EDITORIAL COMMENT
Obstructive Sleep ApneaA Respiratory Syndrome With Protean Cardiovascular Manifestations*
Ian Wilcox, MB, PhD , ,* and
Christopher Semsarian, MB, BS, PhD,,
Sydney Medical School, University of Sydney, Sydney, Australia
Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, New South Wales, Australia
* Reprint requests and correspondence: Dr. Ian Wilcox, Royal Prince Alfred Medical Centre, Department of Cardiology, Suite 407, 100 Carillon Avenue, Newtown, New South Wales 2042, Australia (Email: iw{at}mail.med.usyd.edu.au).
Key Words: sleep • arrhythmia • obesity • apnea • oximetry • obstructive
Obstructive sleep apnea (OSA) presents with respiratory symptoms that include snoring, nocturnal choking, witnessed apneas, fragmented sleep, and symptoms of excessive daytime tiredness and sleepiness. While sleepiness has been associated with OSA, it only affects a minority of those with OSA in community-based studies (1,2). OSA occurs in all racial groups and appears to be common, peaking in midlife, affecting up to 20% of men and 10% of women between the ages of 39 to 65 years, the vast majority of whom remain undiagnosed (2). Despite presenting with respiratory symptoms, the most serious associations of OSA are cardiovascular, including arrhythmias, hypertension, coronary disease, heart failure, and stroke (3–6).
Polysomnography (PSG) was used in early studies of sleep performed by Dement and Kleitman (7) in the 1950s and later came to be used extensively in research and clinical practice in sleep-disordered breathing. OSA was defined empirically using a combination of electroencephalogram and respiratory variables with the diagnosis defined by an apnea-hypopnea index of 5 to 15 events/h. The use of PSG as a diagnostic tool to measure and define OSA preceded our knowledge of how common heart disease was in patients with OSA, and its possible contribution to cardiovascular pathophysiology, by many years. A confounder of attempts to establish that OSA is an independent risk factor for heart disease has been the strong association between it and other known risk factors, in particular the metabolic "syndrome X." In 1998 we proposed the term "syndrome Z" to draw attention to clinicians and their patients to this relationship (8).
In this issue of the Journal, reports by Monahan et al. (9) and Eleid et al. (10) give important new insights into the pathophysiology of OSA and cardiovascular disease and have the potential to provide new therapeutic options for patients with heart disease.
Early studies of heavy snorers, a marker for an increased risk of having OSA, reported an increased risk of sudden death during the night (11). Since then, a series of retrospective studies have shown a relationship between OSA and tachyarrhythmias including atrial fibrillation (AF) and complex ventricular arrhythmias during single overnight PSGs, as well as an increased risk of subsequent sudden death, particularly at night (12,13). The magnitude of the risk has been impressive, with an approximately 4-fold risk of nocturnal AF and nonsustained ventricular tachycardia. Similarly, a study of relatively young patients with normal left ventricular function and paroxysmal or persistent AF showed that these patients were 3 times as likely to have OSA (apnea-hypopnea index >15) as control subjects (14). These findings contrast with studies such as the Euro Heart Survey (15), which reported that OSA was a very uncommon trigger of symptomatic paroxysmal AF (0.3%).
Monahan et al. (9) examined the temporal relationship between breathing events and cardiac arrhythmias during unattended home PSG studies performed at a follow-up examination of a cohort (n = 2,816) of the original large prospective multicenter Sleep Heart Health study. The original study recruited 6,441 men and women age >40 years with or without snoring, excluding patients already on continuous positive airway pressure treatment (4,13). The recruitment process resulted in a study population that included predominantly snorers with relatively mild sleep apnea. The purpose of the present study was to examine the temporal relationship between respiratory events and cardiac arrhythmias. In this population, the absolute risk of an arrhythmia was low, as would be expected in a well population with a short period of electrocardiogram recording during sleep. Detection of arrhythmias using 24-h recordings is well known to be an insensitive method compared with longer duration recording methods such as implanted pacemakers, defibrillators, or loop recorders. The study design would therefore tend to significantly underestimate the true frequency of AF in patients with OSA. Indeed, the risk of developing AF and its consequences will clearly be affected by comorbidities such as obesity and other proinflammatory states, hypertension, left ventricular hypertrophy, and heart failure. Despite these limitations, the authors were able to demonstrate that an arrhythmia was 18 times more likely to occur after a breathing disturbance than normal sleep. These findings add significantly to what is already known about triggering of atrial and ventricular arrhythmias in heart disease in general and OSA in particular.
