Shinshu Med J, 67⑷：241～251, 2019

Relationship between Sympathetic Nerve Activity Evaluatedby Pulse Rate Variability and Blood Pressure Earlyin the Morning in Sleep Disordered Breathing
Akikazu Uematsu1） and Keisaku Fujimoto2）＊
1） Department of Biomedical Laboratory Sciences, Graduate School of Medicine, Shinshu University2） Department of Clinical Laboratory Sciences, Shinshu University School of Health Sciences

Objective/Background : This study was performed to clarify whether sleep disordered breathing (SDB) con­tributes to increases in sympathetic nerve (SN) activity during sleep and the development of hypertension.
Patients/Methods : Polysomnography and pulse rate variability (PRV) analysis using a photoplethysmographwere performed simultaneously in 153 male subjects and evaluated by instantaneous time-frequency analysis
using the complex demodulation method. Parasympathetic nerve (PN) activity and SN activity were assessed by
the amplitude of high-frequency (HF) and the ratio of low-frequency (LF) to HF amplitude (LF/HF ratio), re­spectively. Blood pressure (BP) before going to bed and early in the morning were measured in all subjects.
Results : The subjects were classified according to the severity of SDB as normal (apnea hypopnea index (AHI)＜5 events/h, n＝99), mild SDB (5 ≤ AHI＜15 events/h, n＝28), and moderate-to-severe SDB groups (AHI ≥ 15
events/h, n＝26). The mean LF/HF ratio was higher according to sleep stage in the order REM sleep＞lightsleep＞slow wave sleep in all groups. The mean LF/HF ratio in each sleep stage and BP both before going to
bed and early in the morning were significantly higher in the moderate-to-severe SDB group compared withnormal subjects and the mild SDB group and showed a significant correlation with arousal index. The multiple
regression model showed that independent associations for the systolic BP early in the morning were age, BMI,
cumulative ％ time with SpO2＜90 ％ (CT90) as an index of hypoxemia during sleep, and decreased sleep
efficiency.
Conclusion : The findings of this study suggested that the frequent arousal due to SDB may contribute to theincreased SN activity, and that hypoxemia during sleep and sleep disturbance in addition to age and obesity
may be associated with increased SBP early in the morning in moderate-to-severe SDB. Shinshu Med J
67 : 241―251, 2019
(Received for publication October 25, 2018 ; accepted in revised form April 10, 2019)
Key words : obstructive sleep apnea, heart rate variability, electric photoplethysmograph, arousal index,
hypoxemia

Ⅰ Introduction

capnia, and large swings of intrathoracic pressure,which may result in increased sympathetic nerve

In patients with obstructive sleep apnea (OSA), the(SN) activity1）-3）. Increased SN activity may contrib­

repeated episodes of apnea and hypopnea during

ute to the development of comorbidities, including

sleep result in sleep disturbance, hypoxemia, hyper­

hypertension4）, myocardial infarction5）, and cerebro­
vascular disease6）, and adversely affect prognosis7）8）.

＊

Corresponding author : Keisaku Fujimoto
Department of Clinical Laboratory Sciences,
Shinshu University School of Health Sciences, 3-1-1
Asahi, Matsumoto, Nagano 390-8621, Japan
E-mail : keisaku@shinshu-u.ac.jp

No. 4, 2019

OSA has been listed as an important risk factor forthe development of hypertension early in the morn­ing and poorly controlled hypertension9）. It has beensuggested that the increased SN activity may con­241

Uematsu・Fujimoto

tribute to the development of hypertension, especial­complete survey of all male workers (n＝165) fromly early in the morning.

this company. All subjects were of Japanese ethnici­

Analysis of heart rate variability (HRV) is a simple

ty and were not undergoing continuous positive

and non-invasive method to assess autonomic nerve

airway pressure (CPAP) treatment. Subjects whofunction, generally evaluated by power spectrum

showed arrhythmia＞10 ％ of total pulse rate, atrial

analysis of HRV10）. The ratio of the power of low-

fibrillation, and who were receiving treatment withfrequency bundle (LF) and high-frequency bundle

agents affecting AN function or antihypertensive(HF), the LF/HF ratio, represents SN activity andagents were excluded from the analysis.

