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The relationship between obstructive sleep apnea and atrial fibrillation in special patient populations Expert Rev. Cardiovasc. Ther. Early online, 1–12 (2014)

Doran Drew, Amro Qaddoura and Adrian Baranchuk* Cardiology Division, Kingston General Hospital, Queen’s University, Kingston, Ontario, Canada *Author for correspondence Tel.: +1 613 549 6666; extn. 3801 Fax: +1 613 548 1387 [email protected]

Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder associated with both cardiovascular morbidity and mortality. Studies have shown a strong relationship between OSA and the most common cardiac arrhythmia – atrial fibrillation (AF). In this review, the authors intend to analyze AF in the context of OSA in populations of special medical interest; specifically investigating OSA in post-cardioversion, post-pulmonary isolation and post-coronary artery bypass graft patients as well as those afflicted by congestive heart failure, hypertrophic cardiomyopathy, coronary artery disease, erectile dysfunction and stroke. Moreover, the authors will highlight the importance of OSA severity, our current understanding of its mechanistic link to AF pathophysiology and treatment options. KEYWORDS: atrial fibrillation • cardioversion • congestive heart failure • continuous positive airway pressure • coronary artery bypass graft • coronary artery disease • hypertrophic cardiomyopathy • obstructive sleep apnea • pulmonary vein isolation • stroke

Obstructive sleep apnea (OSA) has reached epidemic proportions in North America. Research has shown it to be associated with a number of cardiovascular conditions. This review focuses on the effect of OSA in medically relevant subpopulations, how it causes atrial fibrillation (AF) and current treatment conventions. OSA is a common sleep-related breathing disorder (SBD) which has a prevalence of approximately 4% in North America [1,2]. Characterized by repetitive upper airway occlusion during sleep and subsequent bouts of apnea and hypopnea, OSA is thought to predispose affected individuals to cardiovascular disease by bringing about a number of physiological changes [3]. In specific, hypoxemia, inflammation, autonomic dysfunction and intrathoracic pressure changes are the cornerstones of OSA pathology [4]. Diagnosed by overnight polysomnography, disease severity is determined by the apneahypopnea index (AHI) [5,6]. A patient’s AHI value is determined by quantitating the number of apneas/hypopneas per hour of sleep, with values of 5–15, 16–30 and >30 correlating informahealthcare.com

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with mild, moderate and severe disease states, respectively [5]. Despite its already considerable prevalence, the findings of several studies suggest that OSA is staggeringly undiagnosed in contemporary society [7–9]. Meanwhile, other research efforts have been geared toward assessing its substantial economic burden, cumulatively suggesting that OSA may have a greater societal impact than previously suspected [7–9]. A plethora of cardiovascular conditions such as systemic hypertension, pulmonary hypertension, coronary artery disease (CAD), congestive heart failure (CHF), stroke, atherosclerosis and arrhythmias are associated with OSA [2,3,10–14]. Importantly, the literature suggesting a strong, potentially causal link between OSA and the most common arrhythmia – AF – is growing [3,13–16]. AF accounts for one-third of all cardiac rhythm hospitalizations and is associated with impaired quality of life, stroke, CHF and increased overall mortality [13,14,17]. While many factors are thought to precipitate its development, there is a mounting body of evidence suggesting an important association with OSA. In contrast to the aforementioned


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Review

Drew, Qaddoura & Baranchuk

prevalence of approximately 4%, OSA was found to affect 32–49% of patients suffering from AF [18]. Although the relationship between OSA and AF has been thoroughly examined by Oza et al. quite recently, there currently is a lack of information regarding this relationship as it pertains to the previously mentioned special populations [19]. As such, in addition to briefly overviewing OSA and AF in the general population, this review will explore the interrelation between OSA and AF in unique and medically important patient subgroups. Furthermore, we will highlight the mechanisms by which OSA is thought to precipitate AF pathophysiology and how current treatments work to combat this disease and ameliorate its burden.

any relationship between any cardiac arrhythmias and sleep apnea (AHI >10) [25]. Furthermore, Porthan et al. found an only marginally elevated prevalence of OSA in their AF group (32 vs 29%; p = 0.67) [26]. This latter study should be considered cautiously due to the likelihood that their control group was subject to selection bias, as adroitly pointed out by Caples and Somers [27]. In light of such an assembly of literature supporting a connection between OSA and AF, further questions are raised. Two points of particular interest are the influence of OSA severity on AF risk and the relationship between OSA and AF in unique patient populations. The role of severity

Methods

This is a nonsystematic review with references selected at the discretion of the author. The articles of greatest relevance were selected. Those of particular importance are indicated in the references section, along with an explanation of their noteworthy contribution to this publication. The unique patient populations covered in this review were decided on a priori. PubMed and OvidSP MEDLINE databases were used to retrieve articles. OSA is associated with AF Mounting evidence

The first link between OSA and AF was established in the 1970s by Guilleminault et al., where they observed the prevalence of AF in moderate-to-severe OSA (AHI ‡25) patients to be more than three-times that of the general population [20]. A study of OSA and cardiac arrhythmias in 1993 similarly found a 58% prevalence in those with OSA (AHI >10) compared to 42% in those without OSA (AHI £10) (p < 0.0001) [21]. A subsequent study by Gami et al. identified nocturnal oxygen desaturation (a key physiological consequence of OSA) as an independent risk factor for incident AF in patients over 65 years of age [22]. Around this time, the Sleep Heart Health Study demonstrated AF to be significantly more prevalent in individuals with SBD as compared with controls (4.8 vs 0.9%; p = 0.003) [23]. This study however did not discriminate between OSA and central sleep apnea (CSA) [23]. In a study conducted by Braga et al. involving only male participants, OSA was found more frequently in those with chronic persistent and permanent AF than in control subjects (81.6 vs 60.0%; p = 0.03) [24]. Recently, a study by Iwasaki et al. simulated OSA-induced AF using both obese and lean rats [15]. They found that neither population was predisposed to AF induction prior to OSA simulation [15]. Upon upper respiratory obstruction, both populations developed AF, with a greater proportion of obese rats being affected (86 vs 28%; p < 0.001) [15]. Notably, there was no significant difference in the severity of AF episodes (91 ± 35 vs 100 ± 35 s) [15]. While the aforementioned studies illustrate the possibility of a unique and medically important relationship existing between AF and OSA, it is important to also consider studies that reported negative findings. Chiefly, the work of Flemons et al. did not identify doi: 10.1586/14779072.2014.969713