A series of studies have shown that obstructed breathing efforts are associated with atrial dilation, vagal stimulation early during apneas (16), and increased sympathetic nerve activity later during the event, peaking with arousal from sleep and resumption of breathing (17,18). The increased sympathetic nerve activity persists during the wakefulness. This suggests that OSA may well be a more important trigger of both "adrenergic" and "vagotonic" forms of AF (19) than was previously thought (15). These findings suggest that AF plays a key role in the pathophysiology of the increased risk of stroke and congestive heart failure in patients with untreated OSA.
The notion that there is a link between OSA and clinical outcomes in hypertrophic cardiomyopathy (HCM) is a fascinating one, particularly if treatment of OSA results in clinical improvement and a reduced need for either pharmacological or interventional therapy. OSA results in increased sympathetic activity, impaired vagal activity, and vasoconstriction. It is conceivable that the pathophysiological effects of OSA in HCM could include worsening diastolic dysfunction, impaired hypertrophic remodeling, triggering of both atrial and ventricular arrhythmias, as well as an increase in left ventricular outflow tract obstruction, due both to the factors mentioned as well as increases in left ventricular filling pressures and a reduction in cardiac output. A recently reported study by Sengupta et al. (20) of a small cohort of 4 patients with HCM suggested treatment of OSA using continuous positive airway pressure may reduce the need for more aggressive forms of treatment of left ventricular outflow tract obstruction, namely septal reduction approaches.
The questions, however, remain; how prevalent is OSA in patients with HCM, and in those where OSA is present, does treatment of OSA result in improved clinical outcomes in HCM? The study by Eleid et al. (10) suggests a high prevalence of sleep-disordered breathing in 71% of HCM patients tested. It is likely that this is an overestimate of the true prevalence, particularly given the population studied was at a tertiary referral center where the most severe HCM cases are likely to be referred, and the potential modifying role of hypertension (in 55%) in this HCM population. The textbook definition of HCM states a disease characterized by unexplained hypertrophy in the absence of loading conditions such as hypertension. This casts some doubt on whether a small proportion of patients in this cohort truly had HCM, or had HCM exacerbated by coexistent hypertension, and whether genetic testing for the known sarcomere genes was performed in the patients with hypertension. Nevertheless, the presence of OSA in this HCM population appears significant and supports an argument that perhaps all patients with HCM should be tested for OSA using simple investigations such as nocturnal oximetry. In terms of the cardiovascular benefits of treatment of OSA in HCM patients, there are only a handful of reported cases, although promising clinical outcomes are described (20). Clearly, to truly assess the prevalence of OSA in HCM, and to determine whether treatment of OSA in HCM results in clinical improvement, larger, population-based, randomized, prospective studies are needed.
The cost and complexity of PSG has been an important barrier to clinical and research studies in the past, but increasingly, simpler, more cost effective, diagnostic tests are being developed. This process should enhance our ability to design and perform appropriately powered, randomized, controlled studies of the consequences of OSA in patients with heart disease. Fortunately, a highly effective treatment for OSA, nasal continuous positive airway pressure, was described nearly 30 years ago by Sullivan et al. (21). Since then, alternative treatments, such as oral appliances, have also been developed and shown to be effective in addition to sleeping position changes, weight loss, and other measures (22).
Incorporating new paradigms of the importance of OSA in patients with heart disease into clinical practice will be critically dependent on cardiologists being more closely involved in the diagnosis and, potentially, treatment of OSA.
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Footnotes
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Dr. Wilcox is a clinical consultant to ResMed Inc.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep disordered breathing amongst middle aged adults N Engl J Med 1993;328:1230-1235.[CrossRef][Web of Science][Medline]2. Young T, Finn L, Peppard PE, et al. Sleep disordered breathing and mortality: eighteen year follow up of the Wisconsin sleep cohort study Sleep 2008;31:1071-1078.[Web of Science][Medline] 3. Lattimore J-D, Celermajer DS, Wilcox I. Sleep apnea and cardiovascular disease J Am Coll Cardiol 2003;41:1429-1437.[Abstract/Free Full Text] 4. Chami HA, Devereux RB, Gottdiener JS, et al. Left ventricular morphology and systolic function in sleep-disordered breathing. The sleep heart health study. Circulation 2008;117:2599-2607.[Abstract/Free Full Text] 5. Valham F, Mooe T, Rabben T, Stenlund H, Wiklund U, Franklin K. Increased risk of stroke in patients with coronary artery disease and sleep apnea. A 10 year follow-up. Circulation 2008;118:955-960.[Abstract/Free Full Text] 6. 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 Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing J Am Coll Cardiol 2008;52:686-717.[Free Full Text] 7. Dement W, Kleitman N. Cyclic variations in EEG during sleep and their relation to eye movements, body motility, and dreaming Electroencephalogr Clin Neurophysiol 1957;9:673-690.[CrossRef][Medline] 8. Wilcox I, McNamara SG, Collins FL, Grunstein RR, Sullivan CE. ‘Syndrome Z’: the interaction of sleep apnoea, vascular risk factors and heart disease Thorax 1998;53(Suppl 3):S25-S28.[Abstract] 9. Monahan K, Storfer-Isser A, Mehra R, et al. Triggering of nocturnal arrhythmias by sleep disordered breathing events J Am Coll Cardiol 2009;54:1797-1804.[Abstract/Free Full Text] 10. Eleid MF, Konecny T, Orban M, et al. High prevalence of abnormal nocturnal oximetry in patients with hypertrophic cardiomyopathy J Am Coll Cardiol 2009;54:1805-1809.[Abstract/Free Full Text] 11. Seppälä T, Partinen M, Penttilä A, Aspholm R, Tiainen E, Kaukianen A. Sudden death and sleeping history among Finnish men J Int Med 1991;229:23-28.[Medline] 12. Gami AS, Howard DE, Olson EJ, Somers VK. Day-night pattern of sudden death in obstructive sleep apnea N Engl J Med 2005;352:1206-1214.[CrossRef][Web of Science][Medline] 13. 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;173:910-916.[Abstract/Free Full Text] 14. Stevenson IH, Teichtahl H, Cunnington D, Ciavarella S, Gordon I, Kalman JM. Prevalence of sleep disordered breathing in paroxysmal atrial fibrillation patients with normal left ventricular function Eur Heart J 2008;29:1662-1669.[Abstract/Free Full Text] 15. De Vos CB, Niewlaat R, Crijns HJGM, et al. Autonomic trigger patterns and anti-arrhythmic treatment of paroxysmal atrial fibrillation: data from the Euro heart survey Eur Heart J 2008;29:632-639.[Abstract/Free Full Text] 16. Zwillich C, Devlin T, White D, Douglas N, Weill J, Martin R. Bradycardia during sleep apnea: characteristics and mechanism J Clin Invest 1982;69:1286-1292.[Web of Science][Medline] 17. Carlson JT, Hedner J, Elam M, Ejnell H, Sellgren J, Wallin BG. Augmented resting sympathetic activity in awake patients with obstructive sleep apnea Chest 1993;103:1763-1768.[Abstract/Free Full Text] 18. Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea J Clin Invest 1995;96:1897-1904.[Web of Science][Medline] 19. Coumel P. Cardiac arrhythmias and the autonomic nervous system J Cardiovasc Physiol 1993;4:338-355.[Web of Science][Medline] 20. Sengupta PP, Sorajja D, Eleid MF, et al. Hypertrophic obstructive cardiomyopathy and sleep-disordered breathing: an unfavorable combination Nat Clin Pract Cardiovasc Med 2009;6:14-15.[CrossRef][Web of Science][Medline] 21. Sullivan CE, Issa FG, Berthon-Jones M, Eves L. Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares Lancet 1981;i:862-865. 22. Chan AL, Lee RWW, Cistulli PA. Non-positive airway pressure modalities. Mandibular advancement devices/positional therapy. Proc Am Thorac Soc 2008;5:179-184.[Abstract/Free Full Text]
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