the power of HF represents parasympathetic nerve

Ｂ

Protocol(PN) activity. It has been demonstrated that the

The protocol of this study was approved by the

LF/HF ratio is increased in central sleep apnea

institutional research ethics committee of Shinshu

and OSA

10）11）. However, sleep architecture has been
12）

University School of Medicine (No. 657 September 6

shown to affect autonomic nerve (AN) activity , and2005, No. 658 January 4 2006). Subjects underwent

HRV parameters have also been shown to vary

PSG between February 2006 and August 2007. Be­

13）among sleep stages . In rapid eye movement (REM)

fore PSG, all subjects were asked whether they had

sleep, SN activity is the highest among the sleep

arrhythmia and were being treated with agents af­

stages and SN activity is suppressed and PN activity

fecting AN function or antihypertensive agents, andis elevated during slow wave sleep (SWS) in normal

were surveyed for daytime sleepiness using the Jap­

subjects. It has been demonstrated that there is aanese version of the Epworth Sleepiness Scale (JESS)

14）
15）

.

and physical received an examination. Blood pres­One reason for the higher SN activity during sleep

sure (BP) was measured three times at aroundin OSA may involve a lack of SWS. However, there

20 : 30 before the PSG examination and aroundis little evidence regarding whether SN activity is

06 : 30 early in the morning just after PSG. The

also increased at each sleep stage in OSA.

blood pressure was measured in the supine position,

close correlation between SWS and HF power

The present study was performed to clarify

and the second and third measurements were adopt­

whether the status of sleep disordered breathinged and averaged. All subjects underwent simultane­(SDB) may contribute to increases in SN activity

ous PSG and recording of PRV using an electric pho­during each sleep stage and the development of hy­

toplethysmograph (Denso Co., Ltd., Kariya, Japan),pertension early in the morning. Attended polysom­which was installed on the mid-posterior part of thenography (PSG) and recording of pulse rate variabili­

forearm, 5 cm from the left wrist, between 21 : 00

ty (PRV) using an electric photoplethysmographand 06 : 00 in an accommodation facility at the Asahi

instead of electrocardiography (ECG) were simulta­

campus of Shinshu University. To obtain interpreta­

neously performed in 165 male company employees,

ble data and responses from both the PSG andand AN activity in each 30-s epoch on PSG was

pulse-wave measurement, the timing of both devices

evaluated by instantaneous time-frequency analysis

was synchronized. Based on the results of PSG, theof PRV using the complex demodulation method.

subjects were classified according to the severity ofⅡＡMaterials and Methods

Subjects

SDB. Subjects with apnea hypopnea index (AHI)＜5
events/h were classified as the normal group, sub­jects with 5 ≤ AHI＜15 events/h were classified as

All male workers of a transport company werethe mild SDB group, and subjects with AHI ≥ 15

eligible for inclusion in this study. Most were em­

events/h were classified as the moderate-to-severe

ployed to drive trucks over long distances. All malegroup. The autonomic nerve function, PSG data, andworkers provided written informed consent to par­BP were compared among the three groups. Fur­

ticipate in this study. Consequently, we performed ather, the mean HF amplitude and LF/HF ratio in

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Autonomic nerve function and morning blood pressure in SDB

each sleep stage were analyzed in all three groups

time-dependent changes in amplitude of a particularand the differences among sleep stages were com­frequency component as a function of time. The

pared. In addition, the independent determinants of

PRV technique using the same device has alreadyincreased SN activity or increased BP early in the

been validated against the traditional HRV21）. The

morning were analyzed in the mild and mild-to-sampling frequency of the electric plethysmographmoderate SDB groups.

was 20 Hz. When the pulse-wave peak-to-peak in­Ｃterval (PPI) was shortened by＞20 ％ of the mean ofPolysomnographyStandard overnight attended polysomnography

the preceding 10-beat intervals of PPI, the PPI was(PSG) was performed starting at 20 : 00, and the data

automatically excluded from analysis as an isolated/were collected from 21 : 00 to 06 : 00 the next morn­

sporadic premature supraventricular/ventricularing. The bed was covered with a sheet-form respira­contraction or body movement. The frequency