In 1994, Hoffstein et al. began to explore the impact of OSA severity in patients with cardiac arrhythmias [21]. They found that 70% of individuals with an AHI ‡40 suffered from cardiac arrhythmia compared to 42% of individuals with an AHI £10 [21]. Tanigawa et al. showed the severity of sleep disordered breathing (SDB) to be associated with AF risk, with odds ratios (OR) of 2.47 (95% CI 0.91–6.69) and 5.66 (95% CI 1.75– 18.34) for mild (AHI = 5–14) and severe (AHI ‡15) SDB, respectively [28]. Similar to the previously mentioned study by Gami et al., the work of Tanigawa et al. links hypoxemia – a key physiological consequence of OSA – with AF [22,28]. Both P-wave dispersion and atrial electromechanical delay can be used as predictors of AF [29,30]. In patients with OSA, a number of studies found increased P-wave dispersion and atrial electromechanical delay – the magnitude of which were influenced by AHI and thus OSA severity [31–33]. Moreover, studies by Baranchuk et al. and Maeno et al. both found OSA severity to be correlated with elevated signal averaged P-wave dispersion (SAPWD) [34,35]. Overall, the suggestion that OSA severity is closely linked to a key predictor of AF as assessed by numerous techniques provides a robust argument toward the involvement of OSA severity in precipitating AF. In addition to inciting AF, OSA severity has been linked to poorer AF treatment outcomes. Patients with severe OSA (AHI >30) were less likely to respond to antiarrhythmic drugs than patients with mild OSA (AHI = 5–15), with 30 and 61% response rates (p = 0.02), respectively; those who did not respond to treatment also had a higher mean AHI (34 ± 25 vs 22 ± 18 events/h; p = 0.05) [36]. Similarly, patients with AF resistant to pulmonary vein isolation (PVI) were found to have markedly higher mean AHI (27 ± 22 vs 12 ± 16; p = 0.01) [37]. OSA & AF in special populations

OSA is present in a number of populations of special medical interest. Consequently, research efforts have been made to explore the disease and its characteristics in patients of these demographics. OSA & AF related to cardiac procedures Post-pulmonary vein isolation

As previously mentioned, both the presence and severity of OSA are associated with an increased likelihood of treatment Expert Rev. Cardiovasc. Ther.

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OSA & AF in special populations

failure in ablation patients. Further supporting the relationship between OSA severity and AF, a study on pulmonary vein isolation revealed respective 1-year arrhythmia-free probabilities of 48.5, 30.4 and 14.3% for control (AHI £9), nonsevere OSA (AHI = 10–30) and severe OSA (AHI ‡30) cohorts after a single ablation procedure [38]. Although the difference in 1-year arrhythmia-free probabilities between control and nonsevere OSA patients was not significant (p = 0.052), the difference between control and severe OSA patients was significant (p < 0.001) [38]. A meta-analysis of AF recurrence in this population conducted by Ng et al. found the relative risk (RR) of post-ablation AF in those with OSA to be 1.25 (95% CI 1.08–1.45; p = 0.003) [6]. These results are supported by a prospective study by Bitter et al. (conducted following the previously mentioned meta-analysis) which identified SDB (AHI ‡15) as an independent predictor for post-ablation AF recurrence (hazard ratio [HR] 2.95; p = 0.04) [39]. Current evidence suggests that structural and electrical atrial remodeling precipitated by OSA plays a key role in postablation AF recurrence, although the specific mechanism by which these changes recreate an arrhythmogenic substrate is uncertain [40,41]. The role of atrial remodeling in facilitating PVI failure is highlighted by the capacity of continuous positive airway pressure (CPAP) to abrogate this process and consequently enhance PVI success rates [41]. Adherence to CPAP therapy is imperative in patients with OSA following PVI, as non-CPAP users have increased AF recurrence rates (HR 2.15, 95% CI 1.1–5.44; p = 0.02) and decreased 1-year arrhythmia free-survival rates (36.7 vs 71.9%; p = 0.01) as compared with CPAP users [40]. Furthermore, the post-ablation arrhythmia free-survival rates of individuals with OSA who are undergoing CPAP therapy are comparable to those of patients without OSA (71.9 vs 66.7%; p = 0.94) [40]. It is worth noting that the work of Ng et al. also attested to the superiority of polysomnography as compared with the Berlin Questionnaire in correctly diagnosing OSA [6]. This determination stemmed from differences between methods in the ability to use OSA as a predictor of AF (RR 1.40, 95% CI 1.16–1.68; p = 0.0004 vs RR 1.07, 95% CI 0.91–1.27; p = 0.39) [6]. Although the utility of the Berlin Questionnaire is undoubtable due to its practicality, this finding highlights how its poor specificity limits clinical efficacy, and thus stresses that OSA diagnosis should be confirmed by polysomnography.

Review

$153 million/year in the USA as of 1996, presently equating to roughly $232 million/year when accounting for inflation [43]. The association between OSA and PCAF in this demographic is thus of particular interest. In 1996, Mooe et al. identified SDB (oxygen desaturation index ‡5) as an independent predictor of PCAF (RR: 2.8;, 95% CI: 1.2–6.8) [45]. Since this last study, there has been a paucity of decisive literature regarding OSA’s involvement in PCAF. While Sharma et al. identified a high prevalence of OSA in this population, they did not find a statistically significant difference in post-operative complications [46]. It is however important to note that the study suffered from a small sample size and called for further studies to definitively elucidate the role of OSA in PCAF [46]. Van Oosten et al. addressed this issue in 2014 and conducted an adequately powered, single centered prospective study assessing the relationship between OSA and PCAF [47]. Confirming the findings of the aforementioned studies, they identified the prevalence of OSA in this population to be drastically elevated (48%) [47]. Furthermore, they found OSA to be a strong predictor of PCAF (45.5 vs 29.7%; p = 0.007), which was in turn associated with longer hospital stays (6.5 vs 5.3 days; p = 0.006) [47]. Clinically speaking, these findings are crucial as they suggest potential PCAF prevention, improved patient outcomes and more efficient hospital spending via OSA treatment. Post-cardioversion

Gami and colleagues compared patients undergoing electrical cardioversion for AF to those with other cardiovascular diseases and found OSA to be significantly more prevalent in the AF population (49 vs 32%; p = 0.0004). Additionally, an adjusted OR of 2.19 (95% CI 1.40–3.42; p = 0.0006) was identified [48]. Complimenting this finding, work by Kanagala et al. illustrated a marked difference in 1-year AF recurrence following electrical cardioversion between untreated OSA patients and those receiving CPAP therapy (82 vs 42%; p = 0.013) [49]. Further supporting the latter study, Mazza et al. identified an AHI ‡15 as a strong predictor of AF recurrence after successful electrical cardioversion at 1-year follow-up, with respective recurrences of 69 and 43% between the AHI ‡15 and control cohorts (p = 0.001; RR 1.6; 95% CI: 1.21–2.13) [50]. From these studies, we can draw that not only is OSA more prevalent in those undergoing cardioversion treatment for AF but also that it impairs treatment outcomes.

