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Obstructive Sleep Apnea as a Candidate Unifier in Atrial Fibrillation and Cryptogenic Stroke Commentary on Lipford et al. Associations between cardioembolic stroke and obstructive sleep apnea. SLEEP 2015;38:1699–1705. Reena Mehra, MD, MS; Nancy Foldvary-Schaefer, DO, MS Sleep Disorders Center, Neurological Institute, Cleveland Clinic, Cleveland, OH

Greater than 600,000 individuals are estimated to experience ischemic stroke in the United States annually.1 Causative factors remain undetermined in up to 30% of these cases (i.e., cryptogenic stroke).2 Given its intermittent and often asymptomatic nature, occult atrial fibrillation (AF) likely contributes to a substantial proportion of cryptogenic stroke via cardioembolism.3–5 Current guidelines advise up to 30 days of continuous cardiac rhythm monitoring in the setting of cryptogenic stroke, defined as stroke with no readily apparent causal factors.6 Recent data from The Cryptogenic Stroke and Underlying Atrial Fibrillation trial (CRYSTALAF), however, have identified the merit of longer term continuous cardiac monitoring up to 12 months, compared to conventional follow-up in terms of enhancing ability to capture AF, and target therapy accordingly to reduce stroke and associated morbidity.7 Obstructive sleep apnea (OSA) represents a likely unifying link between AF and ischemic stroke. The interrelationships of OSA, AF, and stroke are complex and likely multi-directional. OSA via intermittent hypoxia, autonomic nervous system alterations, hypercapnia, and up-regulation of markers of systemic inflammation and thrombosis serves as a likely pathophysiology in the development of AF, as well as a risk factor for ischemic stroke. Moreover, OSA may exert synergistic effects in augmenting ischemic stroke risk not only via direct effects, but also in tandem via indirect intermediary pathways involving atrial fibrillation, hypertension, and diabetes mellitus. Progress in recognition of OSA as a bona fide risk in ischemic stroke and AF is evidenced respectively by recent inclusion in the American Heart Association/American Stroke Association guidelines for stroke prevention6 and also the Heart Rhythm Society AF Prevention task force guidelines.8 In the current issue of SLEEP, Lipford and colleagues9 aim to further elucidate sleep apnea-AF-stroke relationships. They conducted a retrospective clinic-based study over a span of 11 years to examine the relationship of OSA and ischemic stroke, the latter occurring within one year subsequent to OSA assessment. The approach yielded a total of 53 patients, of whom 60.5% had OSA, defined as an apnea hypopnea index (AHI) > 10, with an overall moderate to severe degree of apnea Submitted for publication September 2015 Accepted for publication September 2015 Address correspondence to: Reena Mehra, MD, MS, Sleep Center, Neurologic Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195; Tel: (216) 444-8777; Fax: (216) 636-0090; Email: [email protected] SLEEP, Vol. 38, No. 11, 2015

burden (AHI mean ~33 and median ~23). Those with OSA had a 4–6 fold higher odds of cardioembolic stroke compared to those without OSA when considering confounding variables individually in statistical models, which was marginally statistically significant in the multivariable model. Specifically, after taking into account AF, there was a 4.5-fold higher odds of cardioembolic stroke in OSA versus those with a lower AHI. Also, although a greater degree of hypoxia was observed in those with cardioembolic strokes compared to other stroke subtypes, the relationship was not statistically significant. The authors conclude that there is a strong magnitude of association of OSA and cardioembolic stroke relative to other stroke subtypes and that this relationship may not be appreciably confounded by AF. A clear strength of the report by Lipford et al.9 is their systematic and standardized approach to the classification of stroke type. Furthermore, the diagnosis of OSA prior to the ischemic stroke event sheds light on the temporality of the relationship, as existing data appear to support bi-directional relationships of OSA and stroke; however, the lack of strict exclusion of baseline stroke prior to OSA diagnosis may be a perceived limitation. As an AHI cutoff of 10 was selected by Lipford et al.,9 the “control” group included a mild degree of sleep apnea, which could potentially bias towards the null. Moreover, the effect of OSA treatment is unclear. Consideration of other AHI thresholds, as well as the AHI measure as a continuous variable to obtain a more refined sense of relationships, would be of interest. Implications of the persistence of an OSA-cardioembolic stroke association after adjustment for AF remain unclear. Although it is conceivable that AF does not appreciably confound the OSA-stroke association, there is also the possibility of misclassification of AF status given that extended cardiac monitoring beyond 30 days is not the clinical standard and may have resulted in inaccuracy or underestimation of AF designation. The findings of the Lipford and colleagues9 are compelling in terms of implicating moderate-to-severe OSA as a risk for cardioembolic stroke. The role of atrial fibrillation in this relationship remains unclear. Future investigation should focus on enhanced characterization of AF not only as a direct risk factor, but also as an important intermediary risk of stroke in relation to OSA. Prospective studies involving larger sample sizes aimed to better characterize these relationships are essential in order to adequately inform OSA severity threshold and specific OSA subgroups based upon biomarker or genetic susceptibilities, who may benefit from longer term cardiac monitoring to more accurately identify atrial fibrillation as a risk of otherwise defined cryptogenic cardioembolic stroke.


Editorial—Mehra and Foldvary-Schaefer

This also allows opportunity for development of personalized medicine and possibly even precision-medicine based initiatives to tailor prevention and treatment of AF in OSA to reduce stroke-related morbidity and mortality. CITATION Mehra R, Foldvary-Schaefer N. Obstructive sleep apnea as a candidate unifier in atrial fibrillation and cryptogenic stroke. SLEEP 2015;38(11):1669–1670. DISCLOSURE STATEMENT The authors have indicated no financial conflicts of interest. REFERENCES

1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics--2015 update: a report from the American Heart Association. Circulation;131:e29–322. 2. Kolominsky-Rabas PL, Weber M, Gefeller O, Neundoerfer B, Heuschmann PU. Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study. Stroke 2001;32:2735–40.

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3. Page RL, Wilkinson WE, Clair WK, McCarthy EA, Pritchett EL. Asymptomatic arrhythmias in patients with symptomatic paroxysmal atrial fibrillation and paroxysmal supraventricular tachycardia. Circulation 1994;89:224–7. 4. Quirino G, Giammaria M, Corbucci G, et al. Diagnosis of paroxysmal atrial fibrillation in patients with implanted pacemakers: relationship to symptoms and other variables. Pacing Clin Electrophysiol 2009;32:91–8. 5. Strickberger SA, Ip J, Saksena S, Curry K, Bahnson TD, Ziegler PD. Relationship between atrial tachyarrhythmias and symptoms. Heart Rhythm 2005;2:125–31. 6. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014;45:2160–236. 7. Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014;370:2478–86. 8. Van Wagoner DR, Piccini JP, Albert CM, et al. Progress towards the prevention and treatment of atrial fibrillation: a summary of the Heart Rhythm Society Research Forum on the Treatment and Prevention of Atrial Fibrillation, Washington, DC, December 9-10, 2013. Heart Rhythm 2015;12:e5–29. 9. Lipford MC, Flemming KD, Calvin AD, et al. Associations between cardioembolic stroke and obstructive sleep apnea. Sleep 2015;38:1699–705.

Editorial—Mehra and Foldvary-Schaefer

Obstructive Sleep Apnea as a Candidate Unifier in Atrial Fibrillation and Cryptogenic Stroke.

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