Articles. Obesity, Sleep Apnea Syndrome, and Rhythmogenic Risk. Wolfram Grimm, 1 and Heinrich F. Becker 2. Obesity and Obstructive Sleep Apnea

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1 Obesity, Sleep Apnea Syndrome, and Rhythmogenic Risk Wolfram Grimm, 1 and Heinrich F. Becker 2 Abstract Obstructive sleep apnea is a common disorder and affects approximately 4% of middle-aged men and 2% of middle-aged women. Obstructive sleep apnea is clearly associated with obesity, with more than 50% of patients having a body mass index >30 kg/m 2. Substantial evidence identified obstructive sleep apnea as risk factor not only for excessive daytime sleepiness and road traffic accidents, but also for increased cardiovascular morbidity and mortality. In addition, all kinds of arrhythmias have been observed in patients with sleep apnea ranging from asymptomatic sinus bradycardia to sudden cardiac death. Approximately 5 10% of patients with obstructive sleep apnea show marked apnea-related bradyarrhythmias due to enhanced vagal tone and pronounced hypoxia. Therapeutic options in obese patients with obstructive sleep apnea include consequent weight loss and nasal continuous positive airway pressure (CPAP) ventilation as the therapy of first choice. Weight reduction and effective nasal CPAP therapy significantly decrease cardiovascular morbidity and mortality and eliminate sleep-related bradyarrhythmias in 80 90% of patients obviating the need for pacemaker implantation in these patients. Introduction Sleep apnea can be divided into two forms: obstructive sleep apnea, in which collapse of the upper airway results in decreased airflow despite continued respiratory effort, and central sleep apnea, in which decreased airflow results from reduced respiratory effort. Central sleep apnea is seen most commonly in patients with congestive heart failure and is also termed Cheyne-Stokes respiration, 1 4 although Cheyne in 1818 and later Stokes in 1854 described the agonal breathing pattern in end-stage heart failure patients who were awake rather than asleep. The Cheyne-Stokes respiration pattern of periodic breathing in congestive heart failure is thought to result from increased ventilatory loop gain as a result of prolonged lungto-chemoreceptor circulation time among other factors. 1 Since obstructive but not central sleep apnea is associated with obesity, the following report will focus on obstructive sleep apnea Pathophysiology of Obstructive Sleep Apnea Obstructive sleep apnea is a disease that is characterized by loud snoring and repetitive closure (apnea) or partial closure 1 Department of Internal Medicine and Cardiology, Hospital of the Philipps University of Marburg, Germany. 2 Department of Respiratory Medicine, Hospital of the Philipps University of Marburg, Germany. Reprinted from Urban & Vogel 2006 Herz 2006;31:213 (hypopnea) of the upper airway during sleep. The increased respiratory abdominal and thoracic efforts to overcome airway closure lead to arousals from sleep and fragmentation of the normal sleep pattern. Distinctive characteristics of obstructive sleep apnea during cardiorespiratory polysomnography are shown in Figure 1. Narrowing and/or closure of an unstable upper airway are influenced by the underlying neuromuscular tone, upper airway muscle synchrony, and the stage of sleep. 4,5 Obstructive sleep apnea episodes occur most often during rapid eye movement (REM) sleep, because hypotonia of the upper airway muscles is characteristic of REM sleep. Upper airway size, which is a major determinant of upper airway patency during sleep, is influenced by the amount of soft tissue in addition to skeletal factors. In obese patients, increased adipose tissue may predispose the airway to narrowing. Magnetic resonance imaging has shown increased fatty pharyngeal tissue in obese patients with obstructive sleep apnea. 5 In patients with normal body weight, obstructive sleep apnea may develop in the presence of tonsillar hypertrophy or craniofacial skeletal abnormalities predisposing to airway narrowing. Obesity and Obstructive Sleep Apnea The obstructive sleep apnea syndrome based on the criterion of severe daytime sleepiness and more than five apneas and hypopneas per sleep hour is a common disorder and affects approximately 4% of middle-aged men and 2% of middle-aged women. 6 Only a small portion of cases with sleep apnea has been diagnosed due to insufficient awareness of this disorder among physicians and the public in general. Obstructive sleep apnea is clearly associated with obesity An estimated 58% of patients with obstructive sleep apnea 12 have a body mass index (BMI) > 30 kg/m 2. Conversely, more than 50% of all obese men have obstructive sleep apnea. Arecent study 9 in 133 obese women with a BMI > 30 kg/m 2 found obstructive sleep apnea with an apnea-hypopnea index >10 in 44% of all obese women. The prevalence of obstructive sleep apnea, however, was significantly higher in postmenopausal obese women (67%) compared to premenopausal obese women (31%), which may be due to a different body fat distribution with a higher waistto-hip circumference ratio in postmenopausal obese women. 9 The causal association between the expanding epidemic of excess body weight, which is a modifiable risk factor, and obstructive sleep apnea raises many questions with regard to public health and preventive medicine. This is particularly true with regard to the alarming rate of weight gain in children as well as in adolescents in industrialized nations. Obstructive Sleep Apnea and Cardiovascular Risk There is substantial evidence that obstructive sleep apnea is a risk factor for excessive daytime sleepiness, impaired daytime 38 Sleep Diagnosis and Therapy Vol 2 No 1 February-March 2007

2 Fig min segment of polysomnographic recording in a patient with obstructive sleep apnea during REM sleep characterized by cessation of nasal airflow despite continuous thoracic and abdominal respiratory efforts. After approximately 40 s of apnea, an arousal occurs and ventilation is resumed briefly while apnea-related asystole disappears. Arterial oxygen saturation is decreased considerably following each sleep apnea episode. Abd: abdomen; ECG: electrocardiogram; EEG: electroencephalogram; EMG: electromyogram; EOG: electrooculogram; SaO 2 : oxygen saturation. Fig. 3. Two-channel Holter ECG recordings (25 mm/s) in patients with sleep apnea. A) Sinus bradycardia and sinus arrest. B) Intermittent third-degree AV block. C) Atrial fibrillation with rapid ventricular response und inter-mittent functional right bundle branch block. D) Nonsustained ventricular tachycardia. Fig. 2. Holter ECG (12.5 mm/s) with recurrent sinus arrest and up to 11 s ventricular asystole (arrows) during obstructive sleep apnea. concentration, road traffic accidents, and predisposition to enhanced platelet aggregation, endothelial dysfunction, arterial hypertension, pulmonary hypertension, ischemic heart disease, and cerebrovascular accidents. Last but not least, all kinds of arrhythmias have been observed in patients with sleep apnea ranging from asymptomatic sinus bradycardia to sudden cardiac death 18 28, 31 (Figures 2 to 4). To date, the most comprehensive observational study investigating fatal and nonfatal cardiovascular events in more than 1,000 middle-aged men with treated and untreated obstructive sleep apnea has recently been published by Marin et al. 14 As a result, severe untreated obstructive sleep apnea carried a threefold risk for both, fatal and nonfatal cardiovascular events including myocardial infarction and cerebral stroke compared to healthy men with the same age (Table 1). In addition, Marin et al. 14 were able to demonstrate a significant reduction of the risk for fatal and nonfatal cardiovascular events using continuous positive airway pressure (CPAP) therapy. In the latter study, 14 however, CPAP therapy was not used in a randomized fashion. Fortunately, simple snoring without sleep apnea was not associated with an increased cardiovascular risk in the study by Marin et al. 14 Obstructive Sleep Apnea and Sudden Cardiac Death In the year 1956, Burwell et al. 45 quoted Charles Dickens description from the Pickwick Papers of the messenger Joe, who was a fat and red-faced boy in a state of somnolency. Since this description of Joe resembled patients who suffered from the combination of extreme obesity, alveolar hypoventilation with chronic hypercapnia and hypoxemia and cardiorespiratory failure, they suggested it to be called the Pickwickian syndrome. 45 In 1970, MacGregor et al. 41 described sudden cardiac death as fatal complication in five of 22 patients (23%) with a Pickwickian syndrome. The weights of the 22 patients in the latter series ranged from 209 to 588 pounds with a mean of 398 pounds. To date, only few studies investigated the question whether obstructive sleep apnea is associated with sudden cardiac death (Table 1). Furthermore, only three studies evaluated the day-night pattern of sudden death in adults with sleep disorders. 22, 42, 43 The first study 42 obtained the history of snoring from the cohabitants of 321 men who died suddenly. As a result, habitual snorers were more likely to die suddenly between 04:00 and 08:00 a.m. compared to occasional snorers or nonsnorers. The second study 43 reported that none out of 13 patients with a history of sleep apnea and sudden death died during sleep. The third study retrospectively reviewed polysomnograms and death certificates in 112 adult sudden cardiac death victims. 22 As a result, patients with obstructive sleep apnea had a 2.6-fold risk of sudden death between midnight Sleep Diagnosis and Therapy Vol 2 No 1 February-March

3 Fig. 4. Polysomnographic recording in a patient with sleep apnea-related third-degree AV block, which completely disappeared after initiation of nasal CPAP therapy (not shown). A) 2-min segment showing three episodes of obstructive sleep apnea characterized by cessation of nasal airflow despite continuous thoracic and abdominal respiratory efforts. An arousal occurs and ventilation resumes following approximately 30 s of apnea in each episode. Apnea-related asystole and bradycardia disappear immediately after resumption of airflow. B) Enlargement of the first apnea episode from A. Table 1. Total Mortality and Sudden Cardiac Deaths in Patients with Predominantly Obstructive Sleep Apnea Syndrome Obstructive Sleep Apnea-Associated Bradycardia and Asystole Many studies have described pronounced sleep-related bradyarrhythmias or asystole with up to 15 s duration in 5 10% of patients with obstructive sleep apnea 18 28, 31 (Figures 2 to 4). In a series of 239 consecutive patients, in whom obstructive sleep apnea had been diagnosed at our hospital, 32 sinus bradycardia <30 bpm, second- or third-degree atrio-ventricular (AV) block with pauses >2 s occurred in 17 out of 239 patients (7%). Patients with pronounced nocturnal bradyarrhythmias were significantly more obese with a mean BMI of 39 kg/m 2 and had a higher mean apnea-hypopnea index of 90 (range ) compared to patients with obstructive sleep apnea without nocturnal bradyarrhythmias. Of note, all patients with pronounced nocturnal bradyarrhythmias or asystole in this study 32 had an apnea-hypopnea index 60. Conversely, no patient with an apnea-hypopnea index <60 showed pro- Follow- Patients Age Coronary Hyper- Apnea BMI up Sudden Stroke Authors Year (n) (years) Men Disease tension Index (kg/m 2 ) (months) Mortality Deaths or MI Guilleminault et al. [18] % 7% 49% 43 NA NA NA NA NA He et al. [40] % NA NA % NA NA Köhler et al. [23] % 10% 70% % 0% 2% Keenan et al. [24] % NA NA % 0% NA Partinen et al. [39] % 17% 57% % NA NA Grimm et al. [28] % 21% 66% % 0% 0% Campos % NA 61% % 0.3% NA Rodriguez et al. [13] Yaggi et al. [20] % 0% 60% % NA 3% Doherty et al. [34] % 8% 22% % 2% NA Marin et al. [14] a % 5% 25% % NA 9% Marin et al. [14] b % 8% 35% % NA 6% Marin et al. [14] c % 8% 35% % NA 21% a subgroup of patients with untreated mild to moderate obstructive sleep apnea. b subgroup of patients with nasal CPAP therapy for obstructive sleep apnea. c subgroup of patients with untreated severe obstructive sleep apnea. BMI: Body Mass Index; MI: Myocardial Infarction; NA: not Available or not Reported. and 06:00 a.m. compared to patients without obstructive sleep apnea. Unfortunately, the latter study 22 did not address the question of whether obstructive sleep apnea independently increases the risk for sudden death, since the denominator of the study population is unknown. Obstructive Sleep Apnea and Atrial Fibrillation In an early report, Guilleminault et al. 18 found paroxysmal nocturnal atrial flutter or atrial fibrillation in 13 of 400 patients (3%) with obstructive sleep apnea. Gami et al. 19 described a significant association between atrial fibrillation and obstructive sleep apnea: obstructive sleep apnea was found in 49% of 151 patients with atrial fibrillation compared to 32% of 373 control patients without atrial fibrillation (p < 0.01). Furthermore, Kanagala et al. 44 found a significantly higher incidence of atrial fibrillation recurrences following cardioversion in patients with untreated compared to treated obstructive sleep apnea syndrome. This finding suggests that obstructive sleep apnea may trigger atrial fibrillation. In addition, the higher prevalence of atrial fibrillation in patients with obstructive sleep apnea may, in part, explain the increased risk for stroke and heart failure in these patients Sleep Diagnosis and Therapy Vol 2 No 1 February-March 2007

4 nounced nocturnal bradyarrhythmias during diagnostic polysomnography. The postulated mechanism of sleep apneaassociated bradycardia or asystole is enhanced vagal tone and severe hypoxia. To exclude additional electro-physiological abnormalities of sinus node and AV node function, we performed comprehensive electro-physiological studies in 29 patients with sleep apnea-related ventricular asystole of 7 ± 3s duration (range 3 17 s). 27, 28 In all 29 study patients, electrophysiological studies revealed no evidence for advanced sinus node disease or AV conduction system dysfunction suggesting that prolonged ventricular asystole during obstructive sleep apnea is not due to fixed or anatomic disease of the sinus node or the AV conduction system. 27, 28 In addition, we could demonstrate a favorable prognosis of these patients during a mean prospective follow-up of 54 months after initiation of nasal CPAP therapy without any episodes of syncope and without cardiovascular deaths or sudden cardiac deaths, irrespective of con-comitant pacemaker therapy. 28 Several studies have demonstrated the reversal of sleep apnea-associated sinus arrest or third-degree AV block during effective nasal CPAP therapy in 80 90% of patients obviating the need for pacemaker implantation 24,25,27,28,31,32 Before nasal CPAP therapy has become the initial treatment of choice in clinically important obstructive sleep apnea, the reversibility of sleep apnea-related bradyarrhythmias has also been demonstrated by tracheostomy and by consequent weight loss, e.g., following gastric surgery in patients with extreme obesity. 12,17,29,39 Therapy of Obese Patients with Obstructive Sleep Apnea Therapeutic strategies for patients with obstructive sleep apnea include behavioral, medical, and in rare instances also surgical interventions for corrective anatomic obstruction of the upper airway, e.g., by removal of enlarged tonsils or maxillofacial surgery. 4 7, All patients with sleep apnea should be counseled about the benefit of weight normalization and about the value of avoiding factors that increase upper airway obstruction such as alcohol consumption and use of sedatives. Alcohol selectively reduces the muscle tone of upper airways and increases the frequency of abnormal breathing during sleep. In addition, alcohol prolongs apnea by delaying arousal. In obese patients, weight loss can significantly decrease the severity of sleep apnea as well as sleep apnea-related arrhythmias. 12, 29, 30 Effective nasal CPAP therapy has recently been demonstrated to be associated with significantly decreased serum leptin levels and decreased visceral fat accumulation in obese sleep apnea patients. 26 Unfortunately, only a minority of severely obese patients is willing or able to lose weight during long-term follow-up without surgical interventions. In 2 studies at our institution 27, 28 including 29 severely obese patients with sleep apnea-associated nocturnal asystole, the BMI remained virtually unchanged during 54-month mean follow-up despite repeated patient counseling concerning the importance of weight loss and despite repeated dietary and behavioral recommendations how to lose weight (mean BMI of 35.9 kg/m 2 at baseline vs kg/m 2 at the end of follow-up) 28 In a recently published series of 697 patients with obstructive sleep apnea and a baseline mean BMI of 34 kg/m 2, Yaggi et al. 20 observed a weight reduction of 10% in less than one third of study patients during 3-year follow-up. To date, nasal CPAP therapy is the treatment of choice in clinically relevant obstructive sleep apnea. 4 7,33,35,36 The objective of nasal CPAP therapy for obstructive sleep apnea is to provide sufficient pressure in the upper airway to counteract the inspiratory suction pressure. The result of effective nasal CPAP therapy is rapid restoration of normal sleep, reduction of daytime sleepiness, improvement in neuropsychiatric function, disappearance of arrhythmias, better control of arterial hypertension, decrease in pulmonary hypertension, and improvement of potential congestive heart failure. The major problem with nasal CPAP therapy is limited patient compliance. To increase patient compliance, attempts are being made to improve the device and its mask in order to increase its use. Patients should be followed up regularly in a sleep center to determine treatment quality and to adjust therapy, if necessary. The newer concept of atrial overdrive pacing does not appear to be helpful in patients with obstructive sleep apnea syndrome. 37, 38 References 1. Cables SM, Wolk R, Somers VK. Influence of cardiac function and failure on sleep-disordered breathing: evidence for a causative role. J Appl Physiol 2005;99: Bradley TD, Logan AG, Kimoff RJ, et al., for the CANPAP Investigators. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med 2005; 353: Sinha AM, Skobel EC, Breithardt OA, et al. Cardiac resynchronization therapy improves central sleep apnea and Cheyne-Stokes respiration in patients with chronic heart failure. J Am Coll Cardiol 2004;44: Becker HF, Mayer G, Penzel T. Sleep disorders and sleep related breathing disorders. Internist (Berl) 2004;45: Strollo PJ Jr, Rogers RM. Obstructive sleep apnea. N Engl J Med 1996;334: Young T, Palta M, Dempsey J, et al. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;328: Phillipson EA. Sleep apnea a major public health problem. N Engl J Med 1993;328: Bearpark H, Elliot L, Grunstein R, et al. Snoring and sleep apnea. Apopulation study in Australian men. Am J Respir Crit Care Med 1995;151: Resta O, Bonfitto P, Sabato R, et al. Prevalence of obstructive sleep apnoea in a sample of obese women: effect of meno-pause. Diabetes Nutr Metab 2004;17: Arias MA, Sanchez AM, Fernandez-Guerrero JC, et al. Obstructive sleep apnea in overweight subjects. Hypertension 2006;47:e Somers VK. Sleep a new cardiovascular frontier. N Engl J Med 2005;353: Young T, Peppard PE, Taheri S. Excess weight and sleep-disordered breathing. J Appl Physiol 2005;99: Campos-Rodriguez F, Pena-Grinan N, et al. Mortality in obstructive sleep apnea-hypopnea patients treated with positive airway pressure. Chest 2005;128: Marin JM, Carrizo SJ, Vicente E, et al. Long-term cardiovascular outcomes in men with obstructive sleep apnea-hypopnea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365: Caples SM, Gami AS, Somers VK. Obstructive sleep apnea. Ann Intern Med 2005;142: Caterson ID, Hubbard V, Bray GA, et al. American Heart Association. Prevention Conference VII: Obesity, a worldwide epidemic related to heart disease and stroke: Group III: worldwide comorbidities of obesity. Circulation 2004;110:e476 e Peiser J, Ovnat A, Uwyed K, et al. Cardiac arrhythmias during sleep in morbidly obese sleep apneic patients before and after gastric bypass surgery. Clin Cardiol 1985;8: 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: Sleep Diagnosis and Therapy Vol 2 No 1 February-March

5 19. Gami AS, Pressman G, Caples SM, et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation 2004;110: Yaggi HK, Concato J, Kernan WN, et al. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005;353: Ryan CM, Usui K, Floras JS, et al. Effect of continuous positive airway pressure on ventricular ectopy in heart failure patients with obstructive sleep apnoea. Thorax 2005;60: Gami AS, Howard DE, Olson EJ, et al. Day-night pattern of sudden death in obstructive sleep apnea. N Engl J Med 2005;352: Köhler U, Wetzig T, Peter JH, et al. Morbidity and mortality in sleep apnea and nocturnal bradyarrhythmia. Dtsch Med Wochenschr 1994;119: Keenan SP, Burt H, Rijan F, et al. Long-term survival of patients treated with obstructive sleep apnea treated by uvulopalatophyryngoplasty or nasal CPAP. Chest 1994;105: Koehler U, Fus E, Grimm W, et al. Heart block in patients with obstructive sleep apnoea: pathogenetic factors and effects of treatment. Eur Respir J 1998;11: Chin K, Shimizu K, Nakamura T, et al. Changes in intra-abdominal fat and serum leptin levels in patients with obstructive sleep apnea syndrome following nasal continuous positive airway pressure therapy. Circulation 1999;100: Grimm W, Hoffmann J, Menz V, et al. Electrophysiologic evaluation of sinus node function and atrioventricular conduction in patients with prolonged ventricular asystole during obstructive sleep apnea. Am J Cardiol 1996;77: Grimm W, Koehler U, Fus E, et al. Outcome of patients with sleep apnea-associated severe bradyarrhythmias after continuous positive airway pressure therapy. Am J Cardiol 2000;86: Smith PL, Gold AR, Meyers DA, et al. Weight loss in mildly to moderately obese patients with obstructive sleep apnea. Ann Intern Med 1985;103: Kalra M, Inge T, Garcia V, et al. Obstructive sleep apnea in extremely overweight adolescents undergoing bariatric surgery. Obes Res 2005;13: 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: Becker HF, Jerrentrup A, Ploch T, et al. Effect of nasal continuous positive airway pressure treatment on blood pressure in patients with obstructive sleep apnea. Circulation 2003;107: Doherty LS, Kiely JL, Swan V, et al. Long-term effects of nasal continuous positive airway pressure therapy on cardiovascular outcomes in sleep apnea syndrome. Chest 2005;127: 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: Sajkov D, Wang T, Saunders NA, et al. Continuous positive airway pressure treatment improves pulmonary hemodynamics in patients with obstructive sleep apnea. Am J Respir Crit Care Med 2002;165: Garrigue S, Bordier P, Jais P, et al. Benefit of atrial pacing in sleep apnea syndrome. N Engl J Med 2002;346: Pepin JL, Defaye P, Garrigue S, et al. Overdrive atrial pacing does not improve obstructive sleep apnoea syndrome. Eur Respir J 2005;25: Partinen M, Jamieson A, Guilleminault C. Long-term outcome for obstructive sleep apnea patients. Mortality. Chest 1998;94: He J, Kryger MH, Zorick FJ, et al. Mortality and apnea index in obstructive sleep apnea. Experience in 385 male patients. Chest 1988;94: MacGregor MI, Block AJ, Ball WC Jr. Serious complications and sudden death in the Pickwickian syndrome. Johns Hopkins Med J 1970;126: Seppala T, Partinen M, Penttila A, et al. Sudden death and sleeping history among Finnish men. J Intern Med 1991;229: Gonzales-Rothi RJ, Foresman GE, Block AJ. Do patients with sleep apnea die in their sleep? Chest 1988;94: Kanagala R, Murali NS, Friedman PA, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation 2003;107: Burwell CS, Robin ED, Wahley RD, et al. Extreme obesity associated with alveolar hypoventilation a Pickwickian syndrome. Am J Med 1956;21: Sleep Diagnosis and Therapy Vol 2 No 1 February-March 2007