16）

tory movement sensor . The PSG was recorded

spectra of the PPI data were estimated for the range

with a digital polygraph (Alice III ; Chest Co. Ltd.,

between 0 and 0.40 Hz and divided into two compo­

Tokyo, Japan). We used standard polysomnographic

nents depending on their central frequencies ; onemontages consisting of C4-A2, C3-A1, O2-A1, anddomain between 0.04 and 0.15 Hz was labeled as theO1-A2 electroencephalograms, left and right elec­

band with LF and the other between 0.15 and 0.40

trooculograms, submental electromyogram, nasal

Hz as the band with HF. The LF/HF ratio was usedpressure cannula, oronasal airflow, left and rightas a marker of SN discharge to the cardiac sinus

tibial electromyograms, thoracoabdominal inductancenode9）. The mean values of HF amplitude were used

plethysmograms, percutaneous oxygen saturationas markers of PN discharge22）. The amplitudes of LF(SpO2 ), a neck microphone, body position sensors,and HF bundles and the LF/HF ratio were calculat­

and a modified lead II ECG. The sleep stages anded as the mean values of one epoch (30 s) of PSG

respiratory events were scored according to theconsistent with the analysis of sleep staging. Finally,

AASM Manual for the Scoring of Sleep and Associ­the total mean amplitude of HF and LF/HF ratio in

17）

ated Events . The average hourly frequency ofeach sleep stage (non-REM stage 1-4 and REM

apneic and hypopneic episodes was defined as AHI.

sleep) were calculated.

Total sleep time (TST) was used as the denominator

Ｅ

Statistical analysis

in the calculation of AHI. Arousal index is the mean

Values in the text, tables, and figures are shownnumber of sleep disruption events per hour of total

as the means±SEM. The Mann-Whitney U test was

sleep time. Arousals were defined as rapid EEG

used for comparison of variables among the normal,

frequency shift continued for ≥ 3 s in duration andmild SDB, and moderate-to-severe SDB groups andscored according to the criteria of the American

sleep stages in each group. Spearman’s rank correla­18）

Sleep Disorders Association . Sleep efficiency wastion coefficient was used for bivariate correlation

defined as the ratio of total sleep time (TST) to theanalysis. Multiple linear regression analysis was

total time in bed (TIB). TIB was taken as the time

performed to identify variables that were significant­17）

between lights out and lights on .

ly associated with systolic BP (SBP) early in theＤmorning. Explanatory variables were age, BMI, sleep

Analysis of autonomic nerve function
In this study, we evaluated PRV in the frequency

efficiency, arousal index, cumulative ％ time withdomain using a photoelectric plethysmograph in­

SpO2＜90 ％ (CT90), and mean LF/HF ratio. A value

stead of HRV analyzed by ECG. The nocturnal auto­of P ≤ 0.15 was used to identify candidate variables,

nomic nerve functions were evaluated by instanta­

and then variables were removed from the regres­neous time-frequency analysis of PRV using a com­sion model if P＞0.1. All statistical analyses were

19）
20）

plex demodulation (CD) method. This method, aperformed using StatFlex version 6 for Windows

time local version of harmonic analysis, provides the(Artech Co., Ltd., Osaka, Japan). In all analyses, P＜

No. 4, 2019243

Uematsu・Fujimoto
Table 1 Characteristics among normal subjects (AHI＜5 events/h) and subjects with mild (5 ≤ AHI＜15 events/h) and moderate-to-severe (AHI ≥ 15 events/h) SDB
NormalMild

Moderate-to-severenAge, years

99
40.4±1.22844.5±1.62652.3±1.7＊＊††

BMI, kg/m2

22.7±0.3

24.2±0.5＊＊

26.5±0.7＊＊†

Neck circumference, cm

36.9±0.2

37.6±0.439.5±0.5＊＊††＊＊91.8±2.0＊＊†

Waist circumference, cm

79.6±0.8

85.0±1.5

SBP before going to bed, mmHg

128.0±1.7129.9±2.9138.9±3.0＊＊†

DBP before going to bed, mmHg

79.8±1.2

83.1±2.087.8±2.0＊＊

SBP early in the morning, mmHg

121.8±1.7124.5±3.1140.6±3.1＊＊††

DBP early in the morning, mmHg

78.4±1.280.5±2.0

90.0±2.3＊＊††

ΔSBP, mmHg

－6.2±1.3－5.5±2.4

1.7±2.1＊＊†

ΔDBP, mmHg

－1.4±1.0－2.6±1.4

2.2±1.5†

JESS

4.1±0.4

4.6±0.6

6.0±0.8＊

Values are means±SEM. ＊P＜0.05 and ＊＊P＜0.01 vs. normal. †P＜0.05 and ††P＜0.01 vs. mild SDB.
AHI, apnea hypopnea index ; BMI, body mass index ; SBP, systolic BP ; DBP, diastolic BP ; ΔSBP or ΔDBP,
difference of SBP or DBP before going to bed and early in the morning ; JESS, Japanese version of the
Epworth sleepiness scale ; SDB, sleep disordered breathing.

