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Nocturnal cardiac arrhythmia in patients with obstructive sleep apnea
Sleep Medicine 9 (2008) 475–480 www.elsevier.com/locate/sleep
Original Article
Nocturnal cardiac arrhythmia in patients with obstructive sleep apnea q Francesca Olmetti a, Maria Teresa La Rovere a, Elena Robbi b, Anna Eugenia Taurino b, Francesco Fanfulla b,* a b
Divisione di Cardiologia, Istituto Scientifico di Montescano, Fondazione S. Maugeri, IRCCS, Pavia, Italy Divisione di Pneumologia, Istituto Scientifico di Montescano, Fondazione S. Maugeri, IRCCS, Pavia, Italy Received 21 May 2007; received in revised form 30 July 2007; accepted 19 August 2007 Available online 19 November 2007
Abstract Background and purpose: Nocturnal cardiac arrhythmias occur in patients with obstructive sleep apnea (OSA), reportedly as a consequence of the autonomic effects of recurrent apnea with subsequent oxygen desaturation. We have investigated whether different patterns of OSA are associated with specific arrhythmia during sleep. Patients and methods: Electrocardiographic (ECG) data recorded during polysomnography (PSG) were analysed in 257 consecutive OSA patients to determine the prevalence of cardiac rhythm disturbances, and to relate these to breathing pattern (normal, apnea/ hypopnea, recovering ventilation, snoring) and oxygen saturation. Results: Arrhythmias were found in 18.5% of patients. Patients with nocturnal bradyarrhythmia (BA) had higher values of ventilatory disturbance (apnea–hypopnea index [AHI] 58.8 ± 36.8 vs 37.2 ± 30.3, p = 0.02), mean desaturation amplitude (8.9 ± 4 vs 5.9 ± 3.4%, p = 0.03), and a lower SaO2 nadir (69% vs 77%, p = 0.003) than those without arrhythmia. The prevalence of BA in patients with AHI P 30/h was significantly higher than that observed in those with AHI < 30/h (7.8% vs 1.5%, respectively; v2 = 5.61, p = 0.01). In contrast, patients with tachyarrhythmia (TA) had no significant differences in AHI, mean desaturation amplitude or SaO2 nadir than those without arrhythmia. No associations were found between arrhythmia and the presence of comorbidity or concomitant medical therapy, except for an association between tachyarrhythmia and chronic obstructive pulmonary disease (COPD) (odds ratio 2.53; 95% confidence intervals 1.1–5.8, p = 0.03). Conclusions: We conclude that while BA during sleep is associated with OSA severity, concomitant COPD or b2-treatment may play a role in the development of TA during sleep. Ó 2007 Elsevier B.V. All rights reserved. Keywords: Sleep apnea; OSAS; Cardiac arrhythmia; Hypoxemia; COPD
1. Introduction Obstructive sleep apnea syndrome (OSAS) is a common, although underestimated, clinical problem which
q
The authors for this article have no conflicts of interest to declare. Corresponding author. Address: Sleep Laboratory, Pulmonary Division, Fondazione Salvatore Maugeri IRCCS, Istituto Scientifico di Montescano, Via per Montescano, 27040 Montescano (PV), Italy. Tel.: +39 0385 2471; fax: +39 0385 61386. E-mail address: ff[email protected] (F. Fanfulla). *
1389-9457/$ - see front matter Ó 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2007.08.015
has been increasingly associated with a significantly raised cardiovascular morbidity and mortality. The repetitive nocturnal hypoxemia experienced by OSAS patients is associated with the activation of a number of neural, humoral, thrombotic, metabolic, and inflammatory disease mechanisms of cardiac and vascular disease [1–6]. Continuous positive airway pressure (CPAP) therapy has been demonstrated to significantly reduce the increased risk for cardiac death [7]. Cardiac rhythm disturbances, both in the form of brady (BA)- and tachyarrhythmia (TA), have been
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reported in up to more than 50% of patients with OSA as a consequence of the autonomic effects of recurrent nocturnal apneas with oxygen desaturation [8–10]. Although the observation that treatment of OSA by CPAP may successfully control cardiac rhythm disturbances would suggest a cause–effect relationship [11–13], the confounding effect of comorbidity and cardiovascular disease should also be taken into account. The aim of the present study was to address the relationship among obstructive apneas, oxygen desaturation and different patterns of cardiac arrhythmia during sleep in a consecutive series of subjects undergoing diagnostic overnight polysomnography (PSG) for suspected OSAS. 2. Patients and methods All the patients referred to our laboratory during 2004 for clinical suspicion of OSAS were considered eligible for the study. Only patients with clinical and PSG signs of OSA were enrolled in the study. They suffered from snoring and excessive daytime somnolence (Epworth sleepiness scale score > 9). Exclusion criteria were chronic heart failure, clinically significant autonomic neuropathy, respiratory failure requiring O2-therapy, and having an implanted pacemaker, transplantation, previous ischemic stroke, central sleep apnea, or known arrhythmia that prompted referral by a cardiologist for evaluation of breathing during sleep. So far, among the 439 patients who had a baseline PSG, 247 subjects with OSAS, according to daytime symptoms and an apnea/hypopnea index (AHI) > 5 ev/ h of sleep, were considered for the analysis. The protocol was submitted to the Technical and Ethical Committees. The former approved the protocol and the latter stated that approval was waived since, on admission to hospital, patients were asked to confirm whether they consented or not to the use of their medical records and ‘‘routine’’ examination results for research purposes. We analysed only the records of patients who agreed to the use of their data.
of the American Sleep Disorders Association [15]. Apnea was defined as a cessation of airflow for at least 10 s, while hypopnea was defined as a clear amplitude reduction of a validated measure of breathing during sleep (but less than a 50% reduction from baseline) associated with an oxygen desaturation of >3% or an arousal. AHI was defined as the total number of apneas and hypopneas per hour of sleep. We also calculated the oxygen desaturation index (ODI), defined as the number of desaturations per hour of sleep, the percentage of total sleep time (TST) spent with SaO2 < 90% (TST90) and the mean amplitude of each desaturation episode. ECG was recorded during PSG, which included lead I bipolar ECG sampled at 200 Hz. The ECG data were processed and analysed by the same cardiologist (FO) blinded to respiratory events, with the supervision of a senior cardiologist (MTLR) when doubts or difficulties arose. Arrhythmias and artifacts were properly classified when there was a complete agreement between the two scorers. Ventricular arrhythmia included premature ventricular contractions (PVCs P 10/h), bigeminy, trigeminy, quadrigeminy, and non-sustained ventricular tachycardia (defined as P3 consecutive ventricular beats with an average rate P100 beats/min). Atrial arrhythmia included supraventricular tachycardia and atrial fibrillation. Conduction delay arrhythmias were atrioventricular block (P second degree type 2), intraventricular conduction delay, and sinus pause (P2 s). Other rhythm disturbances recorded but not deemed significant included isolated atrial premature beats and sinus bradycardia or tachycardia. For each episode of cardiac arrhythmia, we recorded the time of onset, sleep stage, breathing status (normal, apnea/hypopnea, recovering ventilation, snoring), and the level of oxygen saturation. For each episode of cardiac arrhythmia that occurred during an apnea or hypopnea episode or during the subsequent phase of recovering ventilation, we analysed the level of SaO2 and the mean heart rate before the arrhythmia as well as the depth of oxygen desaturation.
2.1. Sleep study 3. Statistical analysis Full standard in-laboratory PSG (Embla, Medcare, Reykyiavik, Iceland) was performed using current procedures and scored manually according to the criteria of Rechtschaffen and Kales [14]. The PSG included electroencephalogram (C3–A2, C4–A1; O1–A2, O2–A1), electro-oculograms, submental electromyogram (EMG), anterior tibialis EMGs, nasal cannula airflow signal using a nasal cannula/pressure transducer system, oral thermistor, electrocardiogram (ECG) and body position. SaO2 was recorded by means of an in-built pulseoximeter (Nonin Medical Inc., Minneapolis, MN, USA) with an Oximax sensor (Nellcore, Pleasanton, CA, USA). Arousals were scored according to criteria
Arrhythmias were coded as present or absent and as tachy- or bradycardic. As is customary, ventricular premature beats were classified under tachyarrythmia. Oneway analysis of variance (ANOVA) was used for differences between patients with or without arrhythmia, and for differences between patients with tachy- or bradycardic events. Patients were classified into two groups according to the severity of OSA (AHI< or P30 events per hour of sleep). The v2 test was performed for differences in the prevalence of arrhythmia between patients with more or less severe OSA, and also to evaluate the association of car-
F. Olmetti et al. / Sleep Medicine 9 (2008) 475–480
diac arrhythmias with concomitant disease (e.g., COPD, cardiac ischemic disease, diabetes mellitus, systemic arterial hypertension) or concomitant medication. Simple and multiple logistic regression analyses were performed to identify the risk factors associated with the development of arrhythmia during sleep. All the analyses were performed using the SPSS 13 statistical package, and a p value <0.05 was considered statistically significant.
477
Table 2 Prevalence of each type of arrhythmia in all patients Type of arrhythmias
No. of patients
SVT AF PVCs > 10/h PAUSE (>2 s) AV Block (P second degree type 2)
13 2 22 8 3
SVT = supraventricular tachycardia; AF = atrial fibrillation; PVCs = premature ventricular complex; AV Block = atrio-ventricular block.
4. Results All patients who enrolled completed the study. The most common comorbidities associated with OSA were systemic arterial hypertension (37.6% of patients), COPD (15.8% of patients), diabetes mellitus (11.7% of patients), ischemic heart disease (8.9% of patients), and hypothyroidism (5.7% of patients). Most of the patients received chronic therapy: 28.7% ACE-inhibitors, 16.2% bronchodilators (long-acting B2-agonists), 15% Ca-channel blocker, and 5.2% b-blockers. Anthropometrics, sleep data, comorbidities and concomitant therapies are reported in Table 1. Forty-six patients (18.5%) had rhythm disturbances during sleep; the prevalence of each type of arrhythmias is shown in Table 2. BA was observed in 11, while TA was present in 35 patients. Specifically, supraventricular tachycardia was observed in 13 patients, atrial fibrillation or flutter in 2 patients, PVCs > 10/h in 22 patients, Table 1 General characteristics of patients Age (years) BMI (kg/m2) Smoking status (non/ex/current) TST (min) SE (%) NREM1 (%) NREM2 (%) SWS (%) REM (%) AHI (%) ODI (%) SaO2nadir (%) TST90 (%) Hypertension (n.) CAD (n.) Diabetes (n.) Hypothyroidism (n.) COPD (n.) Bronchodilators (n.) Beta-blocker (n.) ACE-inhibitors (n.) Ca-channel blocker (n.) a-blocker (n.)
54.3 ± 12.7 35.9 ± 10.7 99/93/55 347.0 ± 54.7 83.8 ± 12.4 17.0 ± 17.1 42.5 ± 12.6 22.4 ± 11.6 17.9 ± 8.5 38.3 ± 30.5 45.5 ± 37.5 74.9 ± 13.2 19.4 ± 27.7 37.7 8.9 11.7 5.7 15.8 16.2 4 28.3 14.6 4.9
BMI = body mass index; TST = total sleep time; SE = sleep efficiency; AHI = apnea/hypopnea index; ODI = oxygen desaturation index; TST90 = percentage of Total Sleep Time spent with SaO2 < 90%. CAD = coronary artery disease; COPD = chronic obstructive pulmonary disease.
pauses (>2 s) in 8 patients, and atrioventricular block in 3 patients. Patients with cardiac arrhythmia were older than those with no arrhythmia (57.5 ± 12.6 vs 52.5 ± 13.1 years, p < 0.05). The temporal relationship between each arrhythmia and a respiratory event was different for brady- and tachyarrhythmias. All BA episodes occurred during an episode of apnea or hypopnea, while only the 37.1% of TA events were strictly related to an episode of apnea or hypopnea (during the episode or during the subsequent phase of recovering ventilation). More specifically, PVCs were present during the whole recording with no association with sleep or awake. Patients with BA during sleep presented a higher value of AHI (58.8 ± 36.8 vs 37.2 ± 30.3 ev/hr, p = 0.02) than those without arrhythmia, mean desaturation amplitude (8.9 ± 4 vs 5.9 ± 3.4%, p = 0.03), and a lower SaO2 nadir (69% vs 77%, p = 0.003). No difference was found between BA patients and those without arrhythmia for body mass index (BMI) (34.5 ± 9.3 vs 36.1 ± 10.1 kg/m2, respectively; p = n.s.) or for age (51.8 ± 17.7 vs 53.6 ± 12.6 years, respectively; p = n.s.). Of interest, no differences were found for the presence of arterial hypertension or smoking habit. The occurrence of BA was strictly related to the severity of OSA. Indeed, the prevalence of BA in patients with AHI P 30/h was significantly higher than that observed in those with AHI < 30/h (7.8 vs 1.5%, respectively; v2 = 5.61, p = 0.01), with an odds ratio of 5.33 (95% confidence intervals 1.13–25.3, respectively; p = 0.03). In contrast, patients with TA had no significant difference in AHI, mean desaturation amplitude and SaO2 nadir than those without arrhythmia. The only difference between TA patients and those without arrhythmia was related to age, since patients with TA were older (59.8 ± 9 vs 53.5 ± 12 years; p = 0.005). The occurrence of TA was not related to the severity of OSA: the prevalence of TA in patients with AHI P 30/h was similar to that observed in those with AHI < 30/h (15.5% vs 13%, respectively; p = n.s.). BA patients had a more severe OSA pattern than TA patients, (Table 3). Indeed, the mean amplitude of oxygen desaturations was higher in patients with BA (8.9 ± 4.1 vs 5.4 ± 2.6, p > 0.01), as well as AHI
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Table 3 Sleep respiratory data in patients with brady (BA)- or tachyarrhythmia (TA)
Age (years) BMI (kg/m2) AHI (n/hour of sleep) ODI (n/hour of sleep) Mean desaturation amplitude (%) SaO2nadir (%) TST90 (% of total sleep time)
BA
TA
p
51.8 ± 17.7 34.5 ± 9.3 58.9 ± 36.8 65.8 ± 37.1 8.9 ± 4.1 67.4 ± 15.8 32.5 ± 27.6
59.8 ± 9.9 35.3 ± 10.2 38.5 ± 28 44.1 ± 30 5.4 ± 2.6 75.4 ± 13 20.4 ± 28.7
n.s. n.s. 0.05 0.05 <0.01 n.s. n.s.
(58.9 ± 36.8 vs 38.5 ± 28.0, p = 0.05) and ODI (65.8 ± 37.1 vs 44.1 ± 30.0, p = 0.05) in comparison to those with TA. The level of SaO2 and the heart rate before the arrhythmia did not differ between TA and BA patients (Table 4). In contrast, the depth of desaturation linked to BA was more than that observed during TA (19.7 ± 12.5 vs 3.5 ± 3.6 %, ANOVA F = 20.2, p < 0.0001) (Table 4, Fig. 1). Furthermore, in the logistic regression model, the mean amplitude of oxygen desaturation during apnea/hypopnea represented a risk factors for developing BA and not TA: odds ratio 1.38 (95% confidence intervals 1.04–1.84, p = 0.02). Finally, BA events occurred more frequently during rapid eye
Table 4 Value of baseline SaO2 and heart rate at the beginning of apnea, and SaO2 drops during apnea-related arrhythmia episode in patients with brady (BA)- or tachyarrhythmia (TA)
SaO2 at the beginning of apnea (%) Heart rate at the beginning of apnea (bpm) SaO2 drops during apnea
BA
TA
p
92.9 ± 5.5
92.2 ± 5.8
n.s.
56.2 ± 9
60.9 ± 10.2
n.s.
19.7 ± 12.5
3.5 ± 3.6
0.0001
50 ±1.96 SD
Mean SaO2 drops (%)
40
±1.00 SD Mean
30
20
*
10
0
-10 BA
TA
ARRHYTHMIA Fig. 1. Mean SaO2 drops during apnea-related arrythmia episode in patients with brady- (BA) or tachy- (TA) arrythmia. *p < 0.001.
movement (REM) sleep than did TA (63.4% vs 7.7%, respectively, p < 0.001). No associations were found between BA and the presence of comorbidities or concomitant medical therapy. On the contrary, TA was more frequent in patients with COPD than in those with OSAS alone (v2 = 6.64; p = 0.03). The presence of COPD as a comorbidity, as well as the therapy with broncodilators, represented a risk factor for development of tachyarrhythmias during sleep in OSA patients (odds ratio 2.53; 95% confidence intervals 1.1–5.8, p = 0.03; odds ratio 2.43; 95% confidence intervals 1.1–5.6; p = 0.03; respectively). Age, sex, BMI, concomitant cardiovascular treatment, and smoking habit did not enter into the model. 5. Discussion Our study was designed to investigate the presence of different patterns of OSA in relatively uncomplicated patients who developed different types of cardiac arrhythmia during sleep. The main finding of the present study was that the cardiac rhythm alterations during sleep in OSA patients were associated with different patterns of OSA severity, independently of the degree of obesity. Specifically, BA was associated with more severe OSA, particularly with more pronounced nocturnal hypoxia, at variance with TA that was surprisingly independent of OSA severity. However, these latter rhythm disturbances were frequent in patients with concomitant COPD and/or b2-agonist treatment. The prevalence of each arrhythmia was relatively low in our population of patients, with a very large spectrum of OSA severity. In our study, complex ventricular arrhythmias were present in no more than 9% of patients, while they were more common (25%) in a recent report from the Sleep Heart Health Study [16]. The prevalence of significant BA was also lower than previously reported in the literature [8,17–19], even when looking at patients with more severe OSA (AHI > 30). A possible explanation lay not only in the more restrictive inclusion criteria of our study (e.g., patients with already recognized arrhythmias were excluded) but also in the likely higher treatment of risk factors, such b-blockers for hypertension. However, we did not find any statistically significant association between therapy and b-blockers, nor other cardiovascular drugs or onset of any type of arrhythmia. Studies of individuals free of cardiac disease showed that sinus bradycardia, sinus pauses, and type 1 second-degree atrioventricular block are common in young people in association with sinus arrhythmia; these usually asymptomatic events are generally considered benign [20,21], which is not the case in patients with sleep apnea in whom BA is almost always related to respiratory pauses. Indeed, patients who presented pauses or advanced atrioventricular block had more
F. Olmetti et al. / Sleep Medicine 9 (2008) 475–480
severe OSAS than those without arrhythmia [22,23]. Age and severity of obesity did not influence the development of BA, nor did the presence of arterial hypertension or anti-hypertensive therapy. Several mechanisms have been proposed to explain the increasing vagal tone during the obstructive events: increasing in negative intrathoracic pressure due to inspiratory effort against closed upper airways, or stimulation of chest wall mechanoreceptors due to increased respiratory effort [24]. It has also been suggested that an impairment of baroreflex mechanisms, mainly found in patients with arterial hypertension, could lead patients with OSA to an excessive autonomic response [25]. The development of TA during sleep (unlike slow arrhythmia), seems to be independent of the severity of OSA, both in terms of apnea–hypopnea episodes, number of desaturations, or the degree of nocturnal hypoxia. Furthermore, only 37.1% of TA events were strictly related to an episode of apnea or hypopnea. Autonomic imbalances related to the cyclic alternating of apneas and hyperventilation are likely to be involved also in the occurrence of TA, but in a more complex way. A surge in sympathetic modulation after the obstructive episode has been documented by Spicuzza et al. [26]. However, the extent of increase in sympathetic activity might not be a direct function of the extent of desaturation (as suggested by our data). Moreover, several observations point toward a longlasting sympathetic hyperactivity as several markers of sympathetic drive have been found to be increased also during the day in patients with sleep-disordered breathing [27]. Rather, the final increase in sympathetic activity might be also affected by other factors like the underlying cardiac function or the presence of comorbidities. Our data show a statistically significant association between COPD as a comorbidity of OSA as well as the use of b2-stimulants in the development of TA. COPD patients are at risk of cardiovascular complications [28]; ischemic heart disease, right ventricular hypertrophy and arrhythmia are described in patients with chronic symptoms of COPD. The simultaneous prescription of b2-stimulants to relieve bronchoconstriction might perhaps predispose patients with COPD to an increased risk of cardiovascular complications such as arrhythmia or sudden death. However, a recent study of 2853 patients demonstrated that chronic treatment with salmeterol, the long-acting b2-stimulant taken by our patients, does not seem to increase the risk of adverse cardiovascular effects in a population of COPD patients compared with placebo. In particular, the incidence of TA was <1% of patients, both in placebo and in salmeterol groups. We can hypothesize that the combination of OSA and COPD or OSA and chronic use of b2-stimulants may increase the risk for TA in our group of patients [29].
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5.1. Strengths and limitations We excluded patients with pre-existing cardiac disease that might predispose subjects to develop arrhythmia in order to avoid bias. Furthermore, we excluded from the study patients who were candidates for pacemaker implantation, prior to the sleep study. In this way, we were able to study consecutive patients with only breathing disorders who developed arrhythmia solely during sleep. The prevalence of cardiac arrhythmia in this uncomplicated group was lower than previously reported in the general population [22]. One limitation is the use of a single bipolar lead which prevented full evaluation of ST-T wave abnormality. On the other hand, we did not select patients on the basis of OSA severity, so that we were able to assess that BA is common only in patients with AHI > 30/h and that TA development is independent of OSA severity. 5.2. Clinical implications Our results confirm recent epidemiological studies that reported an increased vulnerability to nocturnal cardiac arrhythmia in patients with OSA and provides new information about the relationship between OSA severity and the pattern of cardiac arrhythmia during sleep [16,30,31]. On the basis of our results, we can emphasize the need for monitoring ECG in the investigation of OSA and stress that more attention should be given to patients with more severe OSA as well as those with concomitant COPD or b2-treatment.
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Original Article
Nocturnal cardiac arrhythmia in patients with obstructive sleep apnea q Francesca Olmetti a, Maria Teresa La Rovere a, Elena Robbi b, Anna Eugenia Taurino b, Francesco Fanfulla b,* a b
Divisione di Cardiologia, Istituto Scientifico di Montescano, Fondazione S. Maugeri, IRCCS, Pavia, Italy Divisione di Pneumologia, Istituto Scientifico di Montescano, Fondazione S. Maugeri, IRCCS, Pavia, Italy Received 21 May 2007; received in revised form 30 July 2007; accepted 19 August 2007 Available online 19 November 2007
Abstract Background and purpose: Nocturnal cardiac arrhythmias occur in patients with obstructive sleep apnea (OSA), reportedly as a consequence of the autonomic effects of recurrent apnea with subsequent oxygen desaturation. We have investigated whether different patterns of OSA are associated with specific arrhythmia during sleep. Patients and methods: Electrocardiographic (ECG) data recorded during polysomnography (PSG) were analysed in 257 consecutive OSA patients to determine the prevalence of cardiac rhythm disturbances, and to relate these to breathing pattern (normal, apnea/ hypopnea, recovering ventilation, snoring) and oxygen saturation. Results: Arrhythmias were found in 18.5% of patients. Patients with nocturnal bradyarrhythmia (BA) had higher values of ventilatory disturbance (apnea–hypopnea index [AHI] 58.8 ± 36.8 vs 37.2 ± 30.3, p = 0.02), mean desaturation amplitude (8.9 ± 4 vs 5.9 ± 3.4%, p = 0.03), and a lower SaO2 nadir (69% vs 77%, p = 0.003) than those without arrhythmia. The prevalence of BA in patients with AHI P 30/h was significantly higher than that observed in those with AHI < 30/h (7.8% vs 1.5%, respectively; v2 = 5.61, p = 0.01). In contrast, patients with tachyarrhythmia (TA) had no significant differences in AHI, mean desaturation amplitude or SaO2 nadir than those without arrhythmia. No associations were found between arrhythmia and the presence of comorbidity or concomitant medical therapy, except for an association between tachyarrhythmia and chronic obstructive pulmonary disease (COPD) (odds ratio 2.53; 95% confidence intervals 1.1–5.8, p = 0.03). Conclusions: We conclude that while BA during sleep is associated with OSA severity, concomitant COPD or b2-treatment may play a role in the development of TA during sleep. Ó 2007 Elsevier B.V. All rights reserved. Keywords: Sleep apnea; OSAS; Cardiac arrhythmia; Hypoxemia; COPD
1. Introduction Obstructive sleep apnea syndrome (OSAS) is a common, although underestimated, clinical problem which
q
The authors for this article have no conflicts of interest to declare. Corresponding author. Address: Sleep Laboratory, Pulmonary Division, Fondazione Salvatore Maugeri IRCCS, Istituto Scientifico di Montescano, Via per Montescano, 27040 Montescano (PV), Italy. Tel.: +39 0385 2471; fax: +39 0385 61386. E-mail address: ff[email protected] (F. Fanfulla). *
1389-9457/$ - see front matter Ó 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2007.08.015
has been increasingly associated with a significantly raised cardiovascular morbidity and mortality. The repetitive nocturnal hypoxemia experienced by OSAS patients is associated with the activation of a number of neural, humoral, thrombotic, metabolic, and inflammatory disease mechanisms of cardiac and vascular disease [1–6]. Continuous positive airway pressure (CPAP) therapy has been demonstrated to significantly reduce the increased risk for cardiac death [7]. Cardiac rhythm disturbances, both in the form of brady (BA)- and tachyarrhythmia (TA), have been
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reported in up to more than 50% of patients with OSA as a consequence of the autonomic effects of recurrent nocturnal apneas with oxygen desaturation [8–10]. Although the observation that treatment of OSA by CPAP may successfully control cardiac rhythm disturbances would suggest a cause–effect relationship [11–13], the confounding effect of comorbidity and cardiovascular disease should also be taken into account. The aim of the present study was to address the relationship among obstructive apneas, oxygen desaturation and different patterns of cardiac arrhythmia during sleep in a consecutive series of subjects undergoing diagnostic overnight polysomnography (PSG) for suspected OSAS. 2. Patients and methods All the patients referred to our laboratory during 2004 for clinical suspicion of OSAS were considered eligible for the study. Only patients with clinical and PSG signs of OSA were enrolled in the study. They suffered from snoring and excessive daytime somnolence (Epworth sleepiness scale score > 9). Exclusion criteria were chronic heart failure, clinically significant autonomic neuropathy, respiratory failure requiring O2-therapy, and having an implanted pacemaker, transplantation, previous ischemic stroke, central sleep apnea, or known arrhythmia that prompted referral by a cardiologist for evaluation of breathing during sleep. So far, among the 439 patients who had a baseline PSG, 247 subjects with OSAS, according to daytime symptoms and an apnea/hypopnea index (AHI) > 5 ev/ h of sleep, were considered for the analysis. The protocol was submitted to the Technical and Ethical Committees. The former approved the protocol and the latter stated that approval was waived since, on admission to hospital, patients were asked to confirm whether they consented or not to the use of their medical records and ‘‘routine’’ examination results for research purposes. We analysed only the records of patients who agreed to the use of their data.
of the American Sleep Disorders Association [15]. Apnea was defined as a cessation of airflow for at least 10 s, while hypopnea was defined as a clear amplitude reduction of a validated measure of breathing during sleep (but less than a 50% reduction from baseline) associated with an oxygen desaturation of >3% or an arousal. AHI was defined as the total number of apneas and hypopneas per hour of sleep. We also calculated the oxygen desaturation index (ODI), defined as the number of desaturations per hour of sleep, the percentage of total sleep time (TST) spent with SaO2 < 90% (TST90) and the mean amplitude of each desaturation episode. ECG was recorded during PSG, which included lead I bipolar ECG sampled at 200 Hz. The ECG data were processed and analysed by the same cardiologist (FO) blinded to respiratory events, with the supervision of a senior cardiologist (MTLR) when doubts or difficulties arose. Arrhythmias and artifacts were properly classified when there was a complete agreement between the two scorers. Ventricular arrhythmia included premature ventricular contractions (PVCs P 10/h), bigeminy, trigeminy, quadrigeminy, and non-sustained ventricular tachycardia (defined as P3 consecutive ventricular beats with an average rate P100 beats/min). Atrial arrhythmia included supraventricular tachycardia and atrial fibrillation. Conduction delay arrhythmias were atrioventricular block (P second degree type 2), intraventricular conduction delay, and sinus pause (P2 s). Other rhythm disturbances recorded but not deemed significant included isolated atrial premature beats and sinus bradycardia or tachycardia. For each episode of cardiac arrhythmia, we recorded the time of onset, sleep stage, breathing status (normal, apnea/hypopnea, recovering ventilation, snoring), and the level of oxygen saturation. For each episode of cardiac arrhythmia that occurred during an apnea or hypopnea episode or during the subsequent phase of recovering ventilation, we analysed the level of SaO2 and the mean heart rate before the arrhythmia as well as the depth of oxygen desaturation.
2.1. Sleep study 3. Statistical analysis Full standard in-laboratory PSG (Embla, Medcare, Reykyiavik, Iceland) was performed using current procedures and scored manually according to the criteria of Rechtschaffen and Kales [14]. The PSG included electroencephalogram (C3–A2, C4–A1; O1–A2, O2–A1), electro-oculograms, submental electromyogram (EMG), anterior tibialis EMGs, nasal cannula airflow signal using a nasal cannula/pressure transducer system, oral thermistor, electrocardiogram (ECG) and body position. SaO2 was recorded by means of an in-built pulseoximeter (Nonin Medical Inc., Minneapolis, MN, USA) with an Oximax sensor (Nellcore, Pleasanton, CA, USA). Arousals were scored according to criteria
Arrhythmias were coded as present or absent and as tachy- or bradycardic. As is customary, ventricular premature beats were classified under tachyarrythmia. Oneway analysis of variance (ANOVA) was used for differences between patients with or without arrhythmia, and for differences between patients with tachy- or bradycardic events. Patients were classified into two groups according to the severity of OSA (AHI< or P30 events per hour of sleep). The v2 test was performed for differences in the prevalence of arrhythmia between patients with more or less severe OSA, and also to evaluate the association of car-
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diac arrhythmias with concomitant disease (e.g., COPD, cardiac ischemic disease, diabetes mellitus, systemic arterial hypertension) or concomitant medication. Simple and multiple logistic regression analyses were performed to identify the risk factors associated with the development of arrhythmia during sleep. All the analyses were performed using the SPSS 13 statistical package, and a p value <0.05 was considered statistically significant.
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Table 2 Prevalence of each type of arrhythmia in all patients Type of arrhythmias
No. of patients
SVT AF PVCs > 10/h PAUSE (>2 s) AV Block (P second degree type 2)
13 2 22 8 3
SVT = supraventricular tachycardia; AF = atrial fibrillation; PVCs = premature ventricular complex; AV Block = atrio-ventricular block.
4. Results All patients who enrolled completed the study. The most common comorbidities associated with OSA were systemic arterial hypertension (37.6% of patients), COPD (15.8% of patients), diabetes mellitus (11.7% of patients), ischemic heart disease (8.9% of patients), and hypothyroidism (5.7% of patients). Most of the patients received chronic therapy: 28.7% ACE-inhibitors, 16.2% bronchodilators (long-acting B2-agonists), 15% Ca-channel blocker, and 5.2% b-blockers. Anthropometrics, sleep data, comorbidities and concomitant therapies are reported in Table 1. Forty-six patients (18.5%) had rhythm disturbances during sleep; the prevalence of each type of arrhythmias is shown in Table 2. BA was observed in 11, while TA was present in 35 patients. Specifically, supraventricular tachycardia was observed in 13 patients, atrial fibrillation or flutter in 2 patients, PVCs > 10/h in 22 patients, Table 1 General characteristics of patients Age (years) BMI (kg/m2) Smoking status (non/ex/current) TST (min) SE (%) NREM1 (%) NREM2 (%) SWS (%) REM (%) AHI (%) ODI (%) SaO2nadir (%) TST90 (%) Hypertension (n.) CAD (n.) Diabetes (n.) Hypothyroidism (n.) COPD (n.) Bronchodilators (n.) Beta-blocker (n.) ACE-inhibitors (n.) Ca-channel blocker (n.) a-blocker (n.)
54.3 ± 12.7 35.9 ± 10.7 99/93/55 347.0 ± 54.7 83.8 ± 12.4 17.0 ± 17.1 42.5 ± 12.6 22.4 ± 11.6 17.9 ± 8.5 38.3 ± 30.5 45.5 ± 37.5 74.9 ± 13.2 19.4 ± 27.7 37.7 8.9 11.7 5.7 15.8 16.2 4 28.3 14.6 4.9
BMI = body mass index; TST = total sleep time; SE = sleep efficiency; AHI = apnea/hypopnea index; ODI = oxygen desaturation index; TST90 = percentage of Total Sleep Time spent with SaO2 < 90%. CAD = coronary artery disease; COPD = chronic obstructive pulmonary disease.
pauses (>2 s) in 8 patients, and atrioventricular block in 3 patients. Patients with cardiac arrhythmia were older than those with no arrhythmia (57.5 ± 12.6 vs 52.5 ± 13.1 years, p < 0.05). The temporal relationship between each arrhythmia and a respiratory event was different for brady- and tachyarrhythmias. All BA episodes occurred during an episode of apnea or hypopnea, while only the 37.1% of TA events were strictly related to an episode of apnea or hypopnea (during the episode or during the subsequent phase of recovering ventilation). More specifically, PVCs were present during the whole recording with no association with sleep or awake. Patients with BA during sleep presented a higher value of AHI (58.8 ± 36.8 vs 37.2 ± 30.3 ev/hr, p = 0.02) than those without arrhythmia, mean desaturation amplitude (8.9 ± 4 vs 5.9 ± 3.4%, p = 0.03), and a lower SaO2 nadir (69% vs 77%, p = 0.003). No difference was found between BA patients and those without arrhythmia for body mass index (BMI) (34.5 ± 9.3 vs 36.1 ± 10.1 kg/m2, respectively; p = n.s.) or for age (51.8 ± 17.7 vs 53.6 ± 12.6 years, respectively; p = n.s.). Of interest, no differences were found for the presence of arterial hypertension or smoking habit. The occurrence of BA was strictly related to the severity of OSA. Indeed, the prevalence of BA in patients with AHI P 30/h was significantly higher than that observed in those with AHI < 30/h (7.8 vs 1.5%, respectively; v2 = 5.61, p = 0.01), with an odds ratio of 5.33 (95% confidence intervals 1.13–25.3, respectively; p = 0.03). In contrast, patients with TA had no significant difference in AHI, mean desaturation amplitude and SaO2 nadir than those without arrhythmia. The only difference between TA patients and those without arrhythmia was related to age, since patients with TA were older (59.8 ± 9 vs 53.5 ± 12 years; p = 0.005). The occurrence of TA was not related to the severity of OSA: the prevalence of TA in patients with AHI P 30/h was similar to that observed in those with AHI < 30/h (15.5% vs 13%, respectively; p = n.s.). BA patients had a more severe OSA pattern than TA patients, (Table 3). Indeed, the mean amplitude of oxygen desaturations was higher in patients with BA (8.9 ± 4.1 vs 5.4 ± 2.6, p > 0.01), as well as AHI
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Table 3 Sleep respiratory data in patients with brady (BA)- or tachyarrhythmia (TA)
Age (years) BMI (kg/m2) AHI (n/hour of sleep) ODI (n/hour of sleep) Mean desaturation amplitude (%) SaO2nadir (%) TST90 (% of total sleep time)
BA
TA
p
51.8 ± 17.7 34.5 ± 9.3 58.9 ± 36.8 65.8 ± 37.1 8.9 ± 4.1 67.4 ± 15.8 32.5 ± 27.6
59.8 ± 9.9 35.3 ± 10.2 38.5 ± 28 44.1 ± 30 5.4 ± 2.6 75.4 ± 13 20.4 ± 28.7
n.s. n.s. 0.05 0.05 <0.01 n.s. n.s.
(58.9 ± 36.8 vs 38.5 ± 28.0, p = 0.05) and ODI (65.8 ± 37.1 vs 44.1 ± 30.0, p = 0.05) in comparison to those with TA. The level of SaO2 and the heart rate before the arrhythmia did not differ between TA and BA patients (Table 4). In contrast, the depth of desaturation linked to BA was more than that observed during TA (19.7 ± 12.5 vs 3.5 ± 3.6 %, ANOVA F = 20.2, p < 0.0001) (Table 4, Fig. 1). Furthermore, in the logistic regression model, the mean amplitude of oxygen desaturation during apnea/hypopnea represented a risk factors for developing BA and not TA: odds ratio 1.38 (95% confidence intervals 1.04–1.84, p = 0.02). Finally, BA events occurred more frequently during rapid eye
Table 4 Value of baseline SaO2 and heart rate at the beginning of apnea, and SaO2 drops during apnea-related arrhythmia episode in patients with brady (BA)- or tachyarrhythmia (TA)
SaO2 at the beginning of apnea (%) Heart rate at the beginning of apnea (bpm) SaO2 drops during apnea
BA
TA
p
92.9 ± 5.5
92.2 ± 5.8
n.s.
56.2 ± 9
60.9 ± 10.2
n.s.
19.7 ± 12.5
3.5 ± 3.6
0.0001
50 ±1.96 SD
Mean SaO2 drops (%)
40
±1.00 SD Mean
30
20
*
10
0
-10 BA
TA
ARRHYTHMIA Fig. 1. Mean SaO2 drops during apnea-related arrythmia episode in patients with brady- (BA) or tachy- (TA) arrythmia. *p < 0.001.
movement (REM) sleep than did TA (63.4% vs 7.7%, respectively, p < 0.001). No associations were found between BA and the presence of comorbidities or concomitant medical therapy. On the contrary, TA was more frequent in patients with COPD than in those with OSAS alone (v2 = 6.64; p = 0.03). The presence of COPD as a comorbidity, as well as the therapy with broncodilators, represented a risk factor for development of tachyarrhythmias during sleep in OSA patients (odds ratio 2.53; 95% confidence intervals 1.1–5.8, p = 0.03; odds ratio 2.43; 95% confidence intervals 1.1–5.6; p = 0.03; respectively). Age, sex, BMI, concomitant cardiovascular treatment, and smoking habit did not enter into the model. 5. Discussion Our study was designed to investigate the presence of different patterns of OSA in relatively uncomplicated patients who developed different types of cardiac arrhythmia during sleep. The main finding of the present study was that the cardiac rhythm alterations during sleep in OSA patients were associated with different patterns of OSA severity, independently of the degree of obesity. Specifically, BA was associated with more severe OSA, particularly with more pronounced nocturnal hypoxia, at variance with TA that was surprisingly independent of OSA severity. However, these latter rhythm disturbances were frequent in patients with concomitant COPD and/or b2-agonist treatment. The prevalence of each arrhythmia was relatively low in our population of patients, with a very large spectrum of OSA severity. In our study, complex ventricular arrhythmias were present in no more than 9% of patients, while they were more common (25%) in a recent report from the Sleep Heart Health Study [16]. The prevalence of significant BA was also lower than previously reported in the literature [8,17–19], even when looking at patients with more severe OSA (AHI > 30). A possible explanation lay not only in the more restrictive inclusion criteria of our study (e.g., patients with already recognized arrhythmias were excluded) but also in the likely higher treatment of risk factors, such b-blockers for hypertension. However, we did not find any statistically significant association between therapy and b-blockers, nor other cardiovascular drugs or onset of any type of arrhythmia. Studies of individuals free of cardiac disease showed that sinus bradycardia, sinus pauses, and type 1 second-degree atrioventricular block are common in young people in association with sinus arrhythmia; these usually asymptomatic events are generally considered benign [20,21], which is not the case in patients with sleep apnea in whom BA is almost always related to respiratory pauses. Indeed, patients who presented pauses or advanced atrioventricular block had more
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severe OSAS than those without arrhythmia [22,23]. Age and severity of obesity did not influence the development of BA, nor did the presence of arterial hypertension or anti-hypertensive therapy. Several mechanisms have been proposed to explain the increasing vagal tone during the obstructive events: increasing in negative intrathoracic pressure due to inspiratory effort against closed upper airways, or stimulation of chest wall mechanoreceptors due to increased respiratory effort [24]. It has also been suggested that an impairment of baroreflex mechanisms, mainly found in patients with arterial hypertension, could lead patients with OSA to an excessive autonomic response [25]. The development of TA during sleep (unlike slow arrhythmia), seems to be independent of the severity of OSA, both in terms of apnea–hypopnea episodes, number of desaturations, or the degree of nocturnal hypoxia. Furthermore, only 37.1% of TA events were strictly related to an episode of apnea or hypopnea. Autonomic imbalances related to the cyclic alternating of apneas and hyperventilation are likely to be involved also in the occurrence of TA, but in a more complex way. A surge in sympathetic modulation after the obstructive episode has been documented by Spicuzza et al. [26]. However, the extent of increase in sympathetic activity might not be a direct function of the extent of desaturation (as suggested by our data). Moreover, several observations point toward a longlasting sympathetic hyperactivity as several markers of sympathetic drive have been found to be increased also during the day in patients with sleep-disordered breathing [27]. Rather, the final increase in sympathetic activity might be also affected by other factors like the underlying cardiac function or the presence of comorbidities. Our data show a statistically significant association between COPD as a comorbidity of OSA as well as the use of b2-stimulants in the development of TA. COPD patients are at risk of cardiovascular complications [28]; ischemic heart disease, right ventricular hypertrophy and arrhythmia are described in patients with chronic symptoms of COPD. The simultaneous prescription of b2-stimulants to relieve bronchoconstriction might perhaps predispose patients with COPD to an increased risk of cardiovascular complications such as arrhythmia or sudden death. However, a recent study of 2853 patients demonstrated that chronic treatment with salmeterol, the long-acting b2-stimulant taken by our patients, does not seem to increase the risk of adverse cardiovascular effects in a population of COPD patients compared with placebo. In particular, the incidence of TA was <1% of patients, both in placebo and in salmeterol groups. We can hypothesize that the combination of OSA and COPD or OSA and chronic use of b2-stimulants may increase the risk for TA in our group of patients [29].
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5.1. Strengths and limitations We excluded patients with pre-existing cardiac disease that might predispose subjects to develop arrhythmia in order to avoid bias. Furthermore, we excluded from the study patients who were candidates for pacemaker implantation, prior to the sleep study. In this way, we were able to study consecutive patients with only breathing disorders who developed arrhythmia solely during sleep. The prevalence of cardiac arrhythmia in this uncomplicated group was lower than previously reported in the general population [22]. One limitation is the use of a single bipolar lead which prevented full evaluation of ST-T wave abnormality. On the other hand, we did not select patients on the basis of OSA severity, so that we were able to assess that BA is common only in patients with AHI > 30/h and that TA development is independent of OSA severity. 5.2. Clinical implications Our results confirm recent epidemiological studies that reported an increased vulnerability to nocturnal cardiac arrhythmia in patients with OSA and provides new information about the relationship between OSA severity and the pattern of cardiac arrhythmia during sleep [16,30,31]. On the basis of our results, we can emphasize the need for monitoring ECG in the investigation of OSA and stress that more attention should be given to patients with more severe OSA as well as those with concomitant COPD or b2-treatment.
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