Post-coronary artery bypass grafting

AF is a common yet serious complication of coronary artery bypass grafting (CABG) associated with increased morbidity, longer hospital (12.8 vs 10.2 days; p < 0.01) and intensive care unit stays (72.5 vs 59.1 h; p < 0.01), threefold higher risk of post-operative stroke (3.3 vs 1.4%; p < 0.0005) and more than doubled in-hospital (5.95 vs 2.95; p < 0.002) and 6-month mortality (9.36 vs 4.17%; p < 0.001) [42–44]. Remarkably, Mathew et al. investigated the economics of post-CABG AF (PCAF) and found its impact to be approximately informahealthcare.com

Congestive heart failure

The development of AF in patients with CHF can facilitate decompensation and worsens prognosis [51]. Understanding the role of OSA in this patient group is thus of considerable import. To do this, Javaheri et al. employed polysomnography to examine 81 male subjects with CHF and left ventricular (LV) ejection fractions 0.05) [53]. Although CHF treatment regimens have changed since these studies were conducted, the prevalence of OSA and CSA has not been dynamic, remaining around 30% [54]. Further solidifying contemporary concerns regarding this population, a study by Wang et al. found mortality to be increased independently of other factors in CHF patients with untreated OSA (AHI ‡15) (8.7 vs 4.2 deaths/100 patient-years; p = 0.029) [55]. Despite mired evidence regarding the role of OSA in CHF, the elevated prevalence of disease, potential association with AF and known association with increased mortality warrant active efforts to diagnose and treat OSA within this patient population. Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a disease of particular interest in the study of OSA. Due to the genetic etiology of HCM, many patients suffering from it do not fit the archetypal depiction common to cardiovascular disease. Specifically, patients with HCM frequently are young individuals with a normal body mass index who lack the myriad of comorbidities commonly found in those with severe cardiac disease [56]. Those with HCM do however face an elevated likelihood of AF development (~1.5% yearly incidence) and associated complications such as stroke (OR: 17.7;, 95% CI: 4.1–75.9; p = 0.0001), severe functional limitation (NYHA III or IV, OR: 2.8;, 95% CI: 1.8–4.5; p < 0.0001) and increased risk of HCM-related death (OR 3.7;, 95% CI: 1.7–8.1; p < 0.002) [9,57]. It is thought that there may be a dangerous synergistic relationship between HCM and OSA due to both of their inclinations to precipitate AF. With the only predictors of OSA in an HCM patient population being age ‡45 years and the presence of AF, it is very likely that OSA is largely undiagnosed – especially in younger HCM subpopulations which have not yet developed AF and as such meet neither of the two aforementioned predictive criteria [56]. Despite this propensity for evading diagnosis, the prevalence of OSA in those with HCM has been found to range between 32 and 71% depending on the diagnostic criteria of the study, suggesting that the OSA doi: 10.1586/14779072.2014.969713

epidemic is widespread in this population [56]. This is particularly concerning, given the nearly fourfold increased prevalence of AF (40 vs 11%; p = 0.005) among those with comorbid SDB and HCM as compared to HCM patients without SDB [58]. Aside from concerns of AF, the capacity for OSA to facilitate atrial remodeling only serves to worsen the prognosis of individuals with HCM [56]. Moreover, OSA was independently associated with poor sleep quality, which by extension is associated with impaired quality of life and consequently prognosis [56]. In light of the evidence suggesting that OSA is a major comorbidity in HCM patients, we feel that OSA screening and treatment should become first line in this population. The interrelation between OSA and HCM continues to prove interesting beyond the patient perspective. Given the unique nature of the HCM population, a case is made against the argument that OSA pathology is actually the result of its common comorbidities such as obesity and hypertension. The debate of whether OSA is an isolated disease or a syndrome encompassing obesity, metabolic syndrome and hypertension is however deserving of more thorough discussion, and thus warrants its own review. The suggestion that OSA has a principle etiological role in cardiovascular disease is particularly important and extends beyond the HCM patient subgroup, especially in light of concerns that it may increase stroke risk even in those who do not experience AF [13,14]. Stroke

The putative relationship between OSA and stroke is of chief interest given the severity of cerebrovascular events. While it is biologically plausible for OSA to cause cerebrovascular infarction through a combination of pathophysiological changes and the development of AF, one must be wary in assessment of the literature as stroke has equal plausibility for causing OSA through weakening of the oropharyngeal muscles and disruption of normal neural tone [11,14]. Further impeding delineation of whether there is a true relationship between OSA and stroke is the syndrome of confounding factors commonly associated with OSA such as obesity, hypertension and metabolic syndrome which are also known to contribute to stroke risk [14]. As highlighted in a study by Valenza et al., sleep apnea patients with an AHI >30 had a higher CHADS2 score than those with an AHI 15) was recently found to be associated with elevated total atheroma volume (461.3 ± 250.4 mm3 vs 299.2 ± 135.6 mm3; p < 0.001) as compared with other CAD patients [60]. Interestingly, despite this notable difference in total atheroma size, there was no difference in the prevalence of thin cap fibroatheroma when comparing between patients with severe OSA to those without (53.1 vs 54.2%; p = 0.919) [60]. In lieu of these findings and the aforementioned association of OSA with PCAF, we find ourselves in agreement with Glantz et al. that secondary prevention protocols are necessary to both slow disease progression and mitigate the risks associated with a fragile patient population at high risk of developing AF and likely to require cardiac surgery [47,59]. Studies assessing the impact of CPAP on CAD would additionally be of great value. Erectile dysfunction

Although it is not a hallmark symptom of OSA, erectile dysfunction (ED) is a frequently encountered development of the disease, with a prevalence ranging from 48 to 64% [61,62]. The etiology of ED development in OSA is uncertain at present, yet may relate to conditions of chronic hypoxia and endothelial dysfunction existing over a background of metabolic disorder, obesity and hypertension [61]. OSA severity was not identified as a determinant of ED (p < 0.403) by Santos et al., suggesting that it is instead the syndrome associated with OSA which might be responsible [62]. Conversely, a meta-analyses conducted by Xu et al. found patients with OSA and ED to have significantly elevated international index of erectile function-5 scores (4.19, 95% CI: 3.01–5.36; p < 0.001) following CPAP therapy [63]. While more research is clearly needed to identify the role OSA plays in ED, the potential role for CPAP to function as a nonpharmacological treatment of ED is an exciting prospect. To summarize, despite the differences existing between the general population and the aforementioned special demographics, OSA has consistently been shown to be a treatable, widespread disease responsible for considerable morbidity and mortality.