0.05 was taken to indicate statistical significance.
Ⅲ

Results

the moderate-to-severe group showed the highest
percentage of stage 1 sleep and lowest percentagesof stage 3 and 4 sleep and REM sleep compared

The data for 12 of the total of 165 subjects werewith the normal group. Almost all of the subjects

excluded because of arrhythmia＞10 ％ and lack ofwith SDB showed obstructive sleep apnea. All of thedata＞10 ％ due to poor device attachment. Subjects

subjects in the moderate-to-severe group showedtreated with antihypertensive agents were also ex­frequent arousal on EEG and desaturation represent­

cluded. Finally, the data of 153 subjects were includ­

ed by 3 ％ ODI (cumulative desaturation events withed in the analyses. Ninety-nine subjects were with­

SpO2 ≥ 3 ％/h) and severe hypoxemia represented byout SDB (normal group), 28 subjects had mild SDB,

CT90 (cumulative ％ time with SpO2＜90 ％) consis­

and 26 subjects had moderate-to-severe SDB. The

tent with episodes of apnea and hypopnea during

subjects in the moderate-to-severe SDB group had

sleep. Table 3 shows the results of AN function ofsignificantly higher age, BMI, and both neck and

TST, light sleep (stage 1＋stage 2 sleep), SWS (stage

waist circumferences in comparison with the normal

3＋stage 4 sleep), and REM sleep. The mean LF/HF

and mild SDB groups (Table 1). In addition, the JESS

ratios showed the order REM sleep＞light sleep＞

score was significantly higher in the moderate-to-

SWS sleep in all groups. The LF/HF ratio in eachsevere group than the normal group. Further­sleep stage and the BP both before going to bed andmore, the SBP before going to bed and both SBP

early in the morning were higher in the moderate-and DBP early in the morning, and the difference into-severe group than in the normal and mild SDB

SBP between before going to bed and early in thegroups. In the mild SDB and moderate-to-severe

morning were significantly higher in the moderate-groups, the mean LF/HF ratio in TST was signifi­

to-severe SDB group than in the normal and mild

cantly correlated with age and arousal index (Fig. 2,

SDB groups (Fig. 1). Table 2 shows the data of PSG

left side) with correlation coefficients＞0.4 (Table 4).

for the three groups. There were no significant dif­

Similarly, the SBP early in the morning was signifi­

ferences in TST, sleep efficiency, or percentage ofcantly correlated with age, DBP early in the morn­stage 2 sleep between the groups. The subjects ining, and mean HF amplitude (Fig. 2, right side). In

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67

Autonomic nerve function and morning blood pressure in SDB

Fig. 1 Changes in systolic BP from the mean values before going to bed to those early in the morning in thenormal group (AHI＜5 events/h), mild SDB group (5 ≤ AHI＜15 events/h), and moderate-to-severe SDB
group (AHI ≥ 15 events/h)
Values are mean±SEM. ＊P＜0.05, ＊＊P＜0.01 vs. values before going to bed, †P＜0.01 vs. normal group, §P＜0.05,§§

P＜0.01 vs. mild SDB group.
Abbreviations : AHI, apnea hypopnea index ; BP, blood pressure ; SDB, sleep disordered breathing.

Table 2 Results of PSG among normal subjects (AHI＜5 events/h) and subjects with mild (5 ≤ AHI＜
15 events/h) and moderate-to-severe (AHI ≥ 15 events/h) SDB
NormalMild

Moderate-to-severenTST, min99
478±1028493±2026483±23Sleep efficiency, ％Stage 1, ％76.6±1.2
18.5±0.979.3±2.2
21.9±1.8＊78.1±3.2

