathis J. . The significance of the sympathetic nervous system in the pathophysiology of periodic leg movements in sleep. Sleep. 2007;30:755-766 [PubMed]journal. [PubMed]
 
Peng Y.J. .Yuan G. .Ramakrishnan D. .et al Heterozygous HIF-1alpha deficiency impairs carotid body-mediated systemic responses and reactive oxygen species generation in mice exposed to intermittent hypoxia. J Physiol. 2006;577:705-716 [PubMed]journal. [CrossRef] [PubMed]
 
Peng Y. .Yuan G. .Overholt J.L. .Kumar G.K. .Prabhakar N.R. . Systemic and cellular responses to intermittent hypoxia: evidence for oxidative stress and mitochondrial dysfunction. Adv Exp Med Biol. 2003;536:559-564 [PubMed]journal. [PubMed]
 
Prabhakar N.R. .Kumar G.K. . Oxidative stress in the systemic and cellular responses to intermittent hypoxia. Biol Chem. 2004;385:217-221 [PubMed]journal. [PubMed]
 
Chen L. .Zhang J. .Gan T.X. .et al Left ventricular dysfunction and associated cellular injury in rats exposed to chronic intermittent hypoxia. J Appl Physiol. 2008;104:218-223 [PubMed]journal. [PubMed]
 
Chen L. .Einbinder E. .Zhang Q. .Hasday J. .Balke C.W. .Scharf S.M. . Oxidative stress and left ventricular function with chronic intermittent hypoxia in rats. Am J Respir Crit Care Med. 2005;172:915-920 [PubMed]journal. [CrossRef] [PubMed]
 
Park A.M. .Suzuki Y.J. . Effects of intermittent hypoxia on oxidative stress-induced myocardial damage in mice. J Appl Physiol. 2007;102:1806-1814 [PubMed]journal. [CrossRef] [PubMed]
 
Brown D.A. .O’Rourke B. . Cardiac mitochondria and arrhythmias. Cardiovasc Res. 2010;88:241-249 [PubMed]journal. [CrossRef] [PubMed]
 
Jeong E.M. .Liu M. .Sturdy M. .et al Metabolic stress, reactive oxygen species, and arrhythmia. J Mol Cell Cardiol. 2012;52:454-463 [PubMed]journal. [CrossRef] [PubMed]
 
Daly M.D. .Scott M.J. . The cardiovascular responses to stimulation of the carotid body chemoreceptors in the dog. J Physiol. 1963;165:179-197 [PubMed]journal. [CrossRef] [PubMed]
 
De Daly M.B. .Scott M.J. . The effects of stimulation of the carotid body chemoreceptors on heart rate in the dog. J Physiol. 1958;144:148-166 [PubMed]journal. [CrossRef] [PubMed]
 
Souvannakitti D. .Kumar G.K. .Fox A. .Prabhakar N.R. . Contrasting effects of intermittent and continuous hypoxia on low O(2) evoked catecholamine secretion from neonatal rat chromaffin cells. Adv Exp Med Biol. 2009;648:345-349 [PubMed]journal. [PubMed]
 
Khayat R. .Patt B. .Hayes D. . Obstructive sleep apnea: the new cardiovascular disease. Part I: obstructive sleep apnea and the pathogenesis of vascular disease. Heart Fail Rev. 2009;14:143-153 [PubMed]journal. [CrossRef] [PubMed]
 
Gutierrez A. .Van Wagoner D.R. . Oxidant and inflammatory mechanisms and targeted therapy in atrial fibrillation: an update. J Cardiovasc Pharmacol. 2015;66:523-529 [PubMed]journal. [CrossRef] [PubMed]
 
Stevenson I.H. .Roberts-Thomson K.C. .Kistler P.M. .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;7:1263-1270 [PubMed]journal. [CrossRef] [PubMed]
 
Parish J.M. .Somers V.K. . Obstructive sleep apnea and cardiovascular disease. Mayo Clin Proc. 2004;79:1036-1046 [PubMed]journal. [CrossRef] [PubMed]
 
Dewland T.A. .Vittinghoff E. .Mandyam M.C. .et al Atrial ectopy as a predictor of incident atrial fibrillation: a cohort study. Ann Intern Med. 2013;159:721-728 [PubMed]journal. [CrossRef] [PubMed]
 
Straus S.M. .Kors J.A. .De Bruin M.L. .et al Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am Coll Cardiol. 2006;47:362-367 [PubMed]journal. [CrossRef] [PubMed]
 
Orban M. .Bruce C.J. .Pressman G.S. .et al Dynamic changes of left ventricular performance and left atrial volume induced by the Mueller maneuver in healthy young adults and implications for obstructive sleep apnea, atrial fibrillation, and heart failure. Am J Cardiol. 2008;102:1557-1561 [PubMed]journal. [CrossRef] [PubMed]
 
Koshino Y. .Villarraga H.R. .Orban M. .et al Changes in left and right ventricular mechanics during the Mueller maneuver in healthy adults: a possible mechanism for abnormal cardiac function in patients with obstructive sleep apnea. Circ Cardiovasc Imaging. 2010;3:282-289 [PubMed]journal. [CrossRef] [PubMed]
 
Drager L.F. .Bortolotto L.A. .Figueiredo A.C. .Silva B.C. .Krieger E.M. .Lorenzi-Filho G. . Obstructive sleep apnea, hypertension, and their interaction on arterial stiffness and heart remodeling. Chest. 2007;131:1379-1386 [PubMed]journal. [CrossRef] [PubMed]
 
Cioffi G. .Russo T.E. .Stefenelli C. .et al Severe obstructive sleep apnea elicits concentric left ventricular geometry. J Hypertens. 2010;28:1074-1082 [PubMed]journal. [CrossRef] [PubMed]
 
Nanduri J. .Vaddi D.R. .Khan S.A. .Wang N. .Makerenko V. .Prabhakar N.R. . Xanthine oxidase mediates hypoxia-inducible factor-2α degradation by intermittent hypoxia. PloS One. 2013;8:e75838- [PubMed]journal. [CrossRef] [PubMed]
 
Eisele H.J. .Markart P. .Schulz R. . Obstructive sleep apnea, oxidative stress, and cardiovascular disease: evidence from human studies. Oxid Med Cell Longev. 2015;2015:608438- [PubMed]journal. [PubMed]
 
DeMartino T. .El Ghoul R. .Wang L. .et al Oxidative stress and inflammation differentially elevated in objective versus habitual subjective reduced sleep duration in obstructive sleep apnea. Sleep. 2016;39:1361-1369 [PubMed]journal. [CrossRef] [PubMed]
 
Nadeem R. .Molnar J. .Madbouly E.M. .et al Serum inflammatory markers in obstructive sleep apnea: a meta-analysis. J Clin Sleep Med. 2013;9:1003-1012 [PubMed]journal. [PubMed]
 
Chung M.K. .Martin D.O. .Sprecher D. .et al C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation. Circulation. 2001;104:2886-2891 [PubMed]journal. [CrossRef] [PubMed]
 
Kaski J.C. .Arrebola-Moreno A.L. . Inflammation and thrombosis in atrial fibrillation [in Spanish]. Rev Esp Cardiol. 2011;64:551-553 [PubMed]journal. [CrossRef] [PubMed]
 
Tousoulis D. .Zisimos K. .Antoniades C. .et al Oxidative stress and inflammatory process in patients with atrial fibrillation: the role of left atrium distension. Int J Cardiol. 2009;136:258-262 [PubMed]journal. [CrossRef] [PubMed]
 
Liak C. .Fitzpatrick M. . Coagulability in obstructive sleep apnea. Can Respir J. 2011;18:338-348 [PubMed]journal. [CrossRef] [PubMed]
 
Spronk HM, De Jong AM, Verheule S, et al. Hypercoagulability causes atrial fibrosis and promotes atrial fibrillation [published online ahead of print April 12, 2016].Eur Heart J.
 
Watson T. .Shantsila E. .Lip G.Y. . Mechanisms of thrombogenesis in atrial fibrillation: Virchow’s triad revisited. Lancet. 2009;373:155-166 [PubMed]journal. [CrossRef] [PubMed]
 
Rahangdale S. .Yeh S.Y. .Novack V. .et al The influence of intermittent hypoxemia on platelet activation in obese patients with obstructive sleep apnea. J Clin Sleep Med. 2011;7:172-178 [PubMed]journal. [PubMed]
 
Wessendorf T.E. .Thilmann A.F. .Wang Y.M. .Schreiber A. .Konietzko N. .Teschler H. . Fibrinogen levels and obstructive sleep apnea in ischemic stroke. Am J Respir Crit Care Med. 2000;162:2039-2042 [PubMed]journal. [CrossRef] [PubMed]
 
Nakanishi K. .Tajima F. .Nakata Y. .et al Hypercoagulable state in a hypobaric, hypoxic environment causes non-bacterial thrombotic endocarditis in rats. J Pathol. 1997;181:338-346 [PubMed]journal. [CrossRef] [PubMed]
 
Mehra R. .Xu F. .Babineau D.C. .et al Sleep-disordered breathing and prothrombotic biomarkers: cross-sectional results of the Cleveland Family Study. Am J Respir Crit Care Med. 2010;182:826-833 [PubMed]journal. [CrossRef] [PubMed]
 
Yagmur J. .Yetkin O. .Cansel M. .et al Assessment of atrial electromechanical delay and influential factors in patients with obstructive sleep apnea. Sleep Breath. 2012;16:83-88 [PubMed]journal. [CrossRef] [PubMed]
 
Chatterjee S. .Bavishi C. .Sardar P. .et al Meta-analysis of left ventricular hypertrophy and sustained arrhythmias. Am J Cardiol. 2014;114:1049-1052 [PubMed]journal. [CrossRef] [PubMed]
 
Nalliah C.J. .Sanders P. .Kalman J.M. . Obstructive sleep apnea treatment and atrial fibrillation: a need for definitive evidence. J Cardiovasc Electrophysiol. 2016;27:1001-1010 [PubMed]journal. [CrossRef] [PubMed]
 
Bonsignore M.R. .Parati G. .Insalaco G. .et al Continuous positive airway pressure treatment improves baroreflex control of heart rate during sleep in severe obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 2002;166:279-286 [PubMed]journal. [CrossRef] [PubMed]
 
Smith J.H. .Baumert M. .Nalivaiko E. .McEvoy R.D. .Catcheside P.G. . Arousal in obstructive sleep apnoea patients is associated with ECG RR and QT interval shortening and PR interval lengthening. J Sleep Res. 2009;18:188-195 [PubMed]journal. [CrossRef] [PubMed]
 
Barta K. .Szabó Z. .Kun C. .et al The effect of sleep apnea on QT interval, QT dispersion, and arrhythmias. Clin Cardiol. 2010;33:E35-E39 [PubMed]journal
 
Dursunoglu D. .Dursunoglu N. .Evrengül H. .et al QT interval dispersion in obstructive sleep apnoea syndrome patients without hypertension. Eur Respir J. 2005;25:677-681 [PubMed]journal. [CrossRef] [PubMed]
 
Cagirci G. .Cay S. .Gulsoy K.G. .et al Tissue Doppler atrial conduction times and electrocardiogram interlead P-wave durations with varying severity of obstructive sleep apnea. J Electrocardiol. 2011;44:478-482 [PubMed]journal. [CrossRef] [PubMed]
 
Dimitri H. .Ng M. .Brooks A.G. .et al Atrial remodeling in obstructive sleep apnea: Implications for atrial fibrillation. Heart Rhythm. 2012;9:321-327 [PubMed]journal. [CrossRef] [PubMed]
 
Kim S.H. .Cho G.Y. .Shin C. .et al Impact of obstructive sleep apnea on left ventricular diastolic function. Am J Cardiol. 2008;101:1663-1668 [PubMed]journal. [CrossRef] [PubMed]
 
Drager L.F. .Bortolotto L.A. .Pedrosa R.P. .Krieger E.M. .Lorenzi-Filho G. . Left atrial diameter is independently associated with arterial stiffness in patients with obstructive sleep apnea: potential implications for atrial fibrillation. Int J Cardiol. 2010;144:257-259 [PubMed]journal. [CrossRef] [PubMed]
 
Matiello M. .Nadal M. .Tamborero D. .et al Low efficacy of atrial fibrillation ablation in severe obstructive sleep apnoea patients. Europace. 2010;12:1084-1089 [PubMed]journal. [CrossRef] [PubMed]
 
Fein A.S. .Shvilkin A. .Shah D. .et al Treatment of obstructive sleep apnea reduces the risk of atrial fibrillation recurrence after catheter ablation. J Am Coll Cardiol. 2013;62:300-305 [PubMed]journal. [CrossRef] [PubMed]
 
Naruse Y. .Tada H. .Satoh M. .et al Concomitant obstructive sleep apnea increases the recurrence of atrial fibrillation following radiofrequency catheter ablation of atrial fibrillation: clinical impact of continuous positive airway pressure therapy. Heart Rhythm. 2013;10:331-337 [PubMed]journal. [CrossRef] [PubMed]
 
Tkacova R. .Dajani H.R. .Rankin F. .Fitzgerald F.S. .Floras J.S. .Douglas Bradley T. . Continuous positive airway pressure improves nocturnal baroreflex sensitivity of patients with heart failure and obstructive sleep apnea. J Hypertens. 2000;18:1257-1262 [PubMed]journal. [CrossRef] [PubMed]
 
Bonsignore M.R. .Parati G. .Insalaco G. .et al Baroreflex control of heart rate during sleep in severe obstructive sleep apnoea: effects of acute CPAP. Eur Respir J. 2006;27:128-135 [PubMed]journal. [CrossRef] [PubMed]
 
Ruttanaumpawan P. .Gilman M.P. .Usui K. .Floras J.S. .Bradley T.D. . Sustained effect of continuous positive airway pressure on baroreflex sensitivity in congestive heart failure patients with obstructive sleep apnea. J Hypertens. 2008;26:1163-1168 [PubMed]journal. [CrossRef] [PubMed]
 
Tamisier R. .Pépin J.L. .Rémy J. .et al 14 nights of intermittent hypoxia elevate daytime blood pressure and sympathetic activity in healthy humans. Eur Respir J. 2011;37:119-128 [PubMed]journal. [CrossRef] [PubMed]
 
Tamisier R. .Nieto L. .Anand A. .Cunnington D. .Weiss J.W. . Sustained muscle sympathetic activity after hypercapnic but not hypocapnic hypoxia in normal humans. Respir Physiol Neurobiol. 2004;141:145-155 [PubMed]journal. [CrossRef] [PubMed]
 
Usui K. .Bradley T.D. .Spaak J. .et al Inhibition of awake sympathetic nerve activity of heart failure patients with obstructive sleep apnea by nocturnal continuous positive airway pressure. J Am Coll Cardiol. 2005;45:2008-2011 [PubMed]journal. [CrossRef] [PubMed]
 
Kohler M. .Stoewhas A.C. .Ayers L. .et al Effects of continuous positive airway pressure therapy withdrawal in patients with obstructive sleep apnea: a randomized controlled trial. Am J Respir Crit Care Med. 2011;184:1192-1199 [PubMed]journal. [CrossRef] [PubMed]
 
Phillips C.L. .Yang Q. .Williams A. .et al The effect of short-term withdrawal from continuous positive airway pressure therapy on sympathetic activity and markers of vascular inflammation in subjects with obstructive sleep apnoea. J Sleep Res. 2007;16:217-225 [PubMed]journal. [CrossRef] [PubMed]
 
Chrysostomakis S.I. .Simantirakis E.N. .Schiza S.E. .et al Continuous positive airway pressure therapy lowers vagal tone in patients with obstructive sleep apnoea-hypopnoea syndrome. Hell J Cardiol. 2006;47:13-20 [PubMed]journal
 
Dursunoglu D. .Dursunoglu N. . Effect of CPAP on QT interval dispersion in obstructive sleep apnea patients without hypertension. Sleep Med. 2007;8:478-483 [PubMed]journal. [CrossRef] [PubMed]
 
Rossi V.A. .Stoewhas A.C. .Camen G. .et al The effects of continuous positive airway pressure therapy withdrawal on cardiac repolarization: data from a randomized controlled trial. Eur Heart J. 2012;33:2206-2212 [PubMed]journal. [CrossRef] [PubMed]
 
Baranchuk A. .Pang H. .Seaborn G.E. .et al Reverse atrial electrical remodelling induced by continuous positive airway pressure in patients with severe obstructive sleep apnoea. J Interv Card Electrophysiol. 2013;36:247-253 [PubMed]journal. [CrossRef] [PubMed]
 
Maeno K. .Kasagi S. .Ueda A. .et al Effects of obstructive sleep apnea and its treatment on signal-averaged P-wave duration in men. Circ Arrhythm Electrophysiol. 2013;6:287-293 [PubMed]journal. [CrossRef] [PubMed]
 
Bayır P.T. .Demirkan B. .Bayır Ö. .et al Impact of continuous positive airway pressure therapy on atrial electromechanical delay and P-wave dispersion in patients with obstructive sleep apnea. Ann Noninvasive Electrocardiol. 2014;19:226-233 [PubMed]journal. [CrossRef] [PubMed]
 
Dursunoglu N. .Dursunoglu D. .Ozkurt S. .et al Effects of CPAP on left ventricular structure and myocardial performance index in male patients with obstructive sleep apnoea. Sleep Med. 2007;8:51-59 [PubMed]journal. [CrossRef] [PubMed]
 
Dursunoglu N. .Dursunoglu D. .Ozkurt S. .Gür S. .Ozalp G. .Evyapan F. . Effects of CPAP on right ventricular myocardial performance index in obstructive sleep apnea patients without hypertension. Respir Res. 2006;7:22- [PubMed]journal. [CrossRef] [PubMed]
 
Oliveira W. .Campos O. .Cintra F. .et al Impact of continuous positive airway pressure treatment on left atrial volume and function in patients with obstructive sleep apnoea assessed by real-time three-dimensional echocardiography. Heart. 2009;95:1872-1878 [PubMed]journal. [CrossRef] [PubMed]
 
Colish J. .Walker J.R. .Elmayergi N. .et al Obstructive sleep apnea: effects of continuous positive airway pressure on cardiac remodeling as assessed by cardiac biomarkers, echocardiography, and cardiac MRI. Chest. 2012;141:674-681 [PubMed]journal. [CrossRef] [PubMed]
 
Oliveira W. .Poyares D. .Cintra F. .et al Impact of continuous positive airway pressure treatment on right ventricle performance in patients with obstructive sleep apnoea, assessed by three-dimensional echocardiography. Sleep Med. 2012;13:510-516 [PubMed]journal. [CrossRef] [PubMed]
 
Vural M.G. .Cetin S. .Firat H. .Akdemir R. .Yeter E. . Impact of continuous positive airway pressure therapy on left atrial function in patients with obstructive sleep apnoea: assessment by conventional and two-dimensional speckle-tracking echocardiography. Acta Cardiol. 2014;69:175-184 [PubMed]journal. [PubMed]
 
Craig S. .Pepperell J.C. .Kohler M. .Crosthwaite N. .Davies R.J. .Stradling J.R. . Continuous positive airway pressure treatment for obstructive sleep apnoea reduces resting heart rate but does not affect dysrhythmias: a randomised controlled trial. J Sleep Res. 2009;18:329-336 [PubMed]journal. [CrossRef] [PubMed]
 
Campen M.J. .Shimoda L.A. .O’Donnell C.P. . Acute and chronic cardiovascular effects of intermittent hypoxia in C57BL/6J mice. J Appl Physiol. 2005;99:2028-2035 [PubMed]journal. [CrossRef] [PubMed]
 
Lesske J. .Fletcher E.C. .Bao G. .Unger T. . Hypertension caused by chronic intermittent hypoxia—influence of chemoreceptors and sympathetic nervous system. J Hypertens. 1997;15:1593-1603 [PubMed]journal. [CrossRef] [PubMed]
 
Linz D. .Hohl M. .Nickel A. .et al Effect of renal denervation on neurohumoral activation triggering atrial fibrillation in obstructive sleep apnea. Hypertension. 2013;62:767-774 [PubMed]journal. [CrossRef] [PubMed]
 
Fletcher E.C. .Lesske J. .Culman J. .Miller C.C. .Unger T. . Sympathetic denervation blocks blood pressure elevation in episodic hypoxia. Hypertension. 1992;20:612-619 [PubMed]journal. [CrossRef] [PubMed]
 
Bao G. .Randhawa P.M. .Fletcher E.C. . Acute blood pressure elevation during repetitive hypocapnic and eucapnic hypoxia in rats. J Appl Physiol. 1997;82:1071-1078 [PubMed]journal. [PubMed]
 
Gao M. .Zhang L. .Scherlag B.J. .et al Low-level vagosympathetic trunk stimulation inhibits atrial fibrillation in a rabbit model of obstructive sleep apnea. Heart Rhythm. 2015;12:818-824 [PubMed]journal. [CrossRef] [PubMed]
 
Ravelli F. .Allessie M. . Effects of atrial dilatation on refractory period and vulnerability to atrial fibrillation in the isolated Langendorff-perfused rabbit heart. Circulation. 1997;96:1686-1695 [PubMed]journal. [CrossRef] [PubMed]
 
Iwasaki Y. .Shi Y. .Benito B. .et al Determinants of atrial fibrillation in an animal model of obesity and acute obstructive sleep apnea. Heart Rhythm. 2012;9:1409-1416.e1 [PubMed]journal. [CrossRef] [PubMed]
 
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