QJM Advance Access originally published online on July 22, 2006
QJM 2006 99(8):545-553; doi:10.1093/qjmed/hcl074
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Effect of nCPAP therapy on heart rate in patients with obstructive sleep apnoea-hypopnoea
From the 1Department of Respiratory Medicine, Kyoto University Graduate School of Medicine, and2Department of Physical Therapeutics, Kyoto University Hospital of Medicine, Kyoto, Japan
Address correspondence to Dr K. Chin, Department of Physical Therapeutics, Kyoto University Hospital of Medicine, 54 Shogoin Kawahara-cho, Sakyo-Ku, 606-8507 Kyoto, Japan. email: chink{at}kuhp.kyoto-u.ac.jp
Received 2 February 2006 and in revised form 5 May 2006
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Background: Elevated heart rate (HR) is a risk factor for cardiovascular disease. The effects of obstructive sleep apnoea-hypopnoea syndrome (OSAHS) on HR are controversial.
Aim: To investigate the effect of nasal continuous positive airway pressure (nCPAP) therapy on HR in OSAHS patients.
Methods: Sixty-two OSAHS patients underwent 24-h electrocardiographic recording, both before and 3 or 4 days after instigation of nCPAP.
Results: After nCPAP was started, HR significantly decreased (mean ± SD 71.8 ± 10.6 vs. 67.5 ± 9.4 bpm, p < 0.0001), both in the daytime (0600–2200 h, 76.3 ± 12.2 vs. 72.2 ± 10.2 bpm, p < 0.0001) and at night-time (2200–0600 h, 64.5 ± 9.1 vs. 60.0 ± 8.9 bpm, p < 0.0001). HR was significantly reduced in both periods in the 44 patients with hypertension and/or diabetes mellitus, but only during the night-time in the 18 with neither condition. Before nCPAP treatment, HR was positively correlated with percentage time of arterial O2 saturation <90% during sleep (p = 0.008) and with the apnoea-hypopnoea index during sleep (p = 0.003). In 15 patients undergoing HR for 2 days before starting nCPAP, the mean HRs for the two periods were similar (p = 0.95).
Discussion: nCPAP therapy appears to decrease HR in OSAHS patients, and may thereby reduce their risk of cardiovascular disease.
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Introduction |
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Approximately 9% of women and 24% of men have >5 episodes of obstructive sleep apnoea and hypopnoea per hour, and approximately 4% of women and 9% of men have >15 episodes per hour.1 Obstructive sleep apnoea (OSA) is an independent risk factor for systemic hypertension, and may be a risk factor for myocardial infarction and stroke.2 Nasal continuous positive airway pressure (nCPAP) therapy in patients with OSA reduced their blood pressure, the frequency of arrhythmia, and the risk of cardiovascular events.2–6
Elevated heart rate is an important risk factor for cardiovascular disease.7 In several large-scale cohort studies, such as the CASTEL and Framingham studies, individuals with an elevated heart rate had a poorer cardiovascular prognosis.8–11 There have been several reports on the results of spectral analysis of RR interval variability in OSA patients,12,13 but few on the heart rate of OSA patients. The results on the effect of nCPAP therapy on the heart rate of OSA patients are controversial, because there are characteristic patterns of bradycardia and tachycardia during sleep in OSA patients.5,12,14–16 It is thus uncertain whether nCPAP therapy changes the heart rate of OSA patients throughout the day. Recently, Ziegler et al.17 reported that CPAP treatment lowered the daytime heart rate in OSA patients (p < 0.05), but not the night-time heart rate. However, the number of patients in their study was small (20 patients vs. 18 controls), and they did not analyse the effect of CPAP treatment on the heart rate of OSA patients with clinical conditions such as hypertension and diabetes mellitus.17 In addition, they measured the heart rate every 15 or 30 min. To investigate the effect of OSA with hypoxaemia, we measured the heart rate in obstructive sleep apnoea-hypopnoea syndrome (OSAHS) patients throughout the day before and after nCPAP treatment.