Stage 2, ％Stage 3, ％62.4±0.9
2.1±0.360.9±1.7
0.6±0.3＊＊59.9±3.0

Stage 4, ％0.2±0.1

0.0±0.0

0.0±0.0＊

REM sleep, min

17.2±0.5

16.1±1.1

13.3±1.0＊＊

AHI, events/h

1.7±0.1

8.5±0.5＊＊37.2±3.2＊＊†

AI, events/h

0.5±0.1

3.2±0.6

21.7±3.1＊＊†＊＊

OAI, events/h

0.3±0.1

2.5±0.5

Arousal index, events/h

25.5±1.3

25.1±2.1

26.3±2.9＊
0.4±0.2＊＊

20.1±3.0＊＊†41.5±2.9＊＊†＊＊12.3±3.0＊＊†35.5±3.0＊＊†

CT90, ％

0.5±0.2

1.2±0.4

3 ％ ODI, events/h

2.7±0.2

9.0±0.6＊＊

Values are means ± SEM. ＊P＜0.05 and ＊＊P＜0.01 vs. normal. †P＜0.01 vs. mild SDB.
AHI, apnea hypopnea index ; TST, total sleep time ; REM, rapid eye movement ; AI, apnea index ; OAI,
obstructive apnea index ; CT90, cumulative ％ time with SpO2＜90 ％ ; 3 ％ODI, cumulative number ofdesaturation events with SpO2 ≥ 3 ％/h ; SDB, sleep disordered breathing.

No. 4, 2019245

Uematsu・Fujimoto
Table 3 Comparison of mean LF/HF ratio and HF amplitude in each sleep stage among normal
subjects (AHI＜5 events/h) and subjects with mild (5 ≤ AHI＜15 events/h) and moderate-tosevere (AHI ≥ 15 events/h) SDB.
NormalMild

Moderate-to-severen
LF/HF ratio
All sleep stages

99

28

26

0.77±0.02

0.83±0.05

1.02±0.05＊＊†

Stage 1 and 2

0.78±0.02

0.83±0.05

1.03±0.05＊＊†

0.69±0.05

0.94±0.07＊＊††§

Stage 3 and 4

0.66±0.02

Stage REM

0.99±0.03§＄＄1.07±0.08§＄＄1.24±0.08＊＊§＄

HF amplitude, ms
All sleep stages

30.9±1.431.6±3.0

24.3±1.6＊†

Stage 1 and 2

31.4±1.4

32.0±2.924.8±1.7＊

Stage 3 and 4
Stage REM

30.8±1.528.8±1.4§30.4±4.3

25.7±2.430.2±3.5

21.7±1.3＊§＄

Values are means ± SEM. ＊P＜0.05 and ＊＊P＜0.01 vs. normal. †P＜0.05 and ††P＜0.01 vs. mild SDB,§

P＜0.01 vs. stage 1 and 2, ＄P＜0.05 and ＄＄P＜0.01 vs. stage 3 and 4.
LF, low frequency ; HF, high frequency ; AHI, apnea hypopnea index ; REM, rapid eye movement ; SDB,
sleep disordered breathing.

Fig. 2 Relationships between the mean LF/HF ratio and arousal index (left side) and between
the mean HF amplitude and systolic blood pressure early in the morning (right side).
Abbreviations : LF, low frequency ; HF, high frequency.

multiple linear regression analysis in the total study

with each other, and the arousal index directly re­population, we selected age, BMI, sleep efficiency,

flected sleep disturbance due to SDB. A regression

arousal index, CT90, and mean LF/HF ratio as ex­

model with the variables age, BMI, sleep efficiency,

planatory variables for SBP early in the morning

arousal index, CT90, and mean LF/HF ratio werebased on single linear regression analysis and medi­

proposed (Table 5 upper panel). Furthermore, thecal evidence regarding the association with SBP.

mean LF/HF ratio was significantly correlated with

Arousal index was selected instead of AHI or 3 ％age (r＝0.42), and the arousal index was significantly

ODI because these variables were closely associatedcorrelated with CT90 (r＝0.45). Both the mean LF/

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Autonomic nerve function and morning blood pressure in SDB
Table 4 Correlation coefficients calculated by single linear regression analysis between the
LF/HF ratio or BP early in the morning and age, anthropometry, JESS, or polysomnog­
raphy data in subjects with mild and moderate-to-severe SDB (n＝54)

Age, years old
2

BMI, kg/m
Neck circumference, cm
Waist circumference, cm
SBP (EM), mmHg

LF/HF ratio

SBP (EM)

0.53＊＊

0.43＊＊

0.06
0.06
0.16
0.34＊

0.17
0.20
0.20
-

＊

DBP (EM), mmHg

0.33

0.85＊＊JESS
Sleep efficiency, ