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Respiratory Medicine (2014) xx, 1e7
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/rmed
Nocturnal snoring decreases daytime baroreceptor sensitivity ¨bel a,b, Ingo Fietze a, Martin Glos a, Christoph Scho Inett Schary a, Alexander Blau a, Gert Baumann b, Thomas Penzel a,* a b
Sleep Medicine Center, Charite´ Universita¨tsmedizin Berlin, Berlin, Germany Center for Cardiology and Angiology, Charite´ Universita¨tsmedizin Berlin, Berlin, Germany
Received 29 December 2013; accepted 24 March 2014
KEYWORDS Snoring; Sleep disordered breathing; Baroreceptor sensitivity; Heart rate variability; Cardiovascular risk
Summary Background: In patients with obstructive sleep apnea heart rate variability and baroreceptor sensitivity during night and daytime are impaired. Snoring without obstructive sleep apnea may already influence heart rate variability and baroreceptor sensitivity during daytime. Methods: Cardiovascular daytime testing was performed in 11 snorers and age, BMI, and gender matched controls. Sleep apnea and snoring were quantified by sleep recordings. Paced breathing was performed during daytime with ECG, non-invasive blood pressure, and respiration recorded. Heart rate variability and blood pressure variability were analyzed in the time and frequency domain. Baroreceptor sensitivity (alpha gain) was calculated. Results: In snorers a significant increase in high frequency systolic blood pressure variability (SBPVeHF) compared to control group (0.37 mm Hg2 vs. 0.11 mm Hg2 for 12 breaths and 0.35 mm Hg2 vs. 0.10 mm Hg2 for 15 breaths) was demonstrated. Furthermore a lower baroreceptor sensitivity was found in snorers compared to controls (9.2 ms/mm Hg vs. 16.2 ms/ mm Hg for 12 breaths and 8.5 ms/mm Hg vs. 17.4 ms/mm Hg for 15 breaths per minute) using the paced breathing protocol. Mean heart rate was elevated in snorers as well. Conclusions: Snorers may have a reduced parasympathetic tone during daytime rather than an increased sympathetic tone. ª 2014 Elsevier Ltd. All rights reserved.
* Corresponding author. Charite ´ Universita ¨tsmedizin Berlin, Sleep Medicine Center, Charite ´platz 1, D-10117 Berlin, Germany. Tel.: þ49 30 450513 013; fax: þ49 30 450513906. E-mail address: [email protected] (T. Penzel). http://dx.doi.org/10.1016/j.rmed.2014.03.012 0954-6111/ª 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Scho ¨bel C, et al., Nocturnal snoring decreases daytime baroreceptor sensitivity, Respiratory Medicine (2014), http://dx.doi.org/10.1016/j.rmed.2014.03.012
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C. Scho ¨bel et al.
Introduction
Methods
Sleep related breathing disorders have a high prevalence and are associated with an elevated cardiovascular risk. Sleep apnea patients have an increased cardiovascular morbidity and mortality [1]. Patients have a lower life expectancy and a higher risk for cardiovascular consequences such as stroke, myocardial infarction, and cardiac arrhythmias. The risk to develop arterial hypertension and heart failure is increased [2,3]. The most important pathophysiological mechanisms in sleep disordered breathing are upper airway obstruction, repetitive intermittent hypoxemia, and intrathoracic pressure changes. Many cardiovascular consequences can be related to concomitant changes in autonomic tone. Each apnea event is a cessation of oronasal airflow for at least 10 s duration. Each hypopnea event is a reduction of airflow by at least 50% in amplitude for at least 10 s accompanied by an oxygen desaturation by at least 3% [4]. Sleep apnea severity is specified by the apnea hypopnea index (AHI) which corresponds to the number of apnea and hypopnea events per hour of sleep. Patients with an AHI between 5 and 15 events/hour suffer from mild sleep apnea, between 15 and 30 events/hour from moderate sleep apnea and above 30 events per hour from severe sleep apnea. Large studies proved that patients with moderate and severe sleep apnea have an increased cardiovascular risk [5]. Snoring is regarded as a precursor for sleep disordered breathing. Whether snoring itself with few apnea and hypopnea events (AHI < 5 events/hour) causes an increased cardiovascular risk is not clarified. A large epidemiological study by Marin et al. did not detect an increase in cardiovascular events in snorers compared to controls after 12 years [1]. However studies in animals showed that snoring associated micro vibrations caused micro lesions on the extracranial vessels which increased the risk for local arteriosclerosis [4,6e8]. Mateika et al. showed a reduction in baroreceptor sensitivity (BRS) in snorers with a low AHI and interpreted this as an indication for increased cardiovascular risk [9]. Assessment of autonomous tone can be done directly and indirectly. Direct recordings require microneurographic recording of sympathetic nerve activity on the perineous nerve [10]. This method is painful and not practical in clinical studies. Indirect assessment of autonomic tone is performed using heart rate variability (HRV), blood pressure variability (BPV), and baroreceptor sensitivity (BRS) [10]. Based on HRV a summarizing value, called sympathovagal balance, can be calculated. Sympathetic tone is increased in patients with sleep disordered breathing not only at nighttime but also during daytime [3]. This is reflected by both an impaired HRV and BRS. This can be an indicator for elevated cardiovascular risk [11]. CPAP treatment in patients with obstructive sleep apnea improves sympathovagal balance after three months usage [12]. That sympathovagal balance is affected in snorers had been shown previously [9]. Whether sympathovagal balance is impaired in snorers not only at nighttime [13e15] but also during daytime, similar to obstructive sleep apnea [16] is the focus of this study.