Adiponectin is a recently discovered 247-amino-acid peptide,18 whose plasma adiponectin concentration is reportedly lower in patients with cardiovascular disease than in normal subjects,19 and significantly negatively correlated with heart rate.20 To elucidate the risk of OSA patients for cardiovascular disease, it is important to investigate the change in heart rate over 24 h. In addition, it seems clinically easier to understand the effect of nCPAP therapy on heart rate rather than on frequency ratio. We hypothesized that obstructive sleep apnoea with hypoxaemia has a significant effect on the heart rate of patients throughout the day, and that nCPAP therapy improves the heart rate. To test the hypothesis, we measured the heart rate in OSAHS patients throughout the day before and the day after nCPAP treatment. We also measured the plasma adiponectin concentration in these patients, to investigate the relationship between plasma adiponectin and heart rate.
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Methods |
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Subjects
We studied 62 patients with OSAHS who were candidates for nCPAP therapy6 (60 male, 2 female). Their mean ± SD age was 53.5 ± 12.1 years, mean ± SD apnoea-hypopnoea index (AHI) was 48.3 ± 15.7 events/h, and mean ± SD body mass index (BMI) was 27.7 ± 4.1 kg/m2. Subjects were selected from a group of 69 consecutive OSA patients who had completed a sleep study and Holter monitoring. Seven patients were excluded from the study because of insufficient polysomnograph or Holter monitor data (e.g. an electrode had been off). The two women were both post-menopausal. The diagnosis of the obstructive sleep apnoea-hypopnoea syndrome (OSAHS) was established based on clinical symptoms and an AHI of >5 events/h on polysomnography.21,22 In Japan, an AHI of >20 events/h is used as a selection criterion for nCPAP treatment.
Mean ± SD ejection fraction (determined by the Teichholz method on two-dimensional echocardiography) was 69.0 ± 7.6% (range 55.0–82.8%). None of the 62 patients showed signs of congestive heart failure.
Of the 62 patients, 38 had hypertension, and 13 had diabetes mellitus. The medications that the patients were taking for hypertension are summarized in Table 1. The drug regimens of the patients were not changed during the interval from 1 month before the first polysomnography recording to after completion of the second polysomnography recording.
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To investigate the possibility of significant changes in heart rate between the two Holter ECG measurements, 15 patients were randomly selected from the 62. These 15 patients underwent Holter monitor recording for 2 days before nCPAP therapy was started. Their age, AHI, body mass index, and anti-hypertensive drug medications did not significantly differ from the respective values for the whole group of 62 before nCPAP therapy was started (Table 1). In addition, the age, AHI, and body mass index of the 15 patients did not differ significantly from the respective values for the remaining 47 patients.
The study was approved by the medical ethics committee of our hospital, and all patients provided informed consent.
Polysomnography
Polysomnography was done before nCPAP therapy, and then again on the first night of nCPAP therapy. The interval between the two polysomnographic recordings was one week. Both nCPAP therapy and second polysomnography were started at 2200 h, and finished at 0600 h. Blood pressure was measured, and a blood sample obtained, at 0700 h. The blood sample was obtained immediately after blood pressure measurement. Polysomnography was done using standard methods.23 The total sleep time, AHI, lowest arterial O2 saturation, and percentage time of arterial O2 saturation <90% during sleep were calculated in each patient.
Measurement of heart rate and other parameters, and nCPAP treatment
Electrocardiographic recording using a Holter monitor over an approximately 24-h (24.1 ± 1.3 h) period was done in all 62 patients before nCPAP therapy was started and 3 or 4 days after nCPAP therapy was started. In each patient, the interval between the two Holter monitor recordings was one week. In all patients, polysomnography was performed on a Monday and Holter monitor recording was performed on the following Wednesday or Thursday, both before and after nCPAP therapy was started. After the first polysomnography, the patient remained in the hospital until completion of the first Holter monitor recording, after which they returned home. On the following Monday, the patient came to our hospital for the first night of nCPAP therapy and the second polysomnographic recording. The patient remained in the hospital until after the second Holter monitor recording, which was on a Wednesday or Thursday with nCPAP therapy. The 15 control OSA patients from among the 62 patients underwent Holter monitor recording for two consecutive days instead of for one day.
Preliminary education or habituation for nCPAP therapy was performed for approximately 30 min in the daytime before the first night of nCPAP treatment. Manual CPAP titrations were performed throughout the night for OSAHS patients on the first night of nCPAP therapy. The mean pressure of nasal CPAP therapy was 9.6 ± 2.7 cm H2O. All of the patients tolerated nCPAP treatment well during the study. We measured blood pressure in the supine position, before and after each polysomnography, in the morning and in the evening.
Diabetes mellitus and heart rate are known to be closely related. Eight patients had already been diagnosed with diabetes mellitus at another hospital. A 75 g oral glucose tolerance test (OGTT) was administered to the remaining 54 patients before nCPAP treatment. A patient was defined as having diabetes if their plasma glucose concentration 2 h after glucose load was 
200 mg/dl, or if their fasting plasma glucose concentration was 126 mg/dl.24
Determination of plasma adiponectin
We measured plasma adiponectin level before nCPAP therapy was started in the 19 patients most recently enrolled in the study, using a commercially available enzyme-linked immunosorbent assay kit (Otsuka Pharmaceuticals, Tokyo, Japan). The intra- and inter-assay coefficients of variation were 4.06% and 4.69%, respectively.
Data analysis
We analysed the electrocardiographic data and calculated the mean heart rate during each one-hour interval (expressed as bpm). Then, we compared the heart rate before nCPAP therapy was started and the heart rate after nCPAP therapy was started. Data were expressed as means ± SD. Data were analysed by a non-parametric method. The heart rates during each 1-h interval were compared between the first and second Holter monitor recordings using Wilcoxon signed rank test. Comparisons of heart rate and other parameters between the whole group of 62 patients and the control subgroup of 15 used the Mann-Whitney U test and the 
2 test. Statistical analyses used StatView software for Windows (Version 5.0; Abacus Concepts). A p value <0.05 was considered significant.
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Effects of nCPAP on sleep apnoea
Polysomnography was performed before nCPAP therapy was started and again on the first night of nCPAP therapy. In the 62 patients with OSAHS, nCPAP therapy reversed the sleep apnoea, with improvements (before vs. after) in AHI (48.3 ± 15.7 vs. 3.6 ± 4.6 events/h, p < 0.0001), mean arterial O2 saturation (94.8% ± 2.1% vs. 96.5% ± 1.4%, p < 0.0001), lowest arterial O2 saturation (67.7% ± 13.2% vs. 85.7% ± 10.0%, p < 0.0001), and percentage time of arterial O2 saturation <90% (24.2% ± 17.7% vs. 0.7% ± 1.7%, p < 0.0001).
Heart rate before and after nCPAP
Holter monitor recording was done before nCPAP therapy was started and again 3 or 4 days after nCPAP therapy was started. nCPAP therapy significantly reduced mean heart rate over the 24-h interval (from 1300 h to 1300 h the following day) (71.8 ± 10.6 vs. 67.5 ± 9.4 bpm, n = 62, p < 0.0001) (Figure 1a).
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We also compared heart rates before and after nCPAP therapy for the daytime (0600 h to 2200 h) and in the night-time (2200 h to 0600 h). Both were significantly reduced (daytime 76.3 ± 12.2 vs. 72.2 ± 10.2 bpm, n = 62, p < 0.0001; night-time 64.5 ± 9.1 vs. 60.0 ± 8.9 bpm, n = 62, p < 0.0001) (Table 2). However, there was no significant difference in heart rate before and after nCPAP treatment (66.4 ± 9.3 vs. 65.8 ± 10.7 bpm, p = 0.65) among the 10 OSAHS patients who were receiving a beta-blocker.
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nCPAP therapy reduced heart rate over the 24-h interval in 50 of the 62 patients (Figure 1a). Figure 2a shows the heart rate for each 1-h interval after nCPAP therapy was started, compared with during the respective interval before nCPAP therapy. In the 62 patients, nCPAP therapy did not significantly affect time of waking, nor the time of going to bed.
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p < 0.01, 
p < 0.001.Heart rate and the severity of OSAHS
In the 62 patients, before nCPAP therapy, heart rate over the 24-h period (beats/min) was positively correlated with AHI during sleep (r = 0.38, p = 0.003). It was also positively correlated with the percentage time of arterial O2 saturation <90% during sleep (r = 0.34, p = 0.008). The degree of the reduction in heart rate after nCPAP therapy was positively correlated with the degree of the decrease in AHI during sleep (r = 0.32, p = 0.015). It was also positively correlated with the degree of the decrease in percentage time of arterial O2 saturation <90% during sleep (r = 0.56, p < 0.0001).
Among the 15 patients whose heart rate was measured for 2 days before nCPAP treatment, heart rates did not differ significantly between the first (1300 h to 1300 h the next day) and the second 24-h interval (69.3 ± 10.8 vs. 69.7 ± 10.4 bpm, p = 0.95) (Figures 1b and 2b). This result was unaltered (70.5 ± 10.8 vs. 70.8 ± 10.2 bpm, p = 0.81) if the two patients (of the 15) who were receiving a beta-blocker were excluded from the analysis.
Heart rate response to nCPAP according to clinical condition
Table 2 shows heart rates before and after nCPAP therapy was started, according to clinical condition (with or without diabetes mellitus or hypertension), during the daytime, night-time, and throughout the day.
Blood pressure and arrhythmia
Blood pressure was measured before and after each polysomnography, in the morning (0700 h) and evening (2100 h). The two evening measurements did not differ significantly (118 ± 9/80 ± 8 vs. 117 ± 12/77 ± 9 mmHg). However, the morning measurement after nCPAP therapy was started was significantly lower than that before nCPAP therapy was started (Table 3).
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Ventricular premature contraction (VPC), and supraventricular premature contraction (SVPC) after nCPAP therapy did not significantly differ from the respective parameters before nCPAP therapy was started (Table 3).
Heart rate and plasma adiponectin level
Adiponectin levels were determined for the last 19 patients enrolled. Plasma adiponectin was negatively correlated with heart rate (over 24 h) before nCPAP therapy was started (r = –0.51, p = 0.032) (Figure 3), but not correlated with AHI nor with the percentage time of arterial O2 saturation <90% during sleep. There was no significant difference in plasma adiponectin level before nCPAP therapy and that after 3 or 4 days of nCPAP therapy (5.78 ± 4.78 vs. 5.33 ± 4.18 mg/l, p = 0.09). There was also no significant difference between the degree of the change in heart rate and the degree of the change in plasma adiponectin level, before and 3 days after nCPAP therapy was started (r = 0.24, p = 0.32). Of the 19 patients in whom the adiponectin level was measured, only one was receiving a beta-blocker. Among the remaining 18 patients, there remained a significant correlation between heart rate and plasma adiponectin level (p = 0.016, r = –0.58).
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Discussion |
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In our patients with OSAHS, AHI and percentage time of arterial O2 saturation <90% during sleep were significantly correlated with heart rate throughout the day, and the improvements in AHI and desaturation during sleep resulting from nCPAP therapy significantly reduced the heart rate. There was also a significant relationship between heart rate and plasma adiponectin level before nCPAP therapy.
Spectral analysis of heart rate variability is frequently used as a non-invasive means of assessing cardiac autonomic function,25,26 with the power of the high-frequency band (0.15–0.4 Hz) widely accepted as a measure of parasympathetic activity.25 The ratio of low-frequency (0.04 to 0.15 Hz) power to high-frequency power (LHR) has been suggested by some researchers to represent sympathetic modulation of heart rate.26 Several studies have reported the results of spectral analysis of RR interval variability in OSAHS patients, which showed an increase in low frequency power, a decrease in high frequency power and an increase in the ratio of low to high frequency power, compared with the respective values in normal controls.12,13,27 However, there have only been a few reports on the heart rate of OSAHS patients.
Many previous studies have reported no difference in the heart rate between patients with OSAHS and normal controls, and no difference in the heart rate among sleep apnoea patients before and with nCPAP treatment.12,14 These results may have been obtained due to the characteristic pattern of bradycardia and tachycardia during sleep in sleep apnoea patients. In addition, the time interval over which the heart rate was recorded in previous studies was relatively short. It was reported that in OSAHS patients with overt congestive heart failure, nCPAP therapy significantly reduced the heart rate at one point in the morning.16 In this study, AHI with hypoxaemia had a significant effect on the heart rate of the OSAHS patients without heart failure throughout a day. In a previous study, nCPAP therapy reduced the blood pressure not only during sleep, but also while the OSAHS patient was awake.3,28 As to the mechanism by which nCPAP therapy reduces blood pressure, it has been proposed that hypoxaemia in addition to OSA during sleep may contribute to elevation of the blood pressure during waking hours.29,30 Somers et al.31,32 suggested that OSAHS patients have high sympathetic nerve activity, which may also contribute to elevation of heart rate in OSAHS patients.
Measuring the heart rate every 15 or 30 min, Ziegler et al.17 reported that nCPAP treatment lowered daytime heart rate (p < 0.05) and that this effect differed significantly from that of placebo CPAP; nCPAP treatment also lowered the night-time heart rate but not significantly differently from placebo.17 In their report, the placebo nCPAP treatment was associated with a 23% drop in respiratory disturbance index (RDI), which may have affected the decrease in night-time heart rate. Based on the results of the present study, hypoxaemia with AHI during sleep may contribute to elevation of the heart rate of OSAHS patients, not only during sleep but also during waking hours.
In this study, nCPAP therapy significantly reduced the mean heart rate throughout the day, regardless of the presence of diabetes mellitus or hypertension (Table 2), suggesting a possible improvement cardiovascular prognosis. In the OSAHS patients who had neither diabetes mellitus nor hypertension, there was no significant difference in daytime heart rates before and after nCPAP therapy (Table 2). Thus although our results may have been affected by the small number of subjects, nCPAP therapy may reduce the daytime heart rate to a greater extent in OSAHS patients with cardiovascular risk factors than in those without. Recently, Gami et al. studied cases of sudden death from cardiac causes and the time of death, and reported that people with obstructive sleep apnoea showed a peak in sudden death from cardiac causes during sleeping hours.33 Since elevated heart rate is an important risk factor for cardiovascular diseases, our report supports their findings that OSAHS patients are more likely to die due to cardiovascular disease while they are asleep.
It was recently reported that young men with high-normal blood pressure have a faster heart rate and lower serum adiponectin level than young men with normal blood pressure.20 In addition, hypoadiponectinaemia may be associated with cardiovascular disease in humans.19 In the present study, OSAHS patients with a higher heart rate also had a lower plasma adiponectin level, suggesting that adiponectin level might also regulate heart rate, in addition to AHI and hypoxaemia. A high heart rate combined with low adiponectin level might be a poor prognostic factor in OSAHS patients.34 Because of the small number of patients in this study, further studies are warranted on plasma adiponectin levels and heart rate of OSAHS patients over a long period of time after nCPAP therapy is started.
The total number of heart beats was measured during a 24-h interval, 3 to 4 days after nCPAP therapy was started. We had ascertained that the nCPAP mask was fitted properly on the patient more than twice during the night of the second Holter monitor recording. All patients had returned to their homes after the first polysomnography and Holter monitor recording, and after 2 or 3 days they came to our hospital for the second polysomnography and Holter monitor recording; in each patient, the number of days between the first polysomnography and the start of the first Holter monitor recording, and the number of days between the second polysomnography and the second Holter monitor recording were the same. Therefore, it seems likely that length of stay in the hospital prior to the start of Holter monitor recording did not affect the heart rate trends in this study. Although various pharmacological agents can affect the heart rate, the OSAHS patients in this study were receiving the same medical regimen, which consisted of antihypertensive agents in 34 patients and oral drugs for diabetes in five, beginning 1 month before the start of this study and throughout the study. Taking these drugs thus seems unlikely to affect the nCPAP therapy-induced changes in heart rate in this study.
We could not perform a randomized control trial by offering sham CPAP treatment. All patients in Japan are under the government insurance system, making it difficult for us to administer sham CPAP treatment to severe OSA patients in this trial. To minimize this limitation and to investigate the possibility of significant changes in heart rates between Holter ECG measurements before nCPAP treatment, we measured Holter ECG over two days for 15 of the 62 patients before nCPAP was started. These 15 were matched in age, BMI, AHI and anti-hypertensive medications to the overall group of 62 patients, and also matched to the remaining 47. The difference in heart rates between two measurements in the 15 patients was small.
Although this study has limitations, it suggests that OSAHS patients have an elevated heart rate and low plasma adiponectin before treatment, and that nCPAP therapy significantly reduces daytime heart rate in these patients. This implies that nCPAP therapy reduces the risk of patients with OSAHS for cardiovascular disease by lowering the heart rate, especially in those with hypertension or diabetes mellitus.
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This work was supported by a Grant-in-Aid for the Respiratory Failure Research Group of the Japanese Ministry of Health, Labour and Welfare, and Japan Vascular Disease Research Foundation. We are grateful to Tomoko Toki for assistance with the manuscript preparation.
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References |
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