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Association between obstructive sleep apnea and premature supraventricular contractions
Journal of Cardiology 63 (2014) 69–72
Contents lists available at ScienceDirect
Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc
Original article
Association between obstructive sleep apnea and premature supraventricular contractions Yoshiyuki Kawano (MD) a , Akira Tamura (MD) a,∗ , Katsushige Ono (MD, PhD) b , Junichi Kadota (MD, PhD) a a b
Internal Medicine 2, Faculty of Medicine, Oita University, Yufu, Japan Department of Pathophysiology, Oita University, Yufu, Japan
a r t i c l e
i n f o
Article history: Received 4 March 2013 Received in revised form 2 July 2013 Accepted 2 July 2013 Available online 7 September 2013 Keywords: Obstructive sleep apnea Premature supraventricular contraction Ambulatory electrocardiography Polysomnography Apnea–hypopnea index
a b s t r a c t Objective: The exact association between obstructive sleep apnea (OSA) and premature supraventricular contractions (PSVCs) has not been established. Methods: We prospectively performed polysomnography together with 24-hour Holter electrocardiography in 431 patients who were clinically suspected of having OSA and examined the association between OSA severity and PSVCs during wakefulness and sleep. The patients were classified into 4 groups according to the apnea–hypopnea index (AHI) quartiles (Q1 = patients with AHI < 13.8, Q2 = those with 13.8 ≤ AHI < 28.8, Q3 = those with 28.8 ≤ AHI < 48.1, Q4 = those with AHI ≥ 48.1). Results: The number of PSVCs/hour during sleep differed significantly among the 4 groups, but the number of PSVCs/hour during wakefulness did not. The prevalence of PSVC ≥ 5/hour during sleep was significantly higher in Q4 (21.0%) than the other 3 groups (Q1, 9.0%; Q2, 8.0%; Q3, 6.0%; all p < 0.05 for Q4), but the prevalence of PSVC ≥ 5/hour during wakefulness did not differ among the 4 groups. A multivariate logistic regression analysis showed that the highest AHI quartile was significantly associated with PSVC ≥ 5/hour during sleep (odds ratio 3.04, 95% confidence interval 1.44–6.42, p = 0.004). Conclusions: Severe OSA can cause PSVCs during sleep, but its effect appears not to be strong. Further studies are needed to clarify the clinical significance of this small but significant increase in PSVCs during sleep in severe OSA patients. © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Introduction Much attention has been recently paid to the association between sleep-disordered breathing and cardiovascular diseases including hypertension, arrhythmias, coronary artery disease, aortic dissection, congestive heart failure, pulmonary hypertension, and strokes [1–3]. Obstructive sleep apnea (OSA), which is a chronic condition characterized by repetitive episodes of upper airway collapse, apnea, and arousal during sleep, is the most frequent sleep-disordered breathing. The association between OSA and premature ventricular contractions has been repeatedly investigated [4–13]. On the other hand, only several investigations have been undertaken about the association between OSA and premature supraventricular contractions (PSVCs) [8–10,12], and the results of these studies are conflicting. It has been demonstrated that an isolated PSVC can trigger atrial fibrillation and
∗ Corresponding author at: Internal Medicine 2, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu 879-5593, Japan. Tel.: +81 097 586 5804; fax: +81 097 549 4245. E-mail address: [email protected] (A. Tamura).
supraventricular tachycardia [14,15] and that frequent PSVCs are associated with increased risks for stroke or death as well as atrial fibrillation [16,17]. Therefore, it is clinically important to clarify whether OSA can contribute to the occurrence of PSVCs. In this study, we prospectively examined the association between OSA severity and PSVCs during wakefulness as well as sleep in patients who were clinically suspected of having OSA.
Methods Subjects A total of 431 patients (336 males and 95 females, median age 56 years) who were clinically suspected of having OSA (severe snoring, daytime sleepiness, and witnessed apnea) and who met the inclusion criteria were prospectively enrolled into this study. All patients underwent full polysomnography together with 24-hour Holter electrocardiography. The inclusion criteria were aged ≥ 20 years, absence of chronic atrial fibrillation/flutter, no use of antiarrhythmic agents, no signs or symptoms of congestive heart failure, no pacemaker implantation and no treatment of OSA with oral
0914-5087/$ – see front matter © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jjcc.2013.07.003
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appliance, continuous positive airway pressure, bi-level positive airway pressure, or adaptive servo-ventilation. Patients with dominantly central sleep apnea (n = 2) and the occurrence of atrial fibrillation on the 24-hour Holter electrocardiogram (n = 2) were excluded. The study protocol was approved by the ethics committee of Oita University Hospital, and informed consent was obtained from each patient before the study.
regression analyses were performed to determine variables associated with PSVC ≥ 5/hour during sleep. A value of p < 0.05 was considered to be statistically significant. Statistical analyses were performed using IBM SPSS Statistics 20 (International Business Machines, New York, NY, USA).
Polysomnography
Of 431 patients, 385 (89.3%) had an AHI ≥ 5. The 431 patients were classified into 4 groups according to the AHI quartiles (Q1 = 107 patients with AHI < 13.8; Q2 = 108 with 13.8 ≤ AHI < 28.8; Q3 = 108 with 28.8 ≤ AHI < 48.1; Q4 = 108 with AHI ≥ 48.1). The patient characteristics are shown in Table 1. Age, body mass index, and the prevalences of male gender, hypertension, diabetes mellitus, calcium antagonist use, and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use differed significantly among the 4 groups. The number of PSVCs/hour during sleep differed significantly among the 4 groups (Q1, 0.4 [0.0–1.2]; Q2, 0.6 [0.2–1.5]; Q3, 0.5 [0.1–1.2]; Q4, 0.9 [0.2–3.1]; p = 0.01), but the number of PSVCs/hour during wakefulness did not (Q1, 0.6 [0.1–1.3]; Q2, 0.6 [0.2–1.6]; Q3, 0.5 [0.2–1.3]; Q4, 0.6 [0.2–2.4]; p = 0.75). The prevalence of PSVC ≥ 5/hour during sleep was significantly higher in Q4 (21.0%) than in the other 3 groups (Q1, 9.0%; Q2, 8.0%; Q3, 6.0%; all p < 0.05 for Q4), but the prevalence of PSVC ≥ 5/hour during wakefulness did not differ significantly among the 4 groups (p = 0.20) (Fig. 1). The number of PSVCs/hour during sleep and that during wakefulness differed significantly among the 4 groups classified by the arousal index (ArI) quartiles (A-Q1 = 107 patients with ArI < 21.2: 0.4 [0.1–0.9]; A-Q2 = 107 with 21.2 ≤ ArI < 31.9: 0.5 [0.1–1.1]; A-Q3 = 109 with 31.9 ≤ ArI < 48.5: 0.6 [0.2–1.6]; AQ4 = 108 with ArI ≥ 48.5: 1.0 [0.2–2.6]; p = 0.001, and A-Q1: 0.4 [0.1–1.2]; A-Q2: 0.6 [0.2–1.3]; A-Q3: 0.7 [0.3–2.0]; A-Q4: 0.7 [0.2–2.1]; p = 0.048, respectively). The prevalence of PSVC ≥ 5/hour during sleep differed significantly among the 4 groups (A-Q1, 6.5%; A-Q2, 4.7%; A-Q3, 11.9%; A-Q4, 17.6%; p < 0.01), and the prevalence of PSVC ≥ 5/hour during wakefulness tended to differ among the 4 groups (A-Q1, 7.5%; A-Q2, 3.7%; A-Q3, 11.0%; A-Q4, 13.9%; p = 0.05). The number of PSVCs/hour during sleep and that during wakefulness did not differ significantly among the 4 groups classified by the lowest SpO2 (L-SpO2 ) quartiles (L-Q1 = 100 with L-SpO2 < 77%: 0.5 [0.1–2.1]; L-Q2 = 105 with 77% ≤ L-SpO2 < 83%: 0.5 [0.3–1.5]; LQ3 = 110 with 83% ≤ L-SpO2 < 88%: 0.6 [0.2–1.6]; L-Q4 = 116 with L-SpO2 ≥ 88%: 0.4 [0.1–1.5]; p = 0.11, and L-Q1: 0.4 [0.1–1.8]; LQ2: 0.6 [0.2–1.6]; L-Q3: 0.7 [0.3–1.7]; L-Q4: 0.6 [0.1–1.3]; p = 0.30, respectively). The prevalence of PSVC ≥ 5/hour during sleep tended to differ among the 4 groups (L-Q1, 16.0%; L-Q2, 11.4%; L-Q3, 5.5%; L-Q4, 8.6%, p = 0.08), but the prevalence of PSVC ≥ 5/hour during
Polysomnography was performed using a computerized recording system (E-series, Compumedics, Abbotsford, Australia). This investigation consisted of monitoring of the electroencephalogram, electrooculogram, submental and limb electromyograms, electrocardiogram, thoraco-abdominal excursions by a piezo belt, oronasal airflow by a nasal pressure transducer and an oronasal thermistor, and the arterial oxyhemoglobin saturation by transcutaneous pulse oximetry. An obstructive apnea event was defined as the absence of oronasal airflow for ≥10 seconds associated with continued or increased inspiratory effort. A central apnea was defined as the absence of oronasal airflow for ≥10 seconds associated with an absent inspiratory effort. A hypopnea was defined as a ≥50% reduction in oronasal airflow for ≥10 seconds, associated with a ≥3% fall in arterial oxyhemoglobin saturation or an arousal. The apnea–hypopnea index (AHI) was calculated as the mean number of apneas and hypopneas per hour of sleep. 24-Hour Holter electrocardiography Together with overnight polysomnography, 24-hour Holter electrocardiography was performed using a digital recorder with 3 channels (RAC-3103, Nihon Koden, Tokyo, Japan). Polysomnography and 24-hour Holter electrocardiography were time-synchronized. The presence or absence of PSVC ≥ 5/hour during wakefulness as well as sleep was assessed. This PSVC cut-off value has been used in previous studies investigating the association between OSA and PSVCs [8,10,12]. The mean numbers of PSVCs/hour during wakefulness as well as sleep was also calculated. Based on the electro-encephalogram, the sleep period was defined as the period from the starting of sleep to the end of sleep. Statistical analysis Continuous data are expressed as the median (first-third quartiles). The Kruskal–Wallis test with the Scheffe’s post hoc test was used for comparisons of continuous data among 4 groups. Comparisons of categorical variables were analyzed by the Fisher’s exact test or chi-square test. The univariate and multivariate logistic
Results
Table 1 Patient characteristics and polysomnographic data. Variables
Q1 (n = 107)
Q2 (n = 108)
Q3 (n = 108)
Q4 (n = 108)
p-Value
Age (years) Male gender Body mass index (kg/m2 ) Hypertension Dyslipidemia Diabetes Current smoker Coronary artery disease AHI Calcium antagonists ACEIs/ARBs Beta-blockers
56.0 (41.0–64.0) 64 (59.8%) 23.3 (21.5–25.8) 53 (49.5%) 64 (59.8%) 14 (13.1%) 22 (20.6%) 19 (17.8%) 6.0 (2.8–9.3) 30 (28.0%) 27 (25.2%) 14 (13.1%)
62.0 (51.0–70.0) 84 (77.8%) 24.4 (22.7–26.7) 73 (67.6%) 70 (64.8%) 25 (23.1%) 24 (22.2%) 22 (20.4%) 20.9 (17.5–23.9) 49 (45.4%) 43 (38.9%) 14 (13.0%)
62.0 (50.3–70.0) 92 (85.2%) 25.5 (23.6–28.7) 76 (70.4%) 78 (72.2%) 33 (30.6%) 17 (15.7%) 16 (14.8%) 36.5 (31.6–42.1) 49 (45.4%) 50 (46.3%) 14 (13.0%)
54.0 (44.0–66.8) 96 (88.9%) 28.4 (25.3–32.7) 74 (68.5%) 79 (73.1%) 33 (30.6%) 23 (21.3%) 8 (7.4%) 65.3 (58.4–81.9) 52 (48.1%) 43 (39.8%) 16 (14.8%)
<0.001 <0.001 <0.001 0.004 0.11 0.01 0.65 0.05 <0.001 0.01 0.01 0.97
Values are presented as the median (first–third quartiles). Q1 = patients with AHI < 13.8; Q2 = those with 13.8 ≤ AHI < 28.8; Q3: those with 28.8 ≤ AHI < 48.1; Q4: those with AHI ≥ 48.1. AHI, apnea–hypopnea index; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.
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Fig. 1. Prevalence of premature supraventricular contractions ≥ 5/hour during wakefulness and that during sleep among 4 groups classified by the AHI quartiles. Q1 = patients with AHI < 13.8; Q2 = those with 13.8 ≤ AHI < 28.8; Q3 = those with 28.8 ≤ AHI < 48.1; Q4: those with AHI ≥ 48.1. *p < 0.05 vs Q4. AHI, apnea–hypopnea index.
wakefulness did not differ significantly among the 4 groups (L-Q1, 9.0%; L-Q2, 13.3%; L-Q3, 6.4%; L-Q4, 7.8%; p = 0.32). A univariate logistic regression analysis showed that the highest AHI quartile was significantly associated with PSVC ≥ 5/hour during sleep (odds ratio 3.15, 95% confidence interval 1.66–5.96, p < 0.001) (Table 2). When we performed a multivariate logistic regression analysis (forward selection method) including age, male gender, body mass index, hypertension, diabetes mellitus, current smoking, coronary artery disease, the highest AHI quartile, renin–angiotensin system inhibitor (angiotensin-enzyme inhibitor or angiotensin receptor blocker) use and beta-blocker use as explanatory variables, the highest AHI quartile was significantly associated with PSVC ≥ 5/hour during sleep (odds ratio 3.04, 95% confidence interval 1.44–6.42, p = 0.004) (Table 2). Discussion There are 3 large-population studies to investigate the association between sleep-disordered breathing or OSA and PSVCs [8,10,12]. The Sleep Heart Health Study showed that PSVC ≥ 5/hour during sleep was more common in 228 subjects with sleepdisordered breathing [respiratory disturbance index (the mean number of apneas and hypopneas per hour of sleep assessed by portable monitoring) ≥ 30] than in 338 without sleep-disordered breathing (respiratory disturbance index < 5) (33.8% vs 24.3%, p = 0.001) [8]. However, that study did not analyze whether sleepdisordered breathing was independently associated with PSVCs during sleep. In addition, it did not examine the association between sleep-disordered breathing and PSVCs during wakefulness. In the MrOS study involving 2911 men aged ≥65 years, the prevalence of PSVC ≥ 5/hour during sleep did not differ significantly among the 4 groups classified by the quartiles of respiratory disturbance index [10]. However, that study included only men
aged ≥65 years, and subjects with central sleep apnea were also included. In a study involving 486 middle-aged (30–65 years) subjects, Namtvedt et al. did not find significant differences in the prevalences of PSVC ≥ 5/hour during daytime as well as nighttime between subjects with OSA (AHI ≥ 5) and those without it (41.7% vs 48.4% and 49.4% vs 49.8%, respectively) [12]. However, in that study, OSA was defined as AHI ≥ 5, and only 14.8% of the subjects had severe OSA (AHI ≥ 30). In addition, the definitions of daytime and nighttime were not described. Thus, the exact association between OSA severity and PSVCs during wakefulness as well as sleep has not yet been established. In the present study, the prevalence of PSVC ≥ 5/hour during sleep was significantly higher in patients with the highest AHI quartile than in the other 3 groups of patients, and the number of PSVCs/hour during sleep differed significantly among the 4 groups. Furthermore, the univariate logistic regression analysis showed that the highest AHI quartile was significantly associated with PSVC ≥ 5/hour during sleep, and the multivariate logistic regression analysis selected the highest AHI quartile as the only independent variable associated with PSVC ≥ 5/hour during sleep. These results suggest that OSA can contribute to the occurrence of PSVCs during sleep and that there may be a threshold effect on the association between OSA severity and the occurrence of PSVCs during sleep. On the other hand, the prevalence of PSVCs during wakefulness and the number of PSVCs/hour during wakefulness did not differ significantly among the 4 groups classified by the AHI quartiles. However, since the prevalence of PSVC ≥ 5/hour during wakefulness tended to be higher in patients with the highest AHI, the association between OSA severity and PSVCs during wakefulness awaits further investigation. In the present study, the number of PSVCs/hour during sleep was only 0.9 (0.2–3.1) in patients with the highest AHI quartile. This result suggests that the effect of OSA on the occurrence of
Table 2 Univariate and multivariate logistic regression analyses to determine variables associated with PSVC ≥ 5/hour during sleep. Variables
Age (years) Male gender Body mass index (kg/m2 ) Hypertension Diabetes Current smoker Coronary artery disease Highest AHI quartile ACEIs/ARBs Beta-blockers
Univariate
Stepwise multivariate
Odds ratio (95% confidence interval)
p-Value
1.00 (0.98–1.03) 1.11 (0.51–2.40) 1.03 (0.97–1.09) 1.23 (0.63–2.39) 1.19 (0.59–2.40) 0.73 (0.32–1.71) 1.07 (0.46–2.52) 3.15 (1.66–5.96) 0.84 (0.44–1.63) 1.25 (0.53–2.95)
0.77 0.79 0.38 0.55 0.64 0.47 0.87 <0.001 0.61 0.62
Odds ratio (95% confidence interval)
p-Value
3.04 (1.44–6.42)
0.004
PSVC, premature supraventricular contraction; AHI, apnea–hypopnea index; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.
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PSVCs during sleep is not strong. It is unclear whether such low frequency PSVCs during sleep have any clinical significance in patients with OSA. However, considering that an isolated PSVC can trigger atrial fibrillation [14,15] and that nocturnal atrial fibrillation is more common in OSA patients than in non-OSA subjects [8,11], the occurrence of PSVCs during sleep might contribute to the future occurrence of nocturnal atrial fibrillation in patients with OSA. Further studies are therefore needed to clarify the association between the presence or number of PSVCs during sleep and future nocturnal atrial fibrillation in patients with OSA. The possible mechanisms by which OSA causes PSVCs are as follows. First, OSA-related hypoxia, hypercapnia, loss of lung inflation, and arousal can all activate the sympathetic nervous system, which can cause PSVCs through abnormal automaticity and triggered activity based on the increase of the intracellular Ca2+ concentration [18]. Also, sympathetic nervous activation shortens the duration of the action potential by the increase of delayed rectifier K+ current [19,20], which can lead to a shortening of the effective refractory period and thereby the occurrence of PSVCs. Second, excessively negative intrathoracic pressure against the occluded upper airway during an obstructive event stretches the atrial muscle and the pulmonary vein, leading to the occurrence of PSVCs though the activation of the L-type Ca2+ channel and the transient receptor potential channels and a resultant increase in the intracellular Ca2+ concentration [21–23]. The present study has several limitations. First, the study included a selected cohort of patients who were clinically suspected of having OSA. Therefore, the findings of the present study may not be applicable to a general population with OSA. Second, the present study excluded patients with antiarrhythmic agent use or the occurrence of atrial fibrillation/flutter at baseline or on the 24-hour Holter electrocardiogram, who would potentially have a larger number of PSVCs than those without it. Therefore, a positive association between OSA and PSVCs during sleep indicated by the present study might have been underestimated. Third, 24-hour Holter electrocardiographic findings may not accurately reflect the actual severity of PSVCs, because there is day-to-day variability in the frequency of PSVCs. Fourth, we did not analyze the association between timing of the occurrence of PSVCs and OSA events. The clarification of this association would provide important information about the cause–effect relationship between OSA and PSVCs during sleep. In conclusion, severe OSA can cause PSVCs during sleep, but its effect appears not to be strong. Further studies are needed to clarify the clinical significance of this small but significant increase in PSVCs during sleep in severe OSA patients. Conflict of interest
[2]
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[9]
[10]
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[12]
[13]
[14]
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[20]
None declared. [21]
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Contents lists available at ScienceDirect
Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc
Original article
Association between obstructive sleep apnea and premature supraventricular contractions Yoshiyuki Kawano (MD) a , Akira Tamura (MD) a,∗ , Katsushige Ono (MD, PhD) b , Junichi Kadota (MD, PhD) a a b
Internal Medicine 2, Faculty of Medicine, Oita University, Yufu, Japan Department of Pathophysiology, Oita University, Yufu, Japan
a r t i c l e
i n f o
Article history: Received 4 March 2013 Received in revised form 2 July 2013 Accepted 2 July 2013 Available online 7 September 2013 Keywords: Obstructive sleep apnea Premature supraventricular contraction Ambulatory electrocardiography Polysomnography Apnea–hypopnea index
a b s t r a c t Objective: The exact association between obstructive sleep apnea (OSA) and premature supraventricular contractions (PSVCs) has not been established. Methods: We prospectively performed polysomnography together with 24-hour Holter electrocardiography in 431 patients who were clinically suspected of having OSA and examined the association between OSA severity and PSVCs during wakefulness and sleep. The patients were classified into 4 groups according to the apnea–hypopnea index (AHI) quartiles (Q1 = patients with AHI < 13.8, Q2 = those with 13.8 ≤ AHI < 28.8, Q3 = those with 28.8 ≤ AHI < 48.1, Q4 = those with AHI ≥ 48.1). Results: The number of PSVCs/hour during sleep differed significantly among the 4 groups, but the number of PSVCs/hour during wakefulness did not. The prevalence of PSVC ≥ 5/hour during sleep was significantly higher in Q4 (21.0%) than the other 3 groups (Q1, 9.0%; Q2, 8.0%; Q3, 6.0%; all p < 0.05 for Q4), but the prevalence of PSVC ≥ 5/hour during wakefulness did not differ among the 4 groups. A multivariate logistic regression analysis showed that the highest AHI quartile was significantly associated with PSVC ≥ 5/hour during sleep (odds ratio 3.04, 95% confidence interval 1.44–6.42, p = 0.004). Conclusions: Severe OSA can cause PSVCs during sleep, but its effect appears not to be strong. Further studies are needed to clarify the clinical significance of this small but significant increase in PSVCs during sleep in severe OSA patients. © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Introduction Much attention has been recently paid to the association between sleep-disordered breathing and cardiovascular diseases including hypertension, arrhythmias, coronary artery disease, aortic dissection, congestive heart failure, pulmonary hypertension, and strokes [1–3]. Obstructive sleep apnea (OSA), which is a chronic condition characterized by repetitive episodes of upper airway collapse, apnea, and arousal during sleep, is the most frequent sleep-disordered breathing. The association between OSA and premature ventricular contractions has been repeatedly investigated [4–13]. On the other hand, only several investigations have been undertaken about the association between OSA and premature supraventricular contractions (PSVCs) [8–10,12], and the results of these studies are conflicting. It has been demonstrated that an isolated PSVC can trigger atrial fibrillation and
∗ Corresponding author at: Internal Medicine 2, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu 879-5593, Japan. Tel.: +81 097 586 5804; fax: +81 097 549 4245. E-mail address: [email protected] (A. Tamura).
supraventricular tachycardia [14,15] and that frequent PSVCs are associated with increased risks for stroke or death as well as atrial fibrillation [16,17]. Therefore, it is clinically important to clarify whether OSA can contribute to the occurrence of PSVCs. In this study, we prospectively examined the association between OSA severity and PSVCs during wakefulness as well as sleep in patients who were clinically suspected of having OSA.
Methods Subjects A total of 431 patients (336 males and 95 females, median age 56 years) who were clinically suspected of having OSA (severe snoring, daytime sleepiness, and witnessed apnea) and who met the inclusion criteria were prospectively enrolled into this study. All patients underwent full polysomnography together with 24-hour Holter electrocardiography. The inclusion criteria were aged ≥ 20 years, absence of chronic atrial fibrillation/flutter, no use of antiarrhythmic agents, no signs or symptoms of congestive heart failure, no pacemaker implantation and no treatment of OSA with oral
0914-5087/$ – see front matter © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jjcc.2013.07.003
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appliance, continuous positive airway pressure, bi-level positive airway pressure, or adaptive servo-ventilation. Patients with dominantly central sleep apnea (n = 2) and the occurrence of atrial fibrillation on the 24-hour Holter electrocardiogram (n = 2) were excluded. The study protocol was approved by the ethics committee of Oita University Hospital, and informed consent was obtained from each patient before the study.
regression analyses were performed to determine variables associated with PSVC ≥ 5/hour during sleep. A value of p < 0.05 was considered to be statistically significant. Statistical analyses were performed using IBM SPSS Statistics 20 (International Business Machines, New York, NY, USA).
Polysomnography
Of 431 patients, 385 (89.3%) had an AHI ≥ 5. The 431 patients were classified into 4 groups according to the AHI quartiles (Q1 = 107 patients with AHI < 13.8; Q2 = 108 with 13.8 ≤ AHI < 28.8; Q3 = 108 with 28.8 ≤ AHI < 48.1; Q4 = 108 with AHI ≥ 48.1). The patient characteristics are shown in Table 1. Age, body mass index, and the prevalences of male gender, hypertension, diabetes mellitus, calcium antagonist use, and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use differed significantly among the 4 groups. The number of PSVCs/hour during sleep differed significantly among the 4 groups (Q1, 0.4 [0.0–1.2]; Q2, 0.6 [0.2–1.5]; Q3, 0.5 [0.1–1.2]; Q4, 0.9 [0.2–3.1]; p = 0.01), but the number of PSVCs/hour during wakefulness did not (Q1, 0.6 [0.1–1.3]; Q2, 0.6 [0.2–1.6]; Q3, 0.5 [0.2–1.3]; Q4, 0.6 [0.2–2.4]; p = 0.75). The prevalence of PSVC ≥ 5/hour during sleep was significantly higher in Q4 (21.0%) than in the other 3 groups (Q1, 9.0%; Q2, 8.0%; Q3, 6.0%; all p < 0.05 for Q4), but the prevalence of PSVC ≥ 5/hour during wakefulness did not differ significantly among the 4 groups (p = 0.20) (Fig. 1). The number of PSVCs/hour during sleep and that during wakefulness differed significantly among the 4 groups classified by the arousal index (ArI) quartiles (A-Q1 = 107 patients with ArI < 21.2: 0.4 [0.1–0.9]; A-Q2 = 107 with 21.2 ≤ ArI < 31.9: 0.5 [0.1–1.1]; A-Q3 = 109 with 31.9 ≤ ArI < 48.5: 0.6 [0.2–1.6]; AQ4 = 108 with ArI ≥ 48.5: 1.0 [0.2–2.6]; p = 0.001, and A-Q1: 0.4 [0.1–1.2]; A-Q2: 0.6 [0.2–1.3]; A-Q3: 0.7 [0.3–2.0]; A-Q4: 0.7 [0.2–2.1]; p = 0.048, respectively). The prevalence of PSVC ≥ 5/hour during sleep differed significantly among the 4 groups (A-Q1, 6.5%; A-Q2, 4.7%; A-Q3, 11.9%; A-Q4, 17.6%; p < 0.01), and the prevalence of PSVC ≥ 5/hour during wakefulness tended to differ among the 4 groups (A-Q1, 7.5%; A-Q2, 3.7%; A-Q3, 11.0%; A-Q4, 13.9%; p = 0.05). The number of PSVCs/hour during sleep and that during wakefulness did not differ significantly among the 4 groups classified by the lowest SpO2 (L-SpO2 ) quartiles (L-Q1 = 100 with L-SpO2 < 77%: 0.5 [0.1–2.1]; L-Q2 = 105 with 77% ≤ L-SpO2 < 83%: 0.5 [0.3–1.5]; LQ3 = 110 with 83% ≤ L-SpO2 < 88%: 0.6 [0.2–1.6]; L-Q4 = 116 with L-SpO2 ≥ 88%: 0.4 [0.1–1.5]; p = 0.11, and L-Q1: 0.4 [0.1–1.8]; LQ2: 0.6 [0.2–1.6]; L-Q3: 0.7 [0.3–1.7]; L-Q4: 0.6 [0.1–1.3]; p = 0.30, respectively). The prevalence of PSVC ≥ 5/hour during sleep tended to differ among the 4 groups (L-Q1, 16.0%; L-Q2, 11.4%; L-Q3, 5.5%; L-Q4, 8.6%, p = 0.08), but the prevalence of PSVC ≥ 5/hour during
Polysomnography was performed using a computerized recording system (E-series, Compumedics, Abbotsford, Australia). This investigation consisted of monitoring of the electroencephalogram, electrooculogram, submental and limb electromyograms, electrocardiogram, thoraco-abdominal excursions by a piezo belt, oronasal airflow by a nasal pressure transducer and an oronasal thermistor, and the arterial oxyhemoglobin saturation by transcutaneous pulse oximetry. An obstructive apnea event was defined as the absence of oronasal airflow for ≥10 seconds associated with continued or increased inspiratory effort. A central apnea was defined as the absence of oronasal airflow for ≥10 seconds associated with an absent inspiratory effort. A hypopnea was defined as a ≥50% reduction in oronasal airflow for ≥10 seconds, associated with a ≥3% fall in arterial oxyhemoglobin saturation or an arousal. The apnea–hypopnea index (AHI) was calculated as the mean number of apneas and hypopneas per hour of sleep. 24-Hour Holter electrocardiography Together with overnight polysomnography, 24-hour Holter electrocardiography was performed using a digital recorder with 3 channels (RAC-3103, Nihon Koden, Tokyo, Japan). Polysomnography and 24-hour Holter electrocardiography were time-synchronized. The presence or absence of PSVC ≥ 5/hour during wakefulness as well as sleep was assessed. This PSVC cut-off value has been used in previous studies investigating the association between OSA and PSVCs [8,10,12]. The mean numbers of PSVCs/hour during wakefulness as well as sleep was also calculated. Based on the electro-encephalogram, the sleep period was defined as the period from the starting of sleep to the end of sleep. Statistical analysis Continuous data are expressed as the median (first-third quartiles). The Kruskal–Wallis test with the Scheffe’s post hoc test was used for comparisons of continuous data among 4 groups. Comparisons of categorical variables were analyzed by the Fisher’s exact test or chi-square test. The univariate and multivariate logistic
Results
Table 1 Patient characteristics and polysomnographic data. Variables
Q1 (n = 107)
Q2 (n = 108)
Q3 (n = 108)
Q4 (n = 108)
p-Value
Age (years) Male gender Body mass index (kg/m2 ) Hypertension Dyslipidemia Diabetes Current smoker Coronary artery disease AHI Calcium antagonists ACEIs/ARBs Beta-blockers
56.0 (41.0–64.0) 64 (59.8%) 23.3 (21.5–25.8) 53 (49.5%) 64 (59.8%) 14 (13.1%) 22 (20.6%) 19 (17.8%) 6.0 (2.8–9.3) 30 (28.0%) 27 (25.2%) 14 (13.1%)
62.0 (51.0–70.0) 84 (77.8%) 24.4 (22.7–26.7) 73 (67.6%) 70 (64.8%) 25 (23.1%) 24 (22.2%) 22 (20.4%) 20.9 (17.5–23.9) 49 (45.4%) 43 (38.9%) 14 (13.0%)
62.0 (50.3–70.0) 92 (85.2%) 25.5 (23.6–28.7) 76 (70.4%) 78 (72.2%) 33 (30.6%) 17 (15.7%) 16 (14.8%) 36.5 (31.6–42.1) 49 (45.4%) 50 (46.3%) 14 (13.0%)
54.0 (44.0–66.8) 96 (88.9%) 28.4 (25.3–32.7) 74 (68.5%) 79 (73.1%) 33 (30.6%) 23 (21.3%) 8 (7.4%) 65.3 (58.4–81.9) 52 (48.1%) 43 (39.8%) 16 (14.8%)
<0.001 <0.001 <0.001 0.004 0.11 0.01 0.65 0.05 <0.001 0.01 0.01 0.97
Values are presented as the median (first–third quartiles). Q1 = patients with AHI < 13.8; Q2 = those with 13.8 ≤ AHI < 28.8; Q3: those with 28.8 ≤ AHI < 48.1; Q4: those with AHI ≥ 48.1. AHI, apnea–hypopnea index; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.
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Fig. 1. Prevalence of premature supraventricular contractions ≥ 5/hour during wakefulness and that during sleep among 4 groups classified by the AHI quartiles. Q1 = patients with AHI < 13.8; Q2 = those with 13.8 ≤ AHI < 28.8; Q3 = those with 28.8 ≤ AHI < 48.1; Q4: those with AHI ≥ 48.1. *p < 0.05 vs Q4. AHI, apnea–hypopnea index.
wakefulness did not differ significantly among the 4 groups (L-Q1, 9.0%; L-Q2, 13.3%; L-Q3, 6.4%; L-Q4, 7.8%; p = 0.32). A univariate logistic regression analysis showed that the highest AHI quartile was significantly associated with PSVC ≥ 5/hour during sleep (odds ratio 3.15, 95% confidence interval 1.66–5.96, p < 0.001) (Table 2). When we performed a multivariate logistic regression analysis (forward selection method) including age, male gender, body mass index, hypertension, diabetes mellitus, current smoking, coronary artery disease, the highest AHI quartile, renin–angiotensin system inhibitor (angiotensin-enzyme inhibitor or angiotensin receptor blocker) use and beta-blocker use as explanatory variables, the highest AHI quartile was significantly associated with PSVC ≥ 5/hour during sleep (odds ratio 3.04, 95% confidence interval 1.44–6.42, p = 0.004) (Table 2). Discussion There are 3 large-population studies to investigate the association between sleep-disordered breathing or OSA and PSVCs [8,10,12]. The Sleep Heart Health Study showed that PSVC ≥ 5/hour during sleep was more common in 228 subjects with sleepdisordered breathing [respiratory disturbance index (the mean number of apneas and hypopneas per hour of sleep assessed by portable monitoring) ≥ 30] than in 338 without sleep-disordered breathing (respiratory disturbance index < 5) (33.8% vs 24.3%, p = 0.001) [8]. However, that study did not analyze whether sleepdisordered breathing was independently associated with PSVCs during sleep. In addition, it did not examine the association between sleep-disordered breathing and PSVCs during wakefulness. In the MrOS study involving 2911 men aged ≥65 years, the prevalence of PSVC ≥ 5/hour during sleep did not differ significantly among the 4 groups classified by the quartiles of respiratory disturbance index [10]. However, that study included only men
aged ≥65 years, and subjects with central sleep apnea were also included. In a study involving 486 middle-aged (30–65 years) subjects, Namtvedt et al. did not find significant differences in the prevalences of PSVC ≥ 5/hour during daytime as well as nighttime between subjects with OSA (AHI ≥ 5) and those without it (41.7% vs 48.4% and 49.4% vs 49.8%, respectively) [12]. However, in that study, OSA was defined as AHI ≥ 5, and only 14.8% of the subjects had severe OSA (AHI ≥ 30). In addition, the definitions of daytime and nighttime were not described. Thus, the exact association between OSA severity and PSVCs during wakefulness as well as sleep has not yet been established. In the present study, the prevalence of PSVC ≥ 5/hour during sleep was significantly higher in patients with the highest AHI quartile than in the other 3 groups of patients, and the number of PSVCs/hour during sleep differed significantly among the 4 groups. Furthermore, the univariate logistic regression analysis showed that the highest AHI quartile was significantly associated with PSVC ≥ 5/hour during sleep, and the multivariate logistic regression analysis selected the highest AHI quartile as the only independent variable associated with PSVC ≥ 5/hour during sleep. These results suggest that OSA can contribute to the occurrence of PSVCs during sleep and that there may be a threshold effect on the association between OSA severity and the occurrence of PSVCs during sleep. On the other hand, the prevalence of PSVCs during wakefulness and the number of PSVCs/hour during wakefulness did not differ significantly among the 4 groups classified by the AHI quartiles. However, since the prevalence of PSVC ≥ 5/hour during wakefulness tended to be higher in patients with the highest AHI, the association between OSA severity and PSVCs during wakefulness awaits further investigation. In the present study, the number of PSVCs/hour during sleep was only 0.9 (0.2–3.1) in patients with the highest AHI quartile. This result suggests that the effect of OSA on the occurrence of
Table 2 Univariate and multivariate logistic regression analyses to determine variables associated with PSVC ≥ 5/hour during sleep. Variables
Age (years) Male gender Body mass index (kg/m2 ) Hypertension Diabetes Current smoker Coronary artery disease Highest AHI quartile ACEIs/ARBs Beta-blockers
Univariate
Stepwise multivariate
Odds ratio (95% confidence interval)
p-Value
1.00 (0.98–1.03) 1.11 (0.51–2.40) 1.03 (0.97–1.09) 1.23 (0.63–2.39) 1.19 (0.59–2.40) 0.73 (0.32–1.71) 1.07 (0.46–2.52) 3.15 (1.66–5.96) 0.84 (0.44–1.63) 1.25 (0.53–2.95)
0.77 0.79 0.38 0.55 0.64 0.47 0.87 <0.001 0.61 0.62
Odds ratio (95% confidence interval)
p-Value
3.04 (1.44–6.42)
0.004
PSVC, premature supraventricular contraction; AHI, apnea–hypopnea index; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.
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PSVCs during sleep is not strong. It is unclear whether such low frequency PSVCs during sleep have any clinical significance in patients with OSA. However, considering that an isolated PSVC can trigger atrial fibrillation [14,15] and that nocturnal atrial fibrillation is more common in OSA patients than in non-OSA subjects [8,11], the occurrence of PSVCs during sleep might contribute to the future occurrence of nocturnal atrial fibrillation in patients with OSA. Further studies are therefore needed to clarify the association between the presence or number of PSVCs during sleep and future nocturnal atrial fibrillation in patients with OSA. The possible mechanisms by which OSA causes PSVCs are as follows. First, OSA-related hypoxia, hypercapnia, loss of lung inflation, and arousal can all activate the sympathetic nervous system, which can cause PSVCs through abnormal automaticity and triggered activity based on the increase of the intracellular Ca2+ concentration [18]. Also, sympathetic nervous activation shortens the duration of the action potential by the increase of delayed rectifier K+ current [19,20], which can lead to a shortening of the effective refractory period and thereby the occurrence of PSVCs. Second, excessively negative intrathoracic pressure against the occluded upper airway during an obstructive event stretches the atrial muscle and the pulmonary vein, leading to the occurrence of PSVCs though the activation of the L-type Ca2+ channel and the transient receptor potential channels and a resultant increase in the intracellular Ca2+ concentration [21–23]. The present study has several limitations. First, the study included a selected cohort of patients who were clinically suspected of having OSA. Therefore, the findings of the present study may not be applicable to a general population with OSA. Second, the present study excluded patients with antiarrhythmic agent use or the occurrence of atrial fibrillation/flutter at baseline or on the 24-hour Holter electrocardiogram, who would potentially have a larger number of PSVCs than those without it. Therefore, a positive association between OSA and PSVCs during sleep indicated by the present study might have been underestimated. Third, 24-hour Holter electrocardiographic findings may not accurately reflect the actual severity of PSVCs, because there is day-to-day variability in the frequency of PSVCs. Fourth, we did not analyze the association between timing of the occurrence of PSVCs and OSA events. The clarification of this association would provide important information about the cause–effect relationship between OSA and PSVCs during sleep. In conclusion, severe OSA can cause PSVCs during sleep, but its effect appears not to be strong. Further studies are needed to clarify the clinical significance of this small but significant increase in PSVCs during sleep in severe OSA patients. Conflict of interest
[2]
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[9]
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None declared. [21]
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