Subjects For the study 14 patients with snoring and without sleep apnea were recruited between February 2004 and July 2005 at the sleep center. Selection criteria were strict and focuses on snoring without sleep apnea. For each snorer a carefully selected healthy control subject was matched for age, BMI and gender. All subjects were investigated for daytime autonomous function using the same experimental protocol. For daytime testing of autonomous functions a customized experimental protocol was used. Because the autonomous nervous system is modulated by many mental and physical factors, a strict and standardized study protocol was conducted in order to standardize these influences. The study was approved by the institutional ethics committee. One patient could not be evaluated due to technical problems with the daytime recording and two other patients resigned from the study without giving reasons. Finally data from 11 patients and 11 matched controls could be used for consequent analysis. The characteristics of the two matched groups of snorers and controls are presented in Table 1. All subjects were recorded with a six-channel portable sleep apnea monitoring device (Embletta, Embla Systems Inc., Broomfield, CO, USA) to evaluate the presence of sleep apnea and to detect sleep related movement disorders (e.g. periodic leg movements during sleep) before daytime testing. The portable sleep monitoring device did record oral airflow, respiratory effort with belt sensors, snoring by an analysis of pressure fluctuations, body position, oxygen saturation and pulse rate. The number of apnea and hypopnea events per hour of estimated sleep (AHI) were evaluated. We used the integrated Embla derived snoring signal by vibration in the nasal cannula as provided by the Somnologica-Software to quantify the time with snoring noise against the total recording time [17]. Subjects completed a clinical investigation, a questionnaire to assess daytime sleepiness (Epworth Sleepiness Scale, ESS), a lung function test to exclude restrictive and obstructive pulmonary disorders, and clinical chemistry of blood to exclude other disorders and drug use. Inclusion criteria were age above 20 years, a BMI lower than 40 kg/ m2, an AHI lower than 5 events per hour, a history of reported snoring and acceptance to participate in the study. Exclusion criteria were misuse of sedating drugs, abuse of
Table 1 Characteristics of the controls and the snorers are presented. There are no significant differences between groups.
Female Male Age [years] BMI [kg/m2] AHI [events/hour]
Controls
Snorers
1 10 41.1 8.5 26.3 3.6 3.18
1 10 43.1 8.7 27.3 3.8 3.45
Please cite this article in press as: Scho ¨bel C, et al., Nocturnal snoring decreases daytime baroreceptor sensitivity, Respiratory Medicine (2014), http://dx.doi.org/10.1016/j.rmed.2014.03.012
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Nocturnal snoring decreases daytime baroreceptor sensitivity alcohol, use of anti-arrhythmic drugs, chronic cardiovascular disorders, pain disorders, acute or chronic inflammatory disorders, thyroid disorders, mental or neurological disorders, disorders which would affect the respiratory system, and other sleep disorders. Eleven healthy control subjects were selected to match in terms of age, gender, and BMI. These subjects were selected from a group of volunteers with undisturbed sleep being recruited for another cohort of healthy sleepers [18]. For the control group all the disorders mentioned above were excluded as well by checking for pathological thresholds. The control group underwent a cardiorespiratory polysomnography in a sleep center in order to exclude all sleep disorders, sleep disordered breathing in particular and presence of snoring as well.
Study protocol Daytime testing of cardiovascular functions in terms of HRV, blood pressure variability (BPV), and BRS took place between 9 and 12 in the morning after the portable sleep testing at home (Embletta, Embla Systems Inc., Broomfield, CO, USA). Subjects were instructed not to use caffeine and vasoactive agents on the morning before the assessment. Testing followed a standardized protocol which proved to be effective in previous investigations [18e20]. Recorded signals were ECG (lead II), nasal airflow with pressure sensors using nasal prongs, ribcage and abdominal respiratory movements with piezo sensors, and non-invasive continuous blood pressure (Portapres). Signals were recorded using a polysomnography recorder (Embla A10, Embla Systems Inc., Broomfield, CO, USA). Subjects were seated with the upper body in 45 resting position. After a test run the protocol was performed in always the same order: six minutes quiet breathing followed by three times 6 min paced breathing at three different paces, 6 then 12 then 15 breaths per minute. At the end of the protocol another 6 min breathing at rest followed. Pacing was performed with a metronome and there were short breaks of two minutes duration between the test sessions. Paced breathing episodes with 6 breaths were not further analyzed because subjects could not maintain this frequency well enough in terms of regularity.
Signal analysis ECG and the blood pressure signal were analyzed using the MATLAB software (The Math-Works Inc., Natick, MA, USA) with previously described algorithms [19e21]. ReR intervals and systolic blood pressure were calculated. Artifacts were removed and episodes with 180 consecutive heart beats were selected. Time series were interpolated using cubic splines, and were re-sampled at 4 Hz. Fast Fourier transform (FFT) was applied to calculate power spectra of HRV and systolic blood pressure variability (SBPV) Low frequency (LF Z 0.04e0.15 Hz) and high frequency (HF Z 0.15e0.4 Hz) spectral bands were integrated for HRV (HRV-LF, HRV-HF) and SBPV (SBPV-LF, SBPV-HF) analysis. In HRV, vagal activity is the main contributor to the HF component for subjects in supine position under controlled respiration without pharmacological or physical
3 interventions. The LF component reflects both sympathetic and vagal autonomic activity [22]. Another important measure of HRV is the root mean square of successive heartbeat interval differences (RMSSD). RMSSD reflects the short-term variation of heart rate and is claimed to be a good surrogate for LF/HF-ratio as marker for sympatho-vagal balance [23]. The spontaneous baroreceptor sensitivity (BRS) is based on the permanent activity of the baroreflex feedback loop integrating spontaneous fluctuations. The BRS was calculated using the squared root of the ratio of HRV and SBPV (so called a-gain). This was performed separately for the LF and HF spectral bands resulting in a-LF and a-HF. Finally, the a index was calculated as the mean of a-LF and a-HF [24]. All BRS values were expressed in ms/mm Hg. The a-LF displayed the gain of the arterial pressureeRR interval relationship in the spectral region not linked to the breathing frequency whilst the a-HF component mirrors the gain in the spectral region of the breathing frequency [25]. The a index presented the average of a-LF and a-HF and provided an evaluation of the overall baroreceptor gain [26]. For statistical analyses SPSS for Windows (version 12.0, SPSS, Chicago, IL) was applied. Result parameters were presented with median, lower and upper quartile to be independent of distribution assumptions. For testing differences between groups (Table 2) ManneWhitney-U-Test was applied for non-parametric variables. Differences were considered significant at a two-tailed p-value of 0.05. Tables 1 and 2 expresses the results as means standard deviation.
Results Both groups were carefully matched and did not differ in terms of age, BMI, and gender. Both groups had no sleep apnea with a confirmed AHI < 5 events/hour of sleep, see Table 1. None of the snorers nor the healthy subjects had arterial hypertension. The mean blood pressure in the snorers was 140/85 mm Hg. Assessing the cardiac autonomic nervous system by quantifying HRV and BPV considered the paced breathing episodes with a pace of 12 and 15 breaths per minute. The results of the comparison are presented in Table 2. With paced breathing at both breathing rates snorers did show an increased heart rate compared to controls (p < 0.05). Heart rate variability measures did not differ between the groups. With respect to blood pressure variability significant differences were observed for the high frequency component of systolic blood pressure variability (SBPVeHF) The other blood pressure variability parameters did not show significant differences between controls and snorers. For baroreceptor sensitivity expressed as alpha gain significant differences were found and shown for a Index (Fig. 1).
Discussion Results showed a significant increase in high frequency blood pressure variability and a significant decrease in baroreceptor sensitivity between healthy volunteers and snorers at the paced breathing tests during daytime. Snorers did show in addition an increased heart rate at paced breathing. Together this may indicate a reduction in
Please cite this article in press as: Scho ¨bel C, et al., Nocturnal snoring decreases daytime baroreceptor sensitivity, Respiratory Medicine (2014), http://dx.doi.org/10.1016/j.rmed.2014.03.012
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C. Scho ¨bel et al. Table 2 Results for heart rate variability, blood pressure variability and baroreceptor sensitivity for the daytime testing during paced breathing. Significant differences were seen for both 12 and 15 breaths per minute for mean RR intervals, SBPV-HF, for aHF, and for a index. Parameter
Controls
Snorers
12/min Mean RR intervals (ms) RMSSD (ms) HRV-LF (ms2) HRV-HF (ms2) Mean SBP (mmHg) SBPV-LF (mm Hg2) SBPV-HF (mm Hg2) Mean DBP (mm Hg) a-LF (ms/mm Hg) a-HF (ms/mm Hg) a index (ms/mm Hg)
948 35.5 23.0 40.2 141.1 0.26 0.11 69.9 10.31 22.16 16.24
15/min 115 14.2 13.0 33.4 17.1 0.13 0.08 8.7 3.7 12.8 7.0
956 39.1 18.2 26.2 136.0 0.31 0.10 69.4 10.13 28.20 17.41
137 21.0 11.1 21.8 19.1 0.21 0.10 9.4 5.1 15.4 8.4
parasympathetic tone in snorers during daytime rather than an increased sympathetic tone. Blood pressure variability reflects periodic variations of blood pressure due to vasomotion and respiration. Paced breathing was used to control the influence of respiration on blood pressure. The low frequency component of BPV mirrors sympathetic activity and the high frequency component mirrors the mechanical influence of respiration on systolic blood pressure [27,28]. Our study showed an increase of BPV-HF and a minor non-significant increase of BPV-LF. This was interpreted as a sign for increased blood pressure variability in snorers. This effect was not been shown before. Lombardi et al. (2000) [29] demonstrated a higher BPV in sleep apnea patients compared to controls. Our data confirmed this effect for people snoring only.
30,0
p < 0.05
p < 0.05
12/min
15/min
p-Value
12/min
Controls Snorers
25,0
20,0
15,0
10,0
5,0
0,0
α index [ms/mmHg]
Figure 1 The alpha index which provides an evaluation of the overall baroreceptor gain is shown for paced breathing at 12 and 15 breaths per minute. Box plots show the significant differences between controls (left side) and snorers (right side) for both breathing rates.
836 36.4 21.2 46.9 124.3 0.39 0.37 72.3 8.56 9.74 9.15
15/min 81 24.2 13.1 54.4 21.1 0.42 0.24 11.5 3.3 3.6 2.5
848 36.3 20.6 46.2 126.4 0.49 0.35 72.5 7.03 9.94 8.48
94 36.9 15.3 81.6 22.5 0.42 0.28 13.1 2.3 5.9 2.7
12/min
15/min
0.029 n. s. n. s. n. s. n. s. n. s. 0.004 n. s. n. s. 0.015 0.015
0.042 n. s. n. s. n. s. n. s. n. s. 0.05 n. s. n. s. 0.014 0.05
Baroreceptor sensitivity reflects the sensitivity of the baroreceptor on changes in arterial blood pressure. During resting conditions the baroreceptor sensitivity characterizes the state of the autonomous tone [30]. The result of normal baroreflex function is an attenuation of short term blood pressure variations. Several studies proved that baroreceptor sensitivity is lower in patients with hypertension, diabetes mellitus, smokers, and obstructive sleep apnea [11,31,32]. Gates et al. [15] found a lower BRS in snorers compared to control subjects only in sleep, but not in wakefulness. Treatment with CPAP had a beneficial effect and led to an increase of BRS in snorers. BRS was calculated using the spontaneous baroreflex-sequencing technique which is well proven but also critiqued [33]. BRS was investigated during spontaneous respiration during NREM sleep and wake state prior to the onset of sleep. Thus it was not possible to eliminate the modulating effect of respiration on gain of baroreceptor reflex [34,35]. Therefore we used a standardized protocol with paced breathing in wakefulness. So we tried to get nearly constant inspiratory time (Ti) at the defined breathing rate as changes of Ti could lead to changes in BRS. Nevertheless we did neither measure exact inspiratory time nor tidal volume. Though we can imagine that paced breathing forced by a metronome can lead to increase in breathing effort by mental focusing on respiration. This can result in higher changes in intrathoracic pressure with possible concomitant activation of the Bainbridge reflex [36,37]. The subsequent increases in sympathetic activity would be reflected in reduced BRS. However this would have also be shown in healthy control group. In general, in our study BRS was calculated using squared root of ratio of HRV and SBPV in LF and HF spectral bands to finally obtain a-index. Therefore findings about BRS changes of our study cannot simply be compared with findings of Gates et al. Thus in our study the a-LF index did not differ between snorers and controls in our study. The reduced a-HF index observed in our study can be interpreted as a sign of reduced parasympathetic reflex activity in snorers. One possible interpretation is a reduced stimulation of lung stretch receptors [29] leading to reduced activity of vagal afferents. Furthermore De Boer [38] mentioned that BRS above a respiratory rate of 0.2 Hz,
Please cite this article in press as: Scho ¨bel C, et al., Nocturnal snoring decreases daytime baroreceptor sensitivity, Respiratory Medicine (2014), http://dx.doi.org/10.1016/j.rmed.2014.03.012
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Nocturnal snoring decreases daytime baroreceptor sensitivity corresponding to 12 breaths per minute is dominated by parasympathetic drive. However other measures of parasympathetic tone such as RMSSD and HRV-HF did not support this assumption. Hilton et al. [16] investigated obstructive sleep apnea patients and found a decrease of the power in the high frequency band during daytime. Young [39] showed small blood pressure differences when comparing primary snorers and healthy subjects. Our study confirmed the results presented by Leroy [40], who did not demonstrate differences in blood pressure when comparing snorers (AHI < 15 events/hour) with sleep apnea patients (AHI 15 events/hour). Heart rate variability which predominantly reflects parasympathetic tone showed no differences between snorers and controls in our study despite mean heart rate was different. Gates et al. [14] investigated HRV during nighttime in snorers and healthy controls and also found no differences. Only with eliminating snoring by CPAP therapy they could show an increase in sympathetic activity (SNSA) and a reduction in parasympathetic activity (PNSA). Discussing their findings they postulated the influence of activated vagal afferents during snoring which may be weaker in non-snoring episodes (e.g. under CPAP treatment) and therefore leading to a reduction in PNSA and an increase in SNSA in non-snoring episodes. However they analyzed HRV only in several 15-min snoring- and nonsnoring segments of NREM sleep (stage 2 or slow-wave sleep according to stage 3) and excluded REM-stage explicitly. We did HRV-analysis selecting 180 consecutive heart beats during testing period in wakefulness. Despite following the standardized protocol to exclude possible modulating factors, autonomous tone in wakefulness is completely different to NREM sleep in which mentioned vagal afferents could have more impact on overall sympathovagal balance than in REM sleep or wake state. Furthermore Gates et al. critically discussed HRV differences as short term effect of CPAP treatment as it was performed in snorers and healthy controls only for 7 days before HRV analysis. Ferini-Strambi [41] reported a reduced HRV only when the AHI was above 10 per hour and Hilton [16] reported a reduced HRV, especially the high frequency components, during daytime in sleep apnea patients, independent of sympathetic tone. A limitation of the present study is a small number of patients and controls. Snorers were subject to portable monitoring with a six-channel sleep apnea monitoring device to exclude the presence of sleep apnea. We are conscious that the calculated AHI only refers to recording time and not to total sleep time as calculated by the gold standard of polysomnography. However, especially in Germany, portable monitoring with a six-channel monitoring device is a well established diagnostic tool used in clinical practice to exclude sleep apnea in patients with snoring. We assessed snoring using the integrated Embla derived snoring signal by vibration in nasal cannula. It could be shown that cannula can only measure a range from 0 to 100 Hz although fundamental frequency of snore events measured by sound analysis is set from 50 to 250 Hz. Therefore cannula vibration assessment of snoring can miss a portion of snore events leading to underestimation of real snoring occurrence [17].
5 Nevertheless the results contribute to the current discussion because the influences of respiration on parameters of autonomous tone were carefully excluded by our study protocol. Studies on parameters derived from the autonomous nervous system regulation during nighttime and spontaneous breathing, have the advantage to avoid psychological influences and to avoid interaction with test instructions. Our protocol with daytime testing may suffer from these effects but still we eliminated the effects of breathing on baroreceptor sensitivity. The only remaining limitation was that during paced breathing there was no quantitative control for breath volume. Nevertheless we are convinced that a standardized approach was useful when comparing these sensitive parameters. For non-invasive recording of blood pressure finger photoplethysmography (Portapres) was used. This method is generally accepted to analyze blood pressure variability but not valid for absolute blood pressure values [42]. When processing the recorded data, single ectopic beats were eliminated by interpolation. Patients with clinically relevant arrhythmias were excluded from the study. Bixler described an association of snoring and arterial hypertension [6]. Mechanisms for the development of hypertension can be the mechanical influence on the carotid arteries and the carotid blood pressure receptors. This may cause carotid atherosclerosis [7,43] and sleep fragmentation as a direct effect of snoring noise [43]. Dunai et al. [44] demonstrated an increased cardiovascular risk in a crosssectional study on heavy snorers compared to quiet snorers. In that study snoring was a reported feature. Heavy snorers reported breathing pauses in addition and therefore obstructive sleep apnea may be responsible for the increased cardiovascular risk in heavy snorers. The Sleep Heart Health Study found no correlation between reported snoring and arterial hypertension [45]. For subjects with an AHI < 10 events/hour morbidity for cardiovascular diseases was not increased. Unfortunately the Wisconsin Sleep Cohort did not assess snoring quantitatively. Checking for the incidence of hypertension in subjects with an AHI < 5 events/hour in this cohort then 40% developed hypertension during an observational period of four years [39]. Rich et al. [8] reported in their communitybased study an elevated overall mortality in subjects with heavy snoring and a BMI < 30 kg/m2 even without obstructive sleep apnea. The study used portable sleep monitoring at home as well to confirm the diagnosis and to identify subjects with an AHI < 5 events/hour. Therefore, once snoring is established in a particular patient, further diagnostic procedures need to follow and treatment should be initiated if additional risk factors are present.
Conflict of interest None of the authors has a conflict of interest.
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Nocturnal snoring decreases daytime baroreceptor sensitivity [38] De Boer RW, Karemaker JM, Strackee J. Hemodynamic fluctuations and baroreflex sensitivity in humans: a beat-to-beat model. Am J Physiol 1987;253:H680e9. [39] Young T, Peppard P, Palta M, Hla KM, Finn L, Morgan B, Skatrud J. Population-based study of sleep-disordered breathing as a risk factor for hypertension. Arch Intern Med 1997;157:1746e52. [40] Leroy M, Van Surell C, Pilliere R, Hagenmuller MP, Aegerter P, Raffestin B, Foucher A. Short-term variability of blood pressure during sleep in snorers with or without apnea. Hypertension 1996;28:937e43. [41] Ferini-Strambi L, Zucconi M, Oldani A, Smirne S. Heart rate variability during sleep in snorers with and without obstructive sleep apnea. Chest 1992;102:1023e7.
7 [42] Persson PB, DiRienzo M, Castiglioni P, Cerutti S, Pagani M, Honzikova N, Akselrod S, Parati G. Time versus frequency domain techniques for assessing baroreflex sensitivity. J Hypertens 2001;19:1699e705. [43] Drager LF, Bortolotto LA, Figueiredo AC, Krieger EM, Lorenzi GF. Effects of continuous positive airway pressure on early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 2007;176:706e12. [44] Dunai A, Keszei AP, Kopp MS, Shapiro CM, Mucsi I, Novak M. Cardiovascular disease and health-care utilization in snorers: a population survey. Sleep 2008;31:411e6. [45] Roux F, D’Ambrosio C, Mohsenin V. Sleep-related breathing disorders and cardiovascular disease. Am J Med 2000;108: 396e402.
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Respiratory Medicine (2014) xx, 1e7
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/rmed
Nocturnal snoring decreases daytime baroreceptor sensitivity ¨bel a,b, Ingo Fietze a, Martin Glos a, Christoph Scho Inett Schary a, Alexander Blau a, Gert Baumann b, Thomas Penzel a,* a b
Sleep Medicine Center, Charite´ Universita¨tsmedizin Berlin, Berlin, Germany Center for Cardiology and Angiology, Charite´ Universita¨tsmedizin Berlin, Berlin, Germany
Received 29 December 2013; accepted 24 March 2014
KEYWORDS Snoring; Sleep disordered breathing; Baroreceptor sensitivity; Heart rate variability; Cardiovascular risk
Summary Background: In patients with obstructive sleep apnea heart rate variability and baroreceptor sensitivity during night and daytime are impaired. Snoring without obstructive sleep apnea may already influence heart rate variability and baroreceptor sensitivity during daytime. Methods: Cardiovascular daytime testing was performed in 11 snorers and age, BMI, and gender matched controls. Sleep apnea and snoring were quantified by sleep recordings. Paced breathing was performed during daytime with ECG, non-invasive blood pressure, and respiration recorded. Heart rate variability and blood pressure variability were analyzed in the time and frequency domain. Baroreceptor sensitivity (alpha gain) was calculated. Results: In snorers a significant increase in high frequency systolic blood pressure variability (SBPVeHF) compared to control group (0.37 mm Hg2 vs. 0.11 mm Hg2 for 12 breaths and 0.35 mm Hg2 vs. 0.10 mm Hg2 for 15 breaths) was demonstrated. Furthermore a lower baroreceptor sensitivity was found in snorers compared to controls (9.2 ms/mm Hg vs. 16.2 ms/ mm Hg for 12 breaths and 8.5 ms/mm Hg vs. 17.4 ms/mm Hg for 15 breaths per minute) using the paced breathing protocol. Mean heart rate was elevated in snorers as well. Conclusions: Snorers may have a reduced parasympathetic tone during daytime rather than an increased sympathetic tone. ª 2014 Elsevier Ltd. All rights reserved.
* Corresponding author. Charite ´ Universita ¨tsmedizin Berlin, Sleep Medicine Center, Charite ´platz 1, D-10117 Berlin, Germany. Tel.: þ49 30 450513 013; fax: þ49 30 450513906. E-mail address: [email protected] (T. Penzel). http://dx.doi.org/10.1016/j.rmed.2014.03.012 0954-6111/ª 2014 Elsevier Ltd. All rights reserved.
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C. Scho ¨bel et al.
Introduction
Methods
Sleep related breathing disorders have a high prevalence and are associated with an elevated cardiovascular risk. Sleep apnea patients have an increased cardiovascular morbidity and mortality [1]. Patients have a lower life expectancy and a higher risk for cardiovascular consequences such as stroke, myocardial infarction, and cardiac arrhythmias. The risk to develop arterial hypertension and heart failure is increased [2,3]. The most important pathophysiological mechanisms in sleep disordered breathing are upper airway obstruction, repetitive intermittent hypoxemia, and intrathoracic pressure changes. Many cardiovascular consequences can be related to concomitant changes in autonomic tone. Each apnea event is a cessation of oronasal airflow for at least 10 s duration. Each hypopnea event is a reduction of airflow by at least 50% in amplitude for at least 10 s accompanied by an oxygen desaturation by at least 3% [4]. Sleep apnea severity is specified by the apnea hypopnea index (AHI) which corresponds to the number of apnea and hypopnea events per hour of sleep. Patients with an AHI between 5 and 15 events/hour suffer from mild sleep apnea, between 15 and 30 events/hour from moderate sleep apnea and above 30 events per hour from severe sleep apnea. Large studies proved that patients with moderate and severe sleep apnea have an increased cardiovascular risk [5]. Snoring is regarded as a precursor for sleep disordered breathing. Whether snoring itself with few apnea and hypopnea events (AHI < 5 events/hour) causes an increased cardiovascular risk is not clarified. A large epidemiological study by Marin et al. did not detect an increase in cardiovascular events in snorers compared to controls after 12 years [1]. However studies in animals showed that snoring associated micro vibrations caused micro lesions on the extracranial vessels which increased the risk for local arteriosclerosis [4,6e8]. Mateika et al. showed a reduction in baroreceptor sensitivity (BRS) in snorers with a low AHI and interpreted this as an indication for increased cardiovascular risk [9]. Assessment of autonomous tone can be done directly and indirectly. Direct recordings require microneurographic recording of sympathetic nerve activity on the perineous nerve [10]. This method is painful and not practical in clinical studies. Indirect assessment of autonomic tone is performed using heart rate variability (HRV), blood pressure variability (BPV), and baroreceptor sensitivity (BRS) [10]. Based on HRV a summarizing value, called sympathovagal balance, can be calculated. Sympathetic tone is increased in patients with sleep disordered breathing not only at nighttime but also during daytime [3]. This is reflected by both an impaired HRV and BRS. This can be an indicator for elevated cardiovascular risk [11]. CPAP treatment in patients with obstructive sleep apnea improves sympathovagal balance after three months usage [12]. That sympathovagal balance is affected in snorers had been shown previously [9]. Whether sympathovagal balance is impaired in snorers not only at nighttime [13e15] but also during daytime, similar to obstructive sleep apnea [16] is the focus of this study.
Subjects For the study 14 patients with snoring and without sleep apnea were recruited between February 2004 and July 2005 at the sleep center. Selection criteria were strict and focuses on snoring without sleep apnea. For each snorer a carefully selected healthy control subject was matched for age, BMI and gender. All subjects were investigated for daytime autonomous function using the same experimental protocol. For daytime testing of autonomous functions a customized experimental protocol was used. Because the autonomous nervous system is modulated by many mental and physical factors, a strict and standardized study protocol was conducted in order to standardize these influences. The study was approved by the institutional ethics committee. One patient could not be evaluated due to technical problems with the daytime recording and two other patients resigned from the study without giving reasons. Finally data from 11 patients and 11 matched controls could be used for consequent analysis. The characteristics of the two matched groups of snorers and controls are presented in Table 1. All subjects were recorded with a six-channel portable sleep apnea monitoring device (Embletta, Embla Systems Inc., Broomfield, CO, USA) to evaluate the presence of sleep apnea and to detect sleep related movement disorders (e.g. periodic leg movements during sleep) before daytime testing. The portable sleep monitoring device did record oral airflow, respiratory effort with belt sensors, snoring by an analysis of pressure fluctuations, body position, oxygen saturation and pulse rate. The number of apnea and hypopnea events per hour of estimated sleep (AHI) were evaluated. We used the integrated Embla derived snoring signal by vibration in the nasal cannula as provided by the Somnologica-Software to quantify the time with snoring noise against the total recording time [17]. Subjects completed a clinical investigation, a questionnaire to assess daytime sleepiness (Epworth Sleepiness Scale, ESS), a lung function test to exclude restrictive and obstructive pulmonary disorders, and clinical chemistry of blood to exclude other disorders and drug use. Inclusion criteria were age above 20 years, a BMI lower than 40 kg/ m2, an AHI lower than 5 events per hour, a history of reported snoring and acceptance to participate in the study. Exclusion criteria were misuse of sedating drugs, abuse of
Table 1 Characteristics of the controls and the snorers are presented. There are no significant differences between groups.
Female Male Age [years] BMI [kg/m2] AHI [events/hour]
Controls
Snorers
1 10 41.1 8.5 26.3 3.6 3.18
1 10 43.1 8.7 27.3 3.8 3.45
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Nocturnal snoring decreases daytime baroreceptor sensitivity alcohol, use of anti-arrhythmic drugs, chronic cardiovascular disorders, pain disorders, acute or chronic inflammatory disorders, thyroid disorders, mental or neurological disorders, disorders which would affect the respiratory system, and other sleep disorders. Eleven healthy control subjects were selected to match in terms of age, gender, and BMI. These subjects were selected from a group of volunteers with undisturbed sleep being recruited for another cohort of healthy sleepers [18]. For the control group all the disorders mentioned above were excluded as well by checking for pathological thresholds. The control group underwent a cardiorespiratory polysomnography in a sleep center in order to exclude all sleep disorders, sleep disordered breathing in particular and presence of snoring as well.
Study protocol Daytime testing of cardiovascular functions in terms of HRV, blood pressure variability (BPV), and BRS took place between 9 and 12 in the morning after the portable sleep testing at home (Embletta, Embla Systems Inc., Broomfield, CO, USA). Subjects were instructed not to use caffeine and vasoactive agents on the morning before the assessment. Testing followed a standardized protocol which proved to be effective in previous investigations [18e20]. Recorded signals were ECG (lead II), nasal airflow with pressure sensors using nasal prongs, ribcage and abdominal respiratory movements with piezo sensors, and non-invasive continuous blood pressure (Portapres). Signals were recorded using a polysomnography recorder (Embla A10, Embla Systems Inc., Broomfield, CO, USA). Subjects were seated with the upper body in 45 resting position. After a test run the protocol was performed in always the same order: six minutes quiet breathing followed by three times 6 min paced breathing at three different paces, 6 then 12 then 15 breaths per minute. At the end of the protocol another 6 min breathing at rest followed. Pacing was performed with a metronome and there were short breaks of two minutes duration between the test sessions. Paced breathing episodes with 6 breaths were not further analyzed because subjects could not maintain this frequency well enough in terms of regularity.
Signal analysis ECG and the blood pressure signal were analyzed using the MATLAB software (The Math-Works Inc., Natick, MA, USA) with previously described algorithms [19e21]. ReR intervals and systolic blood pressure were calculated. Artifacts were removed and episodes with 180 consecutive heart beats were selected. Time series were interpolated using cubic splines, and were re-sampled at 4 Hz. Fast Fourier transform (FFT) was applied to calculate power spectra of HRV and systolic blood pressure variability (SBPV) Low frequency (LF Z 0.04e0.15 Hz) and high frequency (HF Z 0.15e0.4 Hz) spectral bands were integrated for HRV (HRV-LF, HRV-HF) and SBPV (SBPV-LF, SBPV-HF) analysis. In HRV, vagal activity is the main contributor to the HF component for subjects in supine position under controlled respiration without pharmacological or physical
3 interventions. The LF component reflects both sympathetic and vagal autonomic activity [22]. Another important measure of HRV is the root mean square of successive heartbeat interval differences (RMSSD). RMSSD reflects the short-term variation of heart rate and is claimed to be a good surrogate for LF/HF-ratio as marker for sympatho-vagal balance [23]. The spontaneous baroreceptor sensitivity (BRS) is based on the permanent activity of the baroreflex feedback loop integrating spontaneous fluctuations. The BRS was calculated using the squared root of the ratio of HRV and SBPV (so called a-gain). This was performed separately for the LF and HF spectral bands resulting in a-LF and a-HF. Finally, the a index was calculated as the mean of a-LF and a-HF [24]. All BRS values were expressed in ms/mm Hg. The a-LF displayed the gain of the arterial pressureeRR interval relationship in the spectral region not linked to the breathing frequency whilst the a-HF component mirrors the gain in the spectral region of the breathing frequency [25]. The a index presented the average of a-LF and a-HF and provided an evaluation of the overall baroreceptor gain [26]. For statistical analyses SPSS for Windows (version 12.0, SPSS, Chicago, IL) was applied. Result parameters were presented with median, lower and upper quartile to be independent of distribution assumptions. For testing differences between groups (Table 2) ManneWhitney-U-Test was applied for non-parametric variables. Differences were considered significant at a two-tailed p-value of 0.05. Tables 1 and 2 expresses the results as means standard deviation.
Results Both groups were carefully matched and did not differ in terms of age, BMI, and gender. Both groups had no sleep apnea with a confirmed AHI < 5 events/hour of sleep, see Table 1. None of the snorers nor the healthy subjects had arterial hypertension. The mean blood pressure in the snorers was 140/85 mm Hg. Assessing the cardiac autonomic nervous system by quantifying HRV and BPV considered the paced breathing episodes with a pace of 12 and 15 breaths per minute. The results of the comparison are presented in Table 2. With paced breathing at both breathing rates snorers did show an increased heart rate compared to controls (p < 0.05). Heart rate variability measures did not differ between the groups. With respect to blood pressure variability significant differences were observed for the high frequency component of systolic blood pressure variability (SBPVeHF) The other blood pressure variability parameters did not show significant differences between controls and snorers. For baroreceptor sensitivity expressed as alpha gain significant differences were found and shown for a Index (Fig. 1).
Discussion Results showed a significant increase in high frequency blood pressure variability and a significant decrease in baroreceptor sensitivity between healthy volunteers and snorers at the paced breathing tests during daytime. Snorers did show in addition an increased heart rate at paced breathing. Together this may indicate a reduction in
Please cite this article in press as: Scho ¨bel C, et al., Nocturnal snoring decreases daytime baroreceptor sensitivity, Respiratory Medicine (2014), http://dx.doi.org/10.1016/j.rmed.2014.03.012
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C. Scho ¨bel et al. Table 2 Results for heart rate variability, blood pressure variability and baroreceptor sensitivity for the daytime testing during paced breathing. Significant differences were seen for both 12 and 15 breaths per minute for mean RR intervals, SBPV-HF, for aHF, and for a index. Parameter
Controls
Snorers
12/min Mean RR intervals (ms) RMSSD (ms) HRV-LF (ms2) HRV-HF (ms2) Mean SBP (mmHg) SBPV-LF (mm Hg2) SBPV-HF (mm Hg2) Mean DBP (mm Hg) a-LF (ms/mm Hg) a-HF (ms/mm Hg) a index (ms/mm Hg)
948 35.5 23.0 40.2 141.1 0.26 0.11 69.9 10.31 22.16 16.24
15/min 115 14.2 13.0 33.4 17.1 0.13 0.08 8.7 3.7 12.8 7.0
956 39.1 18.2 26.2 136.0 0.31 0.10 69.4 10.13 28.20 17.41
137 21.0 11.1 21.8 19.1 0.21 0.10 9.4 5.1 15.4 8.4
parasympathetic tone in snorers during daytime rather than an increased sympathetic tone. Blood pressure variability reflects periodic variations of blood pressure due to vasomotion and respiration. Paced breathing was used to control the influence of respiration on blood pressure. The low frequency component of BPV mirrors sympathetic activity and the high frequency component mirrors the mechanical influence of respiration on systolic blood pressure [27,28]. Our study showed an increase of BPV-HF and a minor non-significant increase of BPV-LF. This was interpreted as a sign for increased blood pressure variability in snorers. This effect was not been shown before. Lombardi et al. (2000) [29] demonstrated a higher BPV in sleep apnea patients compared to controls. Our data confirmed this effect for people snoring only.
30,0
p < 0.05
p < 0.05
12/min
15/min
p-Value
12/min
Controls Snorers
25,0
20,0
15,0
10,0
5,0
0,0
α index [ms/mmHg]
Figure 1 The alpha index which provides an evaluation of the overall baroreceptor gain is shown for paced breathing at 12 and 15 breaths per minute. Box plots show the significant differences between controls (left side) and snorers (right side) for both breathing rates.
836 36.4 21.2 46.9 124.3 0.39 0.37 72.3 8.56 9.74 9.15
15/min 81 24.2 13.1 54.4 21.1 0.42 0.24 11.5 3.3 3.6 2.5
848 36.3 20.6 46.2 126.4 0.49 0.35 72.5 7.03 9.94 8.48
94 36.9 15.3 81.6 22.5 0.42 0.28 13.1 2.3 5.9 2.7
12/min
15/min
0.029 n. s. n. s. n. s. n. s. n. s. 0.004 n. s. n. s. 0.015 0.015
0.042 n. s. n. s. n. s. n. s. n. s. 0.05 n. s. n. s. 0.014 0.05
Baroreceptor sensitivity reflects the sensitivity of the baroreceptor on changes in arterial blood pressure. During resting conditions the baroreceptor sensitivity characterizes the state of the autonomous tone [30]. The result of normal baroreflex function is an attenuation of short term blood pressure variations. Several studies proved that baroreceptor sensitivity is lower in patients with hypertension, diabetes mellitus, smokers, and obstructive sleep apnea [11,31,32]. Gates et al. [15] found a lower BRS in snorers compared to control subjects only in sleep, but not in wakefulness. Treatment with CPAP had a beneficial effect and led to an increase of BRS in snorers. BRS was calculated using the spontaneous baroreflex-sequencing technique which is well proven but also critiqued [33]. BRS was investigated during spontaneous respiration during NREM sleep and wake state prior to the onset of sleep. Thus it was not possible to eliminate the modulating effect of respiration on gain of baroreceptor reflex [34,35]. Therefore we used a standardized protocol with paced breathing in wakefulness. So we tried to get nearly constant inspiratory time (Ti) at the defined breathing rate as changes of Ti could lead to changes in BRS. Nevertheless we did neither measure exact inspiratory time nor tidal volume. Though we can imagine that paced breathing forced by a metronome can lead to increase in breathing effort by mental focusing on respiration. This can result in higher changes in intrathoracic pressure with possible concomitant activation of the Bainbridge reflex [36,37]. The subsequent increases in sympathetic activity would be reflected in reduced BRS. However this would have also be shown in healthy control group. In general, in our study BRS was calculated using squared root of ratio of HRV and SBPV in LF and HF spectral bands to finally obtain a-index. Therefore findings about BRS changes of our study cannot simply be compared with findings of Gates et al. Thus in our study the a-LF index did not differ between snorers and controls in our study. The reduced a-HF index observed in our study can be interpreted as a sign of reduced parasympathetic reflex activity in snorers. One possible interpretation is a reduced stimulation of lung stretch receptors [29] leading to reduced activity of vagal afferents. Furthermore De Boer [38] mentioned that BRS above a respiratory rate of 0.2 Hz,
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Nocturnal snoring decreases daytime baroreceptor sensitivity corresponding to 12 breaths per minute is dominated by parasympathetic drive. However other measures of parasympathetic tone such as RMSSD and HRV-HF did not support this assumption. Hilton et al. [16] investigated obstructive sleep apnea patients and found a decrease of the power in the high frequency band during daytime. Young [39] showed small blood pressure differences when comparing primary snorers and healthy subjects. Our study confirmed the results presented by Leroy [40], who did not demonstrate differences in blood pressure when comparing snorers (AHI < 15 events/hour) with sleep apnea patients (AHI 15 events/hour). Heart rate variability which predominantly reflects parasympathetic tone showed no differences between snorers and controls in our study despite mean heart rate was different. Gates et al. [14] investigated HRV during nighttime in snorers and healthy controls and also found no differences. Only with eliminating snoring by CPAP therapy they could show an increase in sympathetic activity (SNSA) and a reduction in parasympathetic activity (PNSA). Discussing their findings they postulated the influence of activated vagal afferents during snoring which may be weaker in non-snoring episodes (e.g. under CPAP treatment) and therefore leading to a reduction in PNSA and an increase in SNSA in non-snoring episodes. However they analyzed HRV only in several 15-min snoring- and nonsnoring segments of NREM sleep (stage 2 or slow-wave sleep according to stage 3) and excluded REM-stage explicitly. We did HRV-analysis selecting 180 consecutive heart beats during testing period in wakefulness. Despite following the standardized protocol to exclude possible modulating factors, autonomous tone in wakefulness is completely different to NREM sleep in which mentioned vagal afferents could have more impact on overall sympathovagal balance than in REM sleep or wake state. Furthermore Gates et al. critically discussed HRV differences as short term effect of CPAP treatment as it was performed in snorers and healthy controls only for 7 days before HRV analysis. Ferini-Strambi [41] reported a reduced HRV only when the AHI was above 10 per hour and Hilton [16] reported a reduced HRV, especially the high frequency components, during daytime in sleep apnea patients, independent of sympathetic tone. A limitation of the present study is a small number of patients and controls. Snorers were subject to portable monitoring with a six-channel sleep apnea monitoring device to exclude the presence of sleep apnea. We are conscious that the calculated AHI only refers to recording time and not to total sleep time as calculated by the gold standard of polysomnography. However, especially in Germany, portable monitoring with a six-channel monitoring device is a well established diagnostic tool used in clinical practice to exclude sleep apnea in patients with snoring. We assessed snoring using the integrated Embla derived snoring signal by vibration in nasal cannula. It could be shown that cannula can only measure a range from 0 to 100 Hz although fundamental frequency of snore events measured by sound analysis is set from 50 to 250 Hz. Therefore cannula vibration assessment of snoring can miss a portion of snore events leading to underestimation of real snoring occurrence [17].
5 Nevertheless the results contribute to the current discussion because the influences of respiration on parameters of autonomous tone were carefully excluded by our study protocol. Studies on parameters derived from the autonomous nervous system regulation during nighttime and spontaneous breathing, have the advantage to avoid psychological influences and to avoid interaction with test instructions. Our protocol with daytime testing may suffer from these effects but still we eliminated the effects of breathing on baroreceptor sensitivity. The only remaining limitation was that during paced breathing there was no quantitative control for breath volume. Nevertheless we are convinced that a standardized approach was useful when comparing these sensitive parameters. For non-invasive recording of blood pressure finger photoplethysmography (Portapres) was used. This method is generally accepted to analyze blood pressure variability but not valid for absolute blood pressure values [42]. When processing the recorded data, single ectopic beats were eliminated by interpolation. Patients with clinically relevant arrhythmias were excluded from the study. Bixler described an association of snoring and arterial hypertension [6]. Mechanisms for the development of hypertension can be the mechanical influence on the carotid arteries and the carotid blood pressure receptors. This may cause carotid atherosclerosis [7,43] and sleep fragmentation as a direct effect of snoring noise [43]. Dunai et al. [44] demonstrated an increased cardiovascular risk in a crosssectional study on heavy snorers compared to quiet snorers. In that study snoring was a reported feature. Heavy snorers reported breathing pauses in addition and therefore obstructive sleep apnea may be responsible for the increased cardiovascular risk in heavy snorers. The Sleep Heart Health Study found no correlation between reported snoring and arterial hypertension [45]. For subjects with an AHI < 10 events/hour morbidity for cardiovascular diseases was not increased. Unfortunately the Wisconsin Sleep Cohort did not assess snoring quantitatively. Checking for the incidence of hypertension in subjects with an AHI < 5 events/hour in this cohort then 40% developed hypertension during an observational period of four years [39]. Rich et al. [8] reported in their communitybased study an elevated overall mortality in subjects with heavy snoring and a BMI < 30 kg/m2 even without obstructive sleep apnea. The study used portable sleep monitoring at home as well to confirm the diagnosis and to identify subjects with an AHI < 5 events/hour. Therefore, once snoring is established in a particular patient, further diagnostic procedures need to follow and treatment should be initiated if additional risk factors are present.
Conflict of interest None of the authors has a conflict of interest.
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