The prevalence of atrial fibrillation (AF) is 0.4% in. Prevalence of Sleep Apnea Syndrome in Lone Atrial Fibrillation* A Case-Control Study

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1 Prevalence of Sleep Apnea Syndrome in Lone Atrial Fibrillation* A Case-Control Study Kimmo Markus Porthan, MD; John Henry Melin, MD; Jukka Tapani Kupila, MD; Kari Kauko Kalervo Venho, MD; and Markku Mikael Partinen, MD, PhD Background: According to several studies, obstructive sleep apnea predisposes to cardiac arrhythmias, but the prevalence of sleep apnea in specific arrhythmias has not been determined. Our case-control study assesses prevalence of sleep apnea syndrome (SAS) in lone atrial fibrillation (AF). Methods: Patients with AF (n 59; 48 men and 11 women; mean age, 59 years; age range, 25 to 84 years) without evident cardiovascular diseases, and their 56 gender-matched, age-matched, and cardiovascular morbidity-matched community control subjects underwent an overnight sleep study. Results: Prevalence of SAS in the AF group was 32%, which did not differ from that in control subjects (29%, p 0.67). In men, mean neck circumference was higher in the AF group (40.9 cm vs 39.5 cm, p 0.01) than in control subjects. In men, after adjusting for body mass index and waist circumference, neck circumference was independently related to AF, with an odds ratio (OR) of 1.8 (95% confidence interval, 1.3 to 2.5) per 1-cm increase, and an OR of 5.2 (95% confidence interval, 1.6 to 17.0) for values > 40 cm. Compared to control subjects, the AF group reported more daily/almost-daily tiredness (29% vs 4%, p < 0.001), daily/almost-daily sleepiness (27% vs 7%, p 0.005), and nightly/almost-nightly breathing pauses during sleep (12% vs 2%, p 0.03). Conclusions: SAS seems to be common in lone AF. Nevertheless, we could not show SAS to be more common in patients with AF than in gender-matched, age-matched, and cardiovascular morbidity-matched community control subjects. Compared to control subjects, men with AF seem to have thicker necks, and patients with lone AF report more daytime tiredness, daytime sleepiness, and breathing pauses during sleep. (CHEST 2004; 125: ) Key words: atrial fibrillation; case-control studies; sleep apnea syndromes Abbreviations: AF atrial fibrillation; AHI apnea-hypopnea index; AI apnea index; BMI body mass index; JCH Jyväskylä Central Hospital; OR odds ratio; OSA obstructive sleep apnea; SAS sleep apnea syndrome; S-TSH serum thyroid-stimulating hormone The prevalence of atrial fibrillation (AF) is 0.4% in the general population and 6% for those 80 years old. 1 In middle age, 24% of men and 9% of women have obstructive sleep apnea (OSA) when defined as at least five respiratory pauses per hour of sleep. 2 The prevalence of undiagnosed OSA syndrome is up to 5% for adults in Western countries. 3 *From the Department of Medicine (Dr. Porthan), Helsinki University Central Hospital, Helsinki; Departments of Medicine (Dr. Melin), Clinical Neurophysiology (Dr. Kupila), and Respiratory Medicine (Dr. Venho), Jyväskylä Central Hospital, Jyväskylä; and Rinnekoti Research Center (Dr. Partinen), Espoo, Finland. This work was performed at Jyväskylä Central Hospital, Jyväskylä, Finland. This study was supported by The Finnish Anti-Tuberculosis Association Foundation, The Ida Montin Foundation, The Väinö OSA is connected with cardiac arrhythmias, 4 11 with possible etiologic factors including hypoxemia and elevated catecholamines. OSA also causes disturbances in the autonomic nervous system. 12 Changes in autonomic nervous tone can in turn induce AF. 13 Very little has been known about the prevalence of and Laina Kivi Foundation, The Päivikki and Sakari Sohlberg Foundation, and an EVO (erityisvaltionosuusraha) grant from Jyväskylä Central Hospital. Manuscript received April 15, 2003; revision accepted September 30, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( permissions@chestnet.org). Correspondence to: Kimmo Markus Porthan, MD, Tilkankatu 39 C 5, Helsinki, Finland; porthan@mappi.helsinki.fi CHEST / 125 / 3/ MARCH,

2 sleep apnea in patients with AF. Mooe et al 14 showed sleep-disordered breathing to be more common in patients with postsurgical AF than in those without. We hypothesized that sleep apnea is a risk factor for AF and that the mechanism may be changes in the autonomic nervous system caused by sleep apnea. In this case, sleep apnea may be the explanation for AF in cases traditionally classified as lone AF. Our aim was to compare the prevalence of sleep apnea syndrome (SAS) in patients with lone AF to that in community control subjects, and to compare anthropometric and sleep questionnaire data between these groups. Study Population Materials and Methods We identified AF cases among patients treated for lone AF in Jyväskylä Central Hospital (JCH). The hospital database included 699 patients with International Classification of Diseases, Tenth Revision diagnosis I48 (AF/atrial flutter) in Assessing hospital patient files, we classified AF as lone if the patient did not have any of the known causes of AF: hypertension, ischemic heart disease, valvular heart disease, and hyperthyroidism; and acute causes: alcohol intake, surgery, electrocution, myocarditis, pulmonary embolism, and acute myocardial infarction. 1 We excluded patients with sick sinus syndrome and those with a pacemaker implanted for atrioventricular dissociation, because bradycardia can trigger AF. We excluded also patients with earlier-diagnosed diabetes mellitus, which was a risk factor for AF in a population-based trial. 15 We defined hypertension as receiving antihypertensive medication or BP 140/90 mm Hg based on the average of one or more readings obtained in JCH in Of the 699 patients, 100 patients had lone AF. Among these, to maximize cooperation, we excluded those with metastatic cancer (n 2), dementia (n 4), and severe mental disorder (n 1), leaving 93 suitable patients (70 men and 23 women). We sent a letter to these 93 patients describing our study (and a questionnaire on medical history). Answers came from 92 patients (99%), of whom 67 patients (73%) were willing to participate. After 1999, hypertension had been diagnosed in five patients, coronary heart disease in two patients, and diabetes mellitus in one patient. We excluded these. Two patients had been examined because of suspected SAS in the same sleep laboratory using the same equipment as in our study. For these, we used the earlier sleep recording data and invited the rest to the sleep recording session. As a result, we made an AF group of 59 patients (48 men aged 25 to 76 years [mean, 57 years]; 11 women aged 50 to 84 years [mean, 67 years]). Of these, two patients had paroxysms of both AF and atrial flutter, and the rest had AF only. A specialist in internal medicine or a cardiologist had examined all patients in the AF group, including examinations as follows: clinical examination, ECG, chest radiography, serum thyroid-stimulating hormone (S-TSH; 86%), serum-free thyroxine (56%), echocardiography (58%), and treadmill exercise ECG (41%). AF cases were residents of the city of Jyväskylä, Finland (80,000 inhabitants) or the closely surrounding area. We selected control subjects from the city of Jyväskylä using the Population Information System, which includes data on all inhabitants of Finland and is run by the Population Register Center. We received a random list of names and addresses matched to the AF group by sex and age (birth year). We sent a maximum of 20 letters (same letter as for the AF group) per AF case until we found an appropriate control subject (exclusion criteria: congenital heart disease, valvular heart disease, heart failure, ischemic heart disease, hypertension, hyperthyroidism, diabetes mellitus, AF, sick sinus syndrome, and pacemaker implanted for atrioventricular dissociation). Of the 323 letters, 57% were answered. Of those answered, 51% were excluded because of their diseases. Of the appropriate responders, 56 people (62%) were willing to participate and were invited to the sleep-recording session. We could obtain no control subjects for three patients with AF because 20 letters per case were not enough to find a control subject for them. Questionnaire on Medical History We assessed medical history by asking the following question: Do you have or have you ever had AF (asked of control subjects only), congenital heart disease, heart failure, coronary heart disease, myocardial infarction, some other heart disease (define), hypertension, thyroid disease, chronic lung disease (define), diabetes mellitus, cancer, or some other disease (define)? If any doubt remained, we telephoned the subject to be sure that he/she had none of the diseases we wanted to exclude. We classified the subjects as hypertensive also if they reported attending checkups for hypertension. We assessed alcohol consumption (drinks/ week), current smoking (yes/no), use of sleeping pills (yes/no) and, for the patients with AF, when was their first and last AF paroxysm and whether their AF was chronic (yes/no). Sleep Recording We performed sleep recording in JCH using the AutoSet Portable II Plus device (ResMed Ltd; North Ryde, NSW, Australia) The subjects spent the night in the sleep laboratory and were monitored. The subjects wore a finger pulse oximeter, nasal cannula, and a thoracic belt to measure body position and respiratory effort. We pooled all types of apneas. We calculated apnea index (AI) and apnea-hypopnea index (AHI) by dividing the number of events by total study time in hours. We defined SAS as AI 5 plus AHI 15 combined with symptoms (see following, Sleep Questionnaire ). We classified sleep apnea as mild (AI 5 plus AHI 15 to 29), moderate (AI 5 plus AHI 30 to 44), or severe (AI 5 plus AHI 44). An experienced clinical neurophysiologist (J.T.K.) reviewed the sleep recordings. Procedure Height, weight, body mass index (BMI), abdominal circumference, neck circumference, and height-corrected neck circumference ([measured neck circumference/5.5 height in meters 31] 100). 19 BP was measured in the evening and in the morning (Omron 711 Automatic IS; Omron; Matsusaka, Japan). In the control group, each subject also gave a medical history and underwent a clinical examination performed by a physician (K.M.P.), and an ECG and a blood sample for S-TSH was obtained. Recording duration ranged from 6.0 to 8.9 h in the AF group and from 5.1 to 8.6 h in the control group. No subjects could use any sleeping pills not part of their usual medication at home. One trained nurse (AF group) and one trained physician (K.M.P.) [control group] served as staff in the sleep laboratory. The AF subjects visited the sleep laboratory between June and September 2001 and the control subjects between January and June Clinical Investigations

3 Sleep Questionnaire All subjects filled in a sleep questionnaire. We used the following questions in the definition of SAS: Do you feel tired in the daytime? Do you feel sleepy in the daytime? Do you snore while sleeping? and Have you had breathing pauses during sleep? The subjects answered the following in a 5-point scale manner: (1) never or less than once per month, (2) less than once per week, (3) during 1 to 2 days/nights per week, (4) during 3 to 5 days/nights per week, and (5) daily/nightly or almost daily/nightly. We scored the answers 1, 2, 3, 4, and 5, respectively. We defined SAS as AI 5 plus AHI 15 and the minimum score of 3 at least once. We will report detailed results of the entire questionnaire in a later article. Statistical Methods We compared the AF group data to control group data. Age data were age on the day of sleep recording. Values were means (SD) for continuous variables and proportions for categoric variables. We analyzed these data with SPSS version 10.0 (SPSS; Chicago, IL). We used the t test to compare continuous variables and the 2 test for categoric variables. We used logistic regression analysis when determining the independent association of the variables between groups, and present the results as odds ratios (ORs) with a 95% confidence interval. For all tests, a two-tailed p 0.05 was required for statistical significance. Ethics The local ethics committee approved the study. All subjects gave their informed consent. months). At the time of sleep recording in the AF group, 39 patients (66%) received a beta-blocker, 20 patients (34%) received flecainide, 4 patients (7%) received amiodarone, 4 patients (7%) received digoxin, 1 patient (2%) received quinidine sulfate, and 18 patients (31%) received warfarin. All control subjects were in sinus rhythm, had normal S-TSH, and were clinically euthyroid. Table 1 shows the general characteristics of the participants. Despite being higher in the AF group, as it was in men, neck circumference and heightcorrected neck circumference failed to reach a significant difference in women because of the few women subjects. In men, neck circumference was higher in the AF group also after controlling for the possible confounding effect of BMI and waist circumference (Table 2). Performing logistic regression analysis using height-corrected neck circumference instead of neck circumference (not shown) changed no results. Men with neck circumference 40.0 cm and AHI 15 had elevated risk of belonging to the AF group (OR, 1.6), but this was not statistically significant (p 0.42) because of the small number of such subjects (AF group [n 9], control group [n 6]). Results Characteristics of the Study Population Mean time between the last visit to JCH and sleep recording in the AF group was 24 months (SD, 4 Sleep Recordings All sleep recordings were technically valid. During the sleep recording, two patients (3%) in the AF group and two patients (3%) in the control group used sleeping pills. All patients in the AF group and Table 1 Characteristics of the Study Population* Men Women Characteristics AF Group (n 48) (n 47) p Value AF Group (n 11) (n 9) p Value Age, yr 56.5 (10.5) 57.4 (10.5) (10.7) 65.8 (8.9) 0.53 Height, cm 178 (8) 175 (5) (5) 164 (8) 0.27 Weight, kg 84 (14) 81 (12) (12) 73 (22) 0.80 BMI 26.7 (3.6) 26.4 (3.4) (3.6) 27.0 (6.3) 0.81 Neck circumference, cm 40.9 (2.6) 39.5 (2.7) (1.7) 34.9 (2.2) 0.36 Height-corrected neck circumference, % 100 (6) 97 (6) (4) 87 (5) 0.22 Waist circumference, cm 98.0 (9.9) 96.5 (10.3) (9.6) 92.0 (16.2) 0.24 Systolic BP, mm Hg 138 (19) 137 (17) (15) 153 (32) 0.41 Diastolic BP, mm Hg 88 (9) 89 (9) (8) 92 (15) 0.81 Current smokers Use of sleeping pills at home Alcohol consumption, drinks/wk 5.3 (6.4) 3.3 (5.1) (1.1) 0.9 (0.7) 0.49 Chronic AF Time from the first AF, yr 8.8 (8.1) 5.7 (6.3) Time from the last AF, yr 0.8 (1.2) 0.5 (0.7) *Data are presented as mean (SD) or %. Mean of two measurements. Asked of 46 patients with paroxysmal or persistent AF. CHEST / 125 / 3/ MARCH,

4 Table 2 Multivariate Logistic Regression Analysis Assessing Predictive Value of Anthropometric Data for Presence of AF in Men* Variables all but two subjects in the control group, with AI 5 plus AHI 15, also fulfilled the questionnaire criteria for SAS. Table 3 shows the results of the sleep recordings. No significant differences appeared between groups. The proportion of those in the AF group with moderate or severe SAS was more than twice as high as in the control group (11.9% vs 5.4%), but this was not statistically significant (p 0.22) because of the small number of such subjects (AF group [n 7], control group [n 3]). Testing the prevalence of SAS separately for men and women (not shown) changed no results. Figure 1 shows the prevalence of breathing event indexes in the study groups. OR 95% Confidence Interval Significance of Change Nondichotomized variables BMI Waist circumference Neck circumference Neck circumference dichotomized BMI Waist circumference Neck circumference 40 cm *Relative risk for AF compared to sinus rhythm. Table 3 Results of Sleep Recordings* Variables AF Group (n 59) (n 56) p Value Oxyhemoglobin saturation Lowest value, % 91 (3) 89 (6) %, % of total 29 (32) 32 (30) 0.36 time Breathing event index, episodes/h AHI 16 (21) 13 (11) 0.53 AI 5.6 (6.5) 6.1 (10.7) 0.54 SAS, % of patients All (AI 5 plus AHI 15) Mild (AI 5 plus AHI 15 29) Moderate (AI plus AHI 30 44) Severe (AI 5 plus AHI 44) *Data are presented as mean (SD) or %. See text for the sleep questionnaire criteria. Sleep Questionnaire Table 4 shows that compared to control subjects, the AF group reported more daily/almost-daily tiredness, daily/almost-daily sleepiness, and nightly/almost-nightly breathing pauses during sleep. Testing the data separately for men and women (not shown) changed no results. When we analyzed all data also excluding the three patients with AF without control subjects (not shown), all results (Tables 1 4) remained the same. Discussion To the best of our knowledge, this may be the first report of the prevalence of SAS in lone AF. Using same cut-off values for SAS as in a recent study, 20 AI 5 plus AHI 15, the prevalence of SAS in lone AF was 32%, which is higher than that in populationbased trials. 3 In a population-based study, Sjöström et al 21 reported sleep-disordered breathing in 31% of hypertensive men. We did not exclude subjects by BP measurements made just before they joined the study. It would, in fact, have been difficult to set cut-off values for the AF group, in which 66% received a beta-blocker for AF. Some subjects would probably have been classified as hypertensive and thus excluded if selected based on BP measurements. After all, AF patients had their BP measured in JCH in 1999 at least once, and we required an average level of 140/90 mm Hg at that time. BP levels were the same in study groups at the time of the study. Although we did find a high prevalence of SAS in patients with AF, population studies thus far are not sufficiently standardized to make a direct comparison without our own control group. Nevertheless, the finding that the control group included no cases with earlier-diagnosed SAS, and the AF group only one, may indicate that SAS is an underdiagnosed disorder. The prevalence of SAS in the control group was 29%, which is again high. Of the letters sent to the control candidates, 43% went unanswered, and we did not try again to collect data from nonresponders. It is probable that the control group was biased toward snorers and those having symptoms of sleep apnea. In addition, the control group may have included cases with undiagnosed hypertension, as in the AF group. Of the letters sent to AF patients, 99% were answered, and 69% of those considered suitable took part in the sleep recording, making the data perhaps more dependable in the AF group than among control subjects. Therefore, the main findings of our study reside in the description of a rather large number of patients with lone AF and SAS. We used the AutoSet Portable II Plus device for 882 Clinical Investigations

5 Figure 1. Breathing event indexes in patients with AF and in control subjects. sleep recordings. Bradley et al 17 and Gugger 16 considered the AutoSet useful for diagnosing SAS with a good correlation with polysomnography (r 0.85 to 0.95). The sensitivity of the AutoSet was high (97 to 100%) but its specificity somewhat lower (77 to 92%), which may indicate that some of our subjects classification of SAS may be false-positives and thus may in part explain our high prevalence of SAS. EEG, not available in the device we used, would have enabled us to divide sleep apnea events by sleep time instead of the study time. This would have increased the reliability of sleep apnea scoring. Neck circumference was significantly higher in men with AF than in control subjects also after taking into account possible confounders. To our best knowledge, this is a new finding and interesting from the viewpoint of our original hypothesis (SAS being a risk factor for AF), because an increased neck circumference has been suggested as a better sign of OSA than are other clinical indexes. 22,23 CHEST / 125 / 3/ MARCH,

6 Table 4 Proportions of Answers Daily/Nightly or Almost Daily/Nightly to Sleep Questions* Questions AF Group (n 59) (n 56) p Value Do you feel tired in the daytime? Do you feel sleepy in the daytime? Do you snore while sleeping? Have you had breathing pauses during sleep? *Data are presented as %. Measuring the neck circumference is simple; the staff used the same piece of equipment, they were trained the same way, and the precise site of the measurement was agreed in advance. So we believe that our results are reliable. Despite the high prevalence of SAS in our AF group, it is probably too early to recommend that all patients with lone AF undergo sleep studies. However, we believe that our findings warrant screening of symptoms of SAS among AF patients and to perform sleep studies for selected patients. It has to be remembered that our study does not show that SAS is not more common in patients with AF. On the contrary, the neck circumference finding and also the sleep questionnaire finding indicates that our original hypothesis is still worth studying. We classified AF as lone based on hospital patient files, because it would have proven too complicated to perform cardiovascular examinations for the AF group just before the study. Eight AF patients considered as lone AF in 1999 received a diagnosis of some cardiovascular disease or diabetes mellitus after We cannot know whether they really had lone AF in 1999 or had some undiagnosed disease, and we have to extrapolate this issue also to the study subjects. A specialist had examined AF subjects in JCH in 1999, and all clinically necessary examinations had been performed; a physician examined the control subjects at the time of the sleep recording. We thus consider the AF group to represent lone AF, and the control group to represent healthy subjects well from the perspective of clinical practice. Naturally, many of those with a diagnosis of lone AF will acquire other diseases at a later age. We derived AF cases systematically using a file including all patients treated in JCH in It is probable that we did not miss any patients with AF through imperfect International Classification of Diseases, Tenth Revision coding because, unlike in other types of AF, a patient with lone AF does not have many diagnosis codes. JCH is the only hospital for a population of 264,000 inhabitants with specialists in cardiology and around-the-clock facilities for electroversion of AF. In the JCH area in 1999, electroversion of AF was the first-line treatment in achieving sinus rhythm. In Finland, primary healthcare centers do not normally offer the possibility of electroversion of AF; instead, patients with AF are referred to a hospital. This is standard procedure also in the JCH area. We consider that the AF-patient population treated in our hospital is not biased but reflects well AF in general. As men were the majority in the study, statistical power was low for the calculations for women. We were inspired to perform our study by the following: (1) approximately 12 to 30% of AF patients have lone AF, (2) the prevalence of both sleep apnea and AF increases with age, (3) prevalence of both sleep apnea and AF is higher in men, (4) sleep apnea is a potential risk factor for cardiovascular morbidity among arrhythmias. 1,3,6,8 The number of clinical studies on the connection between sleep apnea and AF is minimal. Mooe et al, 14 in one study on patients with coronary artery disease, found that an oxygen desaturation index of 5 was associated with postoperative AF after coronary artery bypass surgery. They concluded that AF incidence could be reduced by diagnosing and treating disordered breathing more actively. Possible mechanisms in sleep apnea predisposing to AF include hemodynamic alteration, hypoxemia, and altered autonomic nervous system balance. 4,14 Cyclic variation in heart rate is typical in sleep apnea: apnea-induced and hypoxemia-induced bradycardia is followed by tachycardia during the postapneic hyperventilation. That vagal stimulation seems to cause bradycardia in sleep apnea is supported by the finding that bradycardia is prevented by atropine. 8 Vagal stimulation shortens the atrial refractory period and thus can predispose to AF. 24 Sleep arousal in sleep apnea is associated with sympathetic excitation, 25 which raises BP and causes automatism, triggered activity, and microreentry in heart muscle, 26 and can thus serve as a stimulus for arrhythmias. Sleep apnea thus strains the autonomic nervous system. It has already been shown that AF can be induced by increased autonomic nervous system discharge. 13 Sleep apnea may also result in structural cardiac changes: dilation and hypertrophy of the right ventricle, hypertrophy of the left ventricle, and dilation of the right and left atria. 27 Microscopic and electrophysiologic changes in atrial tissue are already documented in AF, but these changes remain to be examined in sleep apnea. One must note also that sleep apnea has recently been seen as a risk factor for hypertension, 21,33 and hypertension is in turn one risk factor for AF. 1 In conclusion, we found that our hypothesis that 884 Clinical Investigations

7 OSA is a risk factor for AF could not be verified by this case-control comparison demonstrating a similar high prevalence of OSA in patients with AF and carefully selected control subjects. However, the higher prevalence of well-known risk factors for OSA (thicker necks, daytime tiredness, witnessed apnea during sleep) in patients with AF does suggest that this relationship needs further study. References 1 Fuster V, Ryden LE, Asinger RW, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary; a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) developed in collaboration with the North American Society of Pacing and Electrophysiology. Circulation 2001; 104: Young T, Palta M, Dempsey J, et al. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993; 328: Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med 2002; 165: Lazarus A, Py A, Guerin F, et al. Arrhythmia and syndrome of obstructive sleep apnea in adults [in French]. Arch Mal Coeur Vaiss 1993; 86: 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: Hoffstein V, Mateika S. Cardiac arrhythmias, snoring, and sleep apnea. Chest 1994; 106: Becker H, Brandenburg U, Peter JH, et al. Reversal of sinus arrest and atrioventricular conduction block in patients with sleep apnea during nasal continuous positive airway pressure. Am J Respir Crit Care Med 1995; 151: Becker HF, Koehler U, Stammnitz A, et al. Heart block in patients with sleep apnoea. Thorax 1998; 53(Suppl 3):S29 S32 9 Liston R, Deegan PC, McCreery C, et al. Role of respiratory sleep disorders in the pathogenesis of nocturnal angina and arrhythmias. Postgrad Med J 1994; 70: Fietze I, Rottig J, Quispe-Bravo S, et al. Sleep apnea syndrome in patients with cardiac pacemaker. Respiration 2000; 67: Koehler U, Dubler H, Glaremin T, et al. Nocturnal myocardial ischemia and cardiac arrhythmia in patients with sleep apnea with and without coronary heart disease. Klin Wochenschr 1991; 69: Zwillich CW. Sleep apnoea and autonomic function. Thorax 1998; 53(Suppl 3):S20 S24 13 Ingemansson MP, Holm M, Olsson SB. Autonomic modulation of the atrial cycle length by the head up tilt test: non-invasive evaluation in patients with chronic atrial fibrillation. Heart 1998; 80: Mooe T, Gullsby S, Rabben T, et al. Sleep-disordered breathing: a novel predictor of atrial fibrillation after coronary artery bypass surgery. Coron Artery Dis 1996; 7: Benjamin EJ, Levy D, Vaziri SM, et al. Independent risk factors for atrial fibrillation in a population-based cohort: The Framingham Heart Study. JAMA 1994; 271: Gugger M. Comparison of ResMed AutoSet (version 3.03) with polysomnography in the diagnosis of the sleep apnoea/ hypopnoea syndrome. Eur Respir J 1997; 10: Bradley PA, Mortimore IL, Douglas NJ. Comparison of polysomnography with ResCare Autoset in the diagnosis of the sleep apnoea/hypopnoea syndrome. Thorax 1995; 50: Fleury B, Rakotonanahary D, Hausser-Hauw C, et al. A laboratory validation study of the diagnostic mode of the Autoset system for sleep-related respiratory disorders. Sleep 1996; 19: Stradling JR, Crosby JH. Predictors and prevalence of obstructive sleep apnoea and snoring in 1001 middle aged men. Thorax 1991; 46: Garrigue S, Bordier P, Jais P, et al. Benefit of atrial pacing in sleep apnea syndrome. N Engl J Med 2002; 346: Sjöström C, Lindberg E, Elmasry A, et al. Prevalence of sleep apnoea and snoring in hypertensive men: a population based study. Thorax 2002; 57: Katz I, Stradling J, Slutsky AS, et al. Do patients with obstructive sleep apnea have thick necks? Am Rev Respir Dis 1990; 141: Davies RJ, Stradling JR. The relationship between neck circumference, radiographic pharyngeal anatomy, and the obstructive sleep apnoea syndrome. Eur Respir J 1990; 3: Euler DE, Scanlon PJ. Acetylcholine release by a stimulus train lowers atrial fibrillation threshold. Am J Physiol 1987; 253:H863 H Waradekar NV, Sinoway LI, Zwillich CW, et al. Influence of treatment on muscle sympathetic nerve activity in sleep apnea. Am J Respir Crit Care Med 1996; 153: Charpentier F, Drouin E, Gauthier C, et al. Early after/ depolarizations and triggered activity: mechanisms and autonomic regulation. Fundam Clin Pharmacol 1993; 7: Sanner B, Konermann M, Sturm A. Structural cardiac changes in patients with obstructive sleep apnea [in German]. Z Kardiol 1995; 84: Frustaci A, Chimenti C, Bellocci F, et al. Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation 1997; 96: Ausma J, Wijffels M, Thone F, et al. Structural changes of atrial myocardium due to sustained atrial fibrillation in the goat. Circulation 1997; 96: Goette A, Honeycutt C, Langberg JJ. Electrical remodeling in atrial fibrillation: time course and mechanisms. Circulation 1996; 94: Hashiba K, Tanigawa M, Fukatani M, et al. Electrophysiologic properties of atrial muscle in paroxysmal atrial fibrillation. Am J Cardiol 1989; 64:20J 23J 32 Kumagai K, Akimitsu S, Kawahira K, et al. Electrophysiological properties in chronic lone atrial fibrillation. Circulation 1991; 84: Peppard PE, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000; 342: CHEST / 125 / 3/ MARCH,