Review

state of chronic systemic inflammation, and thus are predisposed to both hypertension as well as atrial fibrosis [64]. Inflammation

Patients with OSA typically present with both local and systemic inflammation. It is thought that local inflammation of the upper respiratory tract may facilitate airway narrowing as well as reflex and muscle dysfunction, consequently worsening the frequency and intensity of apneic/hypopneic episodes [65]. This increase in severity may lead to disease progression and worsened patient outcomes [21,22,28–38]. With respect to systemic inflammation, a majority of OSA patients was found to have elevated levels of proinflammatory mediators, which may potentiate cardiovascular complications [65]. Of the identified inflammatory markers, a number of studies have specifically investigated the role of C-reactive protein (CRP) in OSA. Shamsuzzaman et al. found CRP levels to be independently associated with OSA, with their magnitude being indicative of severity [66]. Complimenting this finding, the work of Mazza and colleagues identified both CRP levels greater than 0.30 mg/dl and AHI >15 as the strongest predictors of AF recurrence at 1-year follow-up after electrical cardioversion [50]. Notably, a paper published by Chung et al. in 2001 identified non-post-operative arrhythmia patients as having elevated CRP, with more persistent AF being associated with greater CRP levels [67]. While the authors of the study were unable to identify a cause for the inflammatory state, they suggested that structural or electrical remodeling of the atria may have been facilitated by the patient’s inflammatory state, thus predisposing them to AF [67]. We suggest that the underlying cause of this inflammatory state may have in fact been OSA, given its widespread prevalence and association with both AF and inflammatory states [15,20–24,50,65–67]. Intrathoracic pressure changes

Repetitive narrowing or occlusion of the upper respiratory tract during sleep can generate remarkable pressure gradients of up to –65 mm Hg [68]. These repeated oscillations in pressure are believed to cause atrial fibrosis and chamber enlargement – both of which have been identified as AF risk factors [27]. In animal models of OSA, intrathoracic pressure changes have been confirmed to cause left atrial (LA) distension, supporting the role of intrathoracic pressure changes in generating an arrhythmogenic substrate for AF [15].

Mechanisms of OSA pathology in the context of AF

The pathology of OSA is thought to bring about AF through four primary mechanisms: hypoxia, inflammation, intrathoracic pressure changes and progressive autonomic instability. Hypoxia

While hypoxia and subsequent hypoxemia are intuitive developments in OSA, the mechanisms by which they bring about AF are not as readily understood. It is thought that in OSA chronic hypoxia causes continuous vascular endothelial injury via oxidative stress [64]. Consequently, these individuals enter a informahealthcare.com

Autonomic instability

In addition to precipitating AF through structural heart remodeling, negative pressure swings during obstructive respiratory events have been recognized to enhance vagal activation, leading to shortened right atrial refractory periods and thereby serving as a strong trigger for AF [69]. Recurrent apneic and hypopneic episodes during sleep in OSA have been found to alter the autonomic nervous system [70]. The ensuing modification of vagal input, decreased baroreflex sensitivity, impaired control of heart rate variability doi: 10.1586/14779072.2014.969713

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Drew, Qaddoura & Baranchuk

OSA

Autonomic instability

Inflammation

Hypoxia

Intrathoracic pressure changes

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Atrial remodeling

AF

Figure 1. A schematic of obstructive sleep apnea pathophysiology. AF: Atrial fibrillation; OSA: Obstructive sleep apnea.

(HRV) and increased blood pressure variability can manifest as acute cardiac events such as AF or other arrhythmias, myocardial infarction, stroke, heart failure and even death [70,71]. Stemming from the potential severity of these autonomic derangements, efforts have been made to further characterize the role of the autonomic nervous system in OSA pathology. Somewhat paradoxically a study by Seaborn et al. found no difference in any HRV parameters between controls (AHI £5) and subjects with severe OSA (AHI ‡30) nor between CPAPtreated and nontreated patients [72]. These results should however be considered with caution due to a limited study duration and small sample size [72]. In a progressive study by Guzik et al., the derangement of physiological heart rate asymmetry microstructure was investigated as a means of exploring HRV [73]. Using 300-min, nighttime ECGs, heart rate acceleration and deceleration runs were tabulated and contrasted between patients. They found those with severe OSA (AHI = 42.8 ± 17.4) to have overall increased run lengths yet decreased numbers of single length acceleration and deceleration runs relative to moderate OSA (AHI = 21.8 ± 4.0) and mild/no OSA (AHI = 5.1 ± 2.5) groups [73]. Although the clinical value of these findings is presently uncertain, this correlation may hint at compromised fine control of the cardiac system in those afflicted by OSA. Atrial remodeling

Mounting evidence indicates that through a combination of the aforementioned mechanisms, OSA brings about remodeling of the atrial myocardium. One speculated avenue of atrial remodeling is that OSA-induced diastolic dysfunction (DD) elevates LV pressures and thereby causes LA enlargement [70,74]. This gives a plausible explanation for the association between AF and OSA severity, as LA volume, which is closely tied to AF development, increases with worsening DD [74]. Moreover, DD itself is independently predictive of nonvalvular AF and is common in patients with OSA [70,75]. doi: 10.1586/14779072.2014.969713

Causation of DD by OSA is supported by a number of findings indicating that LV DD progresses with OSA severity regardless of comorbidities [76–78]. Furthermore, the association between OSA severity and diastolic systemic hypertension is well detailed in the literature [70,76,77]. Although the effect of OSA on the left ventricle predominately relates to DD, it has also been associated with the evolution of subclinical LV systolic dysfunction (SD) [41,79]. Notably, Andrade et al. identified OSA as the third greatest risk factor for AF, with DD and LV systolic function as the two greatest risk factors [80]. Given the aforementioned association of LV DD and LV SD with OSA, it is clinically important to recognize that OSA plays a major role in the three greatest risk factors for AF and thus strongly influences the development of an arrhythmogenic substrate for AF. Atrial remodeling is a dichotomy made up of structural and electrical changes, both of which complement one another in contributing to elevated cardiovascular risk. Patients with moderate-severe OSA have increased PD, and although the exact cause is not known, disruption of the Bachmann Bundle leads to interatrial block and allows OSA to cultivate an arrhythmogenic substrate [32,81]. Electrical remodeling in OSA additionally is associated with a reduction in voltage as well as site-specific and widespread conduction abnormalities [82]. Alternatively, AF development may be facilitated through OSA destabilized autonomic activity at the pulmonary vein ostia, which is extensively innervated by adrenergic and vagal neurons [83]. Once arrhythmic, a positive feedback loop develops in which OSA perpetuates heart remodeling with the independent assistance of paroxysmal AF-onset remodeling [81]. Iwasaki et al. identified LA distension, and thus structural heart remodeling, to be more indicative of AF development than intrathoracic pressure changes or autonomic instability [15]. Based on this finding, we posit that the aforementioned cornerstones of OSA are principally initiating events which incite atrial remodeling and thus instigate AF (FIGURE 1). Although the mechanistic workings of OSA are uncertain, great progress has been made in understanding the disease and its pathophysiology. It is our hope that continued research efforts will potentiate the development of improved treatments. OSA treatment & implications Continuous positive airway pressure

The current standard of care in OSA treatment is CPAP, which works by preventing airway closure in an actively breathing patient through continuous positive pressure. Compared with untreated patients, CPAP has been found to significantly ameliorate the risk of fatal (0.35 vs 1.06 events per 100 personyears; p = 0.0008) and nonfatal (0.64 vs 2.13 events per 100 person-years; p < 0.0001) cardiovascular events [84]. CPAP functions by reversing both electrical and structural heart remodeling, leading to significant improvement of HRV control, sympathetic neural control, LV DD, diastolic systemic hypertension, pulmonary hypertension, right ventricular volume, LA size, LV mass and SAPWD [34,35,41,71,78]. In severe Expert Rev. Cardiovasc. Ther.

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OSA & AF in special populations

OSA, CPAP was found to reduce SAPWD from 131.9 ± 10.4 to 126.2 ± 8.8 ms (p < 0.001) compared to no change in a control population over the course of 4–6 weeks (FIGURE 2) [22,34]. The success of CPAP seems to stem from its treatment of the pathophysiological origins of OSA disease burden as OSAinduced autonomic instability, intrathoracic pressure shifts and systemic inflammation have all been documented to be mitigated in patients undergoing CPAP therapy [65,71,85]. In addition to ameliorating OSA-related morbidity and mortality in the general population, CPAP has been found to be effective in a number of the special populations mentioned in this review. CPAP-treated CHF patients have shown improved sympathetic control, systolic blood pressure (126 ± 6–116 ± 5 mm Hg; p = 0.02) and LV ejection fraction (LVEF) (25.0 ± 2.8–33.8 ± 2.4; p < 0.001) as well as overall improved quality of life [3,86]. Moreover, patients with untreated OSA have been shown to have higher mortality rates [3,55]. Despite these promising results, caution should be employed in this population as there have been documented decreases in stroke volume and LVEF acutely following CPAP initiation, especially in severe CHF patients [87]. As such, it is important to carefully monitor CHF patients initiating CPAP therapy until more is learned about this deleterious occurrence. Patients with OSA being treated for AF by pulmonary vein isolation or cardioversion should initiate CPAP therapy if they are not already undergoing CPAP treatment. It is additionally pertinent for these patients to continue CPAP therapy following either procedure, as CPAP functions not only to manage OSA but also to minimize AF recurrence [40,41,49]. Many of the cardiac symptoms of OSA both mimic and potentiate HCM. Given the consequences of uncontrolled LV hypertrophy and LV outflow tract impedance in patients with HCM, the ability of CPAP to alleviate these sequelae of OSA is incredibly important [88]. Although research exists regarding the role of CPAP in the previously mentioned special populations, there is a dearth of it pertaining to CABG patients. Given the high prevalence of OSA in these patients and their susceptibility to PCAF, efforts should be made to evaluate the efficacy of CPAP in this demographic [47]. Similarly, the literature has not yet developed regarding the potential protective effect of CPAP on the cerebrovasculature should OSA truly play an independent role in the etiology of stroke. Irrespective of this however, due to known association between OSA and AF, any patients at risk for stroke should be strongly encouraged to adhere to CPAP treatment to minimize the incidence of AF and potential thrombus formation [13,14]. In light of developments regarding the potential role of OSA in atheroma volume, CPAP should be initiated as a secondary preventative measure of atheroma growth and a primary preventative measure of PCAF in patients with CAD [47,59,60]. While ED is not one of the more common symptoms of OSA, it can markedly impair the quality of life; although the mechanism by which CPAP appears to alleviate ED is currently informahealthcare.com

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A Severe OSA – pre-CPAP

B Severe OSA – post-CPAP

C Control group – pre-CPAP

D Control group – post-CPAP

Figure 2. Signal averaged P-wave dispersion profile comparison between a severe OSA (A, B) and control patient (C, D). Panels A and B represent pre-CPAP profiles, while panels B and D represent post-CPAP profiles. The gray area represents average P-wave of 100 heart beats, the x-axis represents time in milliseconds and the y-axis represents signal amplitude in microvolts. Severe OSA patients show reduced signal averaged P-wave dispersion post-CPAP, while control groups maintain baseline. CPAP: Continuous positive airway pressure; OSA: Obstructive sleep apnea. Reproduced with permission from [34].

unknown, the increase it was found to provide on the international index of erectile function-5 equates to nearly a rank increase and thus should be considered clinically relevant [63]. Moreover, early treatment of OSA with CPAP may prevent worsening of cardiovascular health and thus at the very least function as a secondary preventative measure toward ED. In light of the previously outlined points, one can appreciate the utility of CPAP in treating OSA. Of particular and often overlooked import is the potential economic efficacy of treatments such as CPAP [8]. Although more studies are needed to quantify the cost efficiency of CPAP, a secondary preventative approach to major disease is widely regarded as more efficient than tertiary care [8]. Alternative therapies

On the topic of economic treatments, preliminary evidence suggests that the mere avoidance of supine sleeping positions may mitigate the symptoms of OSA [89]. While more confirmatory studies are needed, the simple and harmless nature of this treatment option may be appealing to patients, especially those unwilling to use CPAP [89]. This avenue of treatment may be particularly efficacious as a recommendation from primary care providers to those with suspected mild OSA as a means to manage the disease in its early stages. Furthermore, the merits of exercise should not be overlooked in patients with OSA. Not only will exercise ameliorate frequently coincident obesity and improve functional capacity, but studies have also found that it is capable of improving OSA-associated autonomic instability and inflammatory profiles [90,91]. Again, this approach would best facilitate good patient health if recommended in the early stages of OSA and doi: 10.1586/14779072.2014.969713

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should be iterated by primary care physicians as frequently as necessary. Limitations

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The nonsystematic nature of this review should be recognized as a limitation, as it may have impaired the authors’ ability to assess the topic in a completely objective manner. Moreover, due to the span of the article the authors were able only to discuss the treatment of OSA in the context of each medical condition, rather than treatment of the conditions as a whole. Expert commentary

In light of the substantial prevalence of OSA, we urge for more thorough screening and consistent confirmation of diagnosis by overnight polysomnography. Subsequent to confirmed OSA diagnosis, CPAP and auxiliary therapies and their benefits should be discussed with the patient. This is especially important in patients with known arrhythmias, HCM or CHF. Due to the sometimes insidious nature of OSA, HCM and CHF patients should be carefully assessed for OSA given its potential contribution to disease progression via atrial remodeling. Patients who have undergone or are scheduled to undergo cardioversion, ablation and/or CABG are also a population of concern as a result of their aforementioned propensity to develop post-procedural AF. Early identification and treatment of OSA in these populations is beneficial to both hospitals and patients as it serves to reduce hospital stays and intensive care unit costs while improving patient prognoses. As with any epidemic, primary prevention is the key target and as such should be foremost in the minds of clinicians. With increased surveillance for OSA, early identification of disease and subsequent behavioral modification may allow for attenuation of disease progression and consequent avoidance of severe disease states. In addition to these efforts, secondary prevention via CPAP should be conducted. Importantly, until more literature exists regarding the acute effects of CPAP administration, patients in poor health should be carefully monitored due to documented instances of temporarily decreased stoke volume and LVEF, especially in patients with severe CHF [87]. Widespread control of OSA should be a sought-after goal as it would allow for amelioration of several origins of cardiovascular insult and consequent disease exacerbation. Although lofty, acquisition of such a goal would better patients’ lives across a spectrum of diseases while reducing costs for the health care system. Five-year view

Owing to continued research efforts, a bright picture is painted for the future of OSA. It is our expectation that findings regarding OSA prevalence and severity will be consistent with

doi: 10.1586/14779072.2014.969713

the current literature. With increased awareness regarding the prevalence of the disease, we predict improved disease management owing to earlier screening and treatment. Moreover, it is likely that within this period CPAP as well as auxiliary therapies will be better understood and as such more efficaciously implemented. This time frame should be sufficient for steps to be taken toward better understanding the acute and chronic impacts of CPAP, especially in those with poor health. Specifically, we hope studies will have rectified concerns regarding decreases in cardiac output acutely following CPAP administration in those with severe CHF. Whether this is found to be a major limitation of CPAP or an anomalous finding, discerning the true nature of the matter is of great importance. New insights into the potential protective role of CPAP pertaining to CAD and stroke may serve to reduce the instances or severity of these acute vascular insults. Additionally, we would expect the functionality of CPAP to be explored in post-operative CABG patients given the current lack of information on CPAP treatment in this medically unique population. It is likely that some of the largest steps toward understanding OSA will pertain to its biochemical basis. With further research, we may come to find that OSA increases risk profiles for serious cardiac events both through AF as well as independently of it. This development would be very important as it would strongly support OSA’s contribution to the etiology of cardiovascular disease through atrial remodeling. Furthermore, it would likely be used to advance stratification of OSA severity and modify stroke guidelines such as the CHADS2 score. With a more complete understanding of OSA pathophysiology and how it contributes to cardiovascular disease, new opportunities to develop targeted novel therapeutics will arise. Such a diversification of treatment options will serve to provide patients with more personalized care. Conclusion

Although controversy over the role of OSA in the etiology of AF and other cardiac diseases remains, the existing evidence makes a very robust case for a severity-based and possibly causal association between AF and OSA. Future endeavors should seek to further study OSA in unique patient populations as well as investigate its complicated pathophysiology. Finally, assessment of treatment efficacy, both medically and economically, is warranted. Financial & competing interests disclosure

The project was funded graciously by the McLaughlin Research Studentship Fund. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

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OSA & AF in special populations

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Key issues • Obstructive sleep apnea (OSA) is currently recognized to have a prevalence of approximately 4% in North America. However, there is strong evidence that it is largely undiagnosed. • Diagnosis of OSA should be confirmed by overnight polysomnography, with severity assessed by the apnea-hypopnea index. Values of 5–15, 16–30 and >30 equate to mild, moderate and severe disease states, respectively. • OSA is associated with many cardiovascular conditions. A strong, severity-dependent relationship exists between OSA and atrial fibrillation (AF). This is concerning due to the impact AF has on overall mortality rates, stroke, heart failure risk and quality of life. • Both drug and procedural antiarrhythmic therapies for AF are less effective in patients with OSA. Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Michigan University on 10/18/14 For personal use only.

• Post-ablation, coronary artery bypass graft and cardioversion patients with OSA are markedly more susceptible to recurrent AF. Moreover, OSA seems to make unique etiological contributions to congestive heart failure, hypertrophic cardiomyopathy, stroke, coronary artery disease and erectile dysfunction pathology, leading to worsened patient outcomes in these populations. • OSA is thought to potentiate AF through atrial remodeling, which is mediated principally by OSA-induced intrathoracic pressure changes, hypoxia, inflammation and autonomic instability. • Continuous positive airway pressure therapy markedly reduces OSA severity. By alleviating OSA disease burden and reducing the risk of developing AF, continuous positive airway pressure functions to reduce patient morbidity and mortality. • Exercise and positional sleep therapy are potential alternative or auxiliary OSA treatments.

References

8.

Papers of special note have been highlighted as: • of interest •• of considerable interest

Tarasiuk A, Reuveni H. The economic impact of obstructive sleep apnea. Curr Opin Pulm Med 2013;19(6):639-44

9.

Olivotto I, Cecchi F, Casey SA, et al. Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation 2001;104(21):2517-24

1.

Punjabi NM. The epidemiology of adult obstructive sleep apnea. Proc Am Thorac Soc 2008;5(2):136-43

16.

January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014. [Epub ahead of print]

17.

Falk RH. Atrial fibrillation. N Engl J Med 2001;344(14):1067-78

18.

Valenza MC, Baranchuk A, Valenza-Demet G, et al. Prevalence of risk factors for atrial fibrillation and stroke among 1210 patients with sleep disordered breathing. Int J Cardiol 2014;174(1):73-6

Gami AS, Friedman PA, Chung MK, et al. Therapy Insight: interactions between atrial fibrillation and obstructive sleep apnea. Nat Clin Pract Cardiovasc Med 2005;2(3):145-9

19.

Yazdan-Ashoori P, Baranchuk A. Obstructive sleep apnea may increase the risk of stroke in AF patients: refining the CHADS2 score. Int J Cardiol 2011;146(2): 131-3

Oza N, Baveja S, Khayat R, Houmsse M. Obstructive sleep apnea and atrial fibrillation: understanding the connection. Expert Rev Cardiovasc. Ther 2014;12(5): 613-21

20.

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(9):1409-16.e1

Guilleminault C, Connolly SJ, Winkle RA. Cardiac arrhythmia and conduction disturbances during sleep in 400 patients with sleep apnea syndrome. Am J Cardiol 1983;52(5):490-4

21.

Hoffstein V, Mateika S. Cardiac arrhythmias, snoring, and sleep apnea. Chest 1994;106(2):466-71

22.

Gami AS, Hodge DO, Herges RM, et al. Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation. J Am Coll Cardiol 2007;49(5):565-71

2.

Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea. Am J Respir Crit Care Med 2002;165(9): 1217-39

10.

Lavie P, Herer P, Peled R, et al. Mortality in sleep apnea patients: a multivariate analysis of risk factors. Sleep 1995;18(3): 149-57

3.

Mansfield D, Naughton MT. Obstructive sleep apnoea, congestive heart failure and cardiovascular disease. Heart Lung Circ 2005;14(Suppl 2):S2-7

11.

Weiss JW, Launois SH, Anand A, Garpestad E. Cardiovascular morbidity in obstructive sleep apnea. Prog Cardiovasc Dis 1999;41(5):367-76

4.

Epstein LJ, Kristo D, Strollo PJ, et al. Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults. J Clin Sleep Med 2009;5(3):263-76

12.

Roux F, D’Ambrosio C, Mohsenin V. Sleep-related breathing disorders and cardiovascular disease. Am J Med 2000; 108(5):396-402

5.

6.

7.

Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep 1999;22(5):667-89 Ng CY, Liu T, Shehata M, et al. Meta-analysis of obstructive sleep apnea as predictor of atrial fibrillation recurrence after catheter ablation. Am J Cardiol 2011; 108(1):47-51 Finkel KJ, Searleman AC, Tymkew H, et al. Prevalence of undiagnosed obstructive sleep apnea among adult surgical patients in an academic medical center. Sleep Med 2009; 10(7):753-8

informahealthcare.com

13.

14.

15.

••

timeline in the context of obesity, with findings illustrating an important interaction between obesity and OSA which promoted AF. Furthermore, evidence of OSA facilitating atrial remodeling was discussed.

The relationship between atrial fibrillation (AF) and obstructive sleep apnea (OSA) was studied on an acute

doi: 10.1586/14779072.2014.969713

Review

Mehra R, Benjamin EJ, 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(8):910-16

35.

24.

Braga B, Poyares D, Cintra F, et al. Sleep-disordered breathing and chronic atrial fibrillation. Sleep Med 2009;10(2): 212-16

36.

25.

Flemons WW, Remmers JE, Gillis AM. Sleep apnea and cardiac arrhythmias. Is there a relationship? Am Rev Respir Dis 1993;148(3):618-21

23.

Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Michigan University on 10/18/14 For personal use only.

Drew, Qaddoura & Baranchuk

26.

Porthan KM, Melin JH, Kupila JT, et al. Prevalence of sleep apnea syndrome in lone atrial fibrillation: a case-control study. Chest 2004;125(3):879-85

27.

Caples SM, Somers VK. Sleep-disordered breathing and atrial fibrillation. Prog Cardiovasc Dis 2010;51(5):411-15

28.

Tanigawa T, Yamagishi K, Sakurai S, et al. Arterial oxygen desaturation during sleep and atrial fibrillation. Heart 2006;92(12): 1854-5

29.

Cagirci G, Cay S, Karakurt O, et al. P-wave dispersion increases in prehypertension. Blood Press 2009;18(1-2):51-4

30.

Omi W, Nagai H, Takamura M, et al. Doppler tissue analysis of atrial electromechanical coupling in paroxysmal atrial fibrillation. J Am Soc Echocardiogr 2005;18(1):39-44

31.

Cagirci G, Cay S, Gulsoy KG, et al. Tissue Doppler atrial conduction times and electrocardiogram interlead P-wave durations with varying severity of obstructive sleep apnea. J Electrocardiol 2011;44(4):478-82

32.

Baranchuk A, Parfrey B, Lim L, et al. Interatrial block in patients with obstructive sleep apnea. Cardiol J 2011;18(2):171-5

33.

Maeno K-I, Kasai T, Kasagi S, et al. Relationship between atrial conduction delay and obstructive sleep apnea. Heart Vessels 2013;28(5):639-45

34.

•

Baranchuk A, Pang H, Seaborn GEJ, 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(3):247-53 Highlights the use of signal averaged P-wave dispersion (SAPWD) as a predictor of OSA severity, and the amelioration of OSA burden through reverse atrial electrical remodeling facilitated by continuous positive airway pressure (CPAP) therapy.

doi: 10.1586/14779072.2014.969713

37.

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(2): 287-93 Monahan K, Brewster J, Wang L, 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(3):369-72 Hoyer FF, Lickfett LM, Mittmann-Braun E, et al. High prevalence of obstructive sleep apnea in patients with resistant paroxysmal atrial fibrillation after pulmonary vein isolation. J Interv Card Electrophysiol 2010; 29(1):37-41

38.

Matiello M, Nadal M, Tamborero D, et al. Low efficacy of atrial fibrillation ablation in severe obstructive sleep apnoea patients. Europace 2010;12(8):1084-9

•

OSA leads to ablation treatment failure in a severity-dependent manner.

39.

Bitter T, No¨lker G, Vogt J, et al. Predictors of recurrence in patients undergoing cryoballoon ablation for treatment of atrial fibrillation: the independent role of sleep-disordered breathing. J Cardiovasc Electrophysiol 2012;23(1):18-25

40.

Fein AS, 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(4):300-5

41.

Neilan TG, Farhad H, Dodson JA, et al. Effect of sleep apnea and continuous positive airway pressure on cardiac structure and recurrence of atrial fibrillation. J Am Heart Assoc 2013;2(6):e000421

of atrial fibrillation after coronary artery bypass surgery. Coron Artery Dis 1996;7(6): 475-8 46.

Sharma S, Daggubatti R, Tribble RW, et al. Prevalence of obstructive sleep apnea in patients undergoing coronary artery bypass graft surgery (CABG). A Pilot Study. J Sleep Disord Treat Care 2012;1:2

47.

Van Oosten EM, Hamilton A, Petsikas D, et al. Effect of preoperative obstructive sleep apnea on the frequency of atrial fibrillation after coronary artery bypass grafting. Am J Cardiol 2014;113(6):919-23

•

This study found OSA to be markedly more prevalent in coronary artery bypass graft (CABG) patients and to serve as a strong predictor of PCAF. Additionally, an association between PCAF and increased hospital stay was identified.

48.

Gami AS, Pressman G, Caples SM, et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation 2004; 110(4):364-7

49.

Kanagala R, Murali NS, Friedman PA, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation 2003;107(20):2589-94

50.

Mazza A, Bendini MG, Cristofori M, et al. Baseline apnoea/hypopnoea index and high-sensitivity C-reactive protein for the risk of recurrence of atrial fibrillation after successful electrical cardioversion: a predictive model based upon the multiple effects of significant variables. Europace 2009;11(7):902-9

51.

Wang TJ, Larson MG, Levy D, et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation 2003;107(23): 2920-5

42.

Creswell LL, Schuessler RB, Rosenbloom M , Cox JL. Hazards of postoperative atrial arrhythmias. Ann Thorac Surg 1993;56(3): 539-49

52.

43.

Mathew JP, Parks R, Savino JS, et al. Atrial fibrillation following coronary artery bypass graft surgery: predictors, outcomes, and resource utilization. MultiCenter Study of Perioperative Ischemia Research Group. JAMA 1996;276(4):300-6

Javaheri S, Parker TJ, Liming JD, et al. Sleep apnea in 81 ambulatory male patients with stable heart failure. Types and their prevalences, consequences, and presentations. Circulation 1998;97(21): 2154-9

53.

••

A thorough assessment of the impact post-coronary artery bypass grafting AF (PCAF) has from both economic and medical perspectives.

Sin DD, Fitzgerald F, Parker JD, et al. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med 1999;160(4):1101-6

44.

Almassi GH, Schowalter T, Nicolosi AC, et al. Atrial fibrillation after cardiac surgery: a major morbid event? Ann Surg 1997; 226(4):501-11.discussion 511–3

54.

45.

Mooe T, Gullsby S, Rabben T, Eriksson P. Sleep-disordered breathing: a novel predictor

Yumino D, Wang H, Floras JS, et al. Prevalence and physiological predictors of sleep apnea in patients with heart failure and systolic dysfunction. J Card Fail 2009; 15(4):279-85

55.

Wang H, Parker JD, Newton GE, et al. Influence of obstructive sleep apnea on

Expert Rev. Cardiovasc. Ther.

OSA & AF in special populations

mortality in patients with heart failure. J Am Coll Cardiol 2007;49(15):1625-31 56.

Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Michigan University on 10/18/14 For personal use only.

•

57.

58.

59.

Nerbass FB, Pedrosa RP, Danzi-Soares NJ, et al. Obstructive sleep apnea and hypertrophic cardiomyopathy: a common and potential harmful combination. Sleep Med Rev 2013;17(3):201-6

Maron BJ, Olivotto I, Bellone P, et al. Clinical profile of stroke in 900 patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2002;39(2):301-7 Konecny T, Brady PA, Orban M, et al. Interactions between sleep disordered breathing and atrial fibrillation in patients with hypertrophic cardiomyopathy. Am J Cardiol 2010;105(11):1597-602 Glantz H, Thunstro¨m E, Herlitz J, et al. Occurrence and predictors of obstructive sleep apnea in a revascularized coronary artery disease cohort. Ann Am Thorac Soc 2013;10(4):350-6 Tan A, Hau W, Ho H-H, et al. OSA and coronary plaque characteristics. Chest 2014; 145(2):322-30

61.

Zias N, Bezwada V, Gilman S, Chroneou A. Obstructive sleep apnea and erectile dysfunction: still a neglected risk factor? Sleep Breath 2009;13(1):3-10

63.

64.

65.

66.

68.

A number of issues faced by patients with hypertrophic cardiomyopathy are examined, such as the elevated prevalence of OSA, the implications of the relationship between OSA and AF and the absence of OSA predictors specific to this population.

60.

62.

67.

Santos T, Drummond M, Botelho F. Erectile dysfunction in obstructive sleep apnea syndrome–prevalence and determinants. Rev Port Pneumol 2012; 18(2):64-71 Xu J, Huang P, Song B, Chen J-M. Effect of continuous positive airway pressure on erectile dysfunction in patients with obstructive sleep apnea syndrome: a metaanalysis. Zhonghua Nan Ke Xue 2013; 19(1):77-81 Linz D, Neuberger H-R. Obstructive sleep apnea: the suffocated atrium? Hear Rhythm 2012;9(3):328-9 Hatipog˘lu U, Rubinstein I. Inflammation and obstructive sleep apnea syndrome pathogenesis: a working hypothesis. Respiration 2003;70(6):665-71 Shamsuzzaman ASM, Winnicki M, Lanfranchi P, et al. Elevated C-reactive protein in patients with obstructive sleep apnea. Circulation 2002;105(21):2462-4

informahealthcare.com

Chung MK, Martin DO, Sprecher D, et al. C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation. Circulation 2001;104(24): 2886-91 Somers VK, White DP, Amin R, et al. Sleep apnea and cardiovascular disease: an american heart association/american college of cardiology foundation scientific statement from the american heart association council for high blood pressure research professional education committee, council on. J Am Coll Cardiol 2008;52(8): 686-717

69.

Linz D, Schotten U, Neuberger H-R, et al. Negative tracheal pressure during obstructive respiratory events promotes atrial fibrillation by vagal activation. Heart Rhythm 2011; 8(9):1436-43

70.

Baranchuk A, Simpson CS, Redfearn DP, Fitzpatrick M. It’s time to wake up! Sleep apnea and cardiac arrhythmias. Europace 2008;10(6):666-7

71.

Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995;96(4):1897-904

72.

Seaborn GE, Pang H, Akl SG, et al. Autonomic profile of patients referred to a sleep disorder clinic: impact of CPAP on the autonomic nervous system. Rev Uruguaya Cardiol 2012;27(2):143-7

73.

Guzik P, Piskorski J, Awan K, et al. Obstructive sleep apnea and heart rate asymmetry microstructure during sleep. Clin Auton Res 2013;23(2):91-100

74.

Pritchett AM, Mahoney DW, Jacobsen SJ, et al. Diastolic dysfunction and left atrial volume: a population-based study. J Am Coll Cardiol 2005;45(1):87-92

75.

Tsang TSM, Gersh BJ, Appleton CP, et al. Left ventricular diastolic dysfunction as a predictor of the first diagnosed nonvalvular atrial fibrillation in 840 elderly men and women. J Am Coll Cardiol 2002;40(9): 1636-44

76.

Usui Y, Takata Y, Inoue Y, et al. Severe obstructive sleep apnea impairs left ventricular diastolic function in non-obese men. Sleep Med 2013;14(2):155-9

77.

78.

Kraiczi H, Caidahl K, Samuelsson A, et al. Impairment of vascular endothelial function and left ventricular filling : association with the severity of apnea-induced hypoxemia during sleep. Chest 2001;119(4):1085-91 Alchanatis M, Paradellis G, Pini H, et al. Left ventricular function in patients with obstructive sleep apnoea syndrome before

Review

and after treatment with nasal continuous positive airway pressure. Respiration 2000; 67(4):367-71 79.

Haruki N, Takeuchi M, Nakai H, et al. Overnight sleeping induced daily repetitive left ventricular systolic and diastolic dysfunction in obstructive sleep apnoea: quantitative assessment using tissue Doppler imaging. Eur J Echocardiogr 2009;10(6): 769-75

80.

Andrade J, Khairy P, Dobrev D, Nattel S. The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms. Circ Res 2014;114(9):1453-68

81.

Allessie M, Ausma J, Schotten U. Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res 2002; 54(2):230-46

82.

Dimitri H, Ng M, Brooks AG, et al. Atrial remodeling in obstructive sleep apnea: implications for atrial fibrillation. Heart Rhythm 2012;9(3):321-7

83.

Tan AY, Chen P-S, Chen LS, Fishbein MC. Autonomic nerves in pulmonary veins. Heart Rhythm 2007;4(3 Suppl):S57-60

84.

Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365(9464):1046-53

85.

Pinsky MR. Sleeping with the enemy: the heart in obstructive sleep apnea. Chest 2002;121(4):1022-4

86.

Kaneko Y, Floras JS, Usui K, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med 2003;348(13):1233-41

87.

Johnson CB, Beanlands RS, Yoshinaga K, et al. Acute and chronic effects of continuous positive airway pressure therapy on left ventricular systolic and diastolic function in patients with obstructive sleep apnea and congestive heart failure. Can J Cardiol 2008;24(9):697-704

••

The impacts of acute and chronic CPAP administration in patients with congestive heart failure (CHF) are investigated, and a pointed note is made concerning the potentially dangerous effects of CPAP therapy in those with severe CHF.

88.

Cloward T V, Walker JM, Farney RJ, Anderson JL. Left ventricular hypertrophy is a common echocardiographic abnormality in severe obstructive sleep apnea and

doi: 10.1586/14779072.2014.969713

Review

Drew, Qaddoura & Baranchuk

reverses with nasal continuous positive airway pressure. Chest 2003;124(2):594-601 Oksenberg A, Gadoth N. Are we missing a simple treatment for most adult sleep apnea patients? The avoidance of the supine sleep position. J Sleep Res 2014;23(2):204-10

Kline CE, Crowley EP, Ewing GB, et al. Blunted heart rate recovery is improved following exercise training in overweight adults with obstructive sleep apnea. Int J Cardiol 2013;167(4):1610-15

91.

Alves E da S, Ackel-D’Elia C, Luz GP, et al. Does physical exercise reduce excessive

daytime sleepiness by improving inflammatory profiles in obstructive sleep apnea patients? Sleep Breath 2013;17(2): 505-10

Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Michigan University on 10/18/14 For personal use only.

89.

90.

doi: 10.1586/14779072.2014.969713

Expert Rev. Cardiovasc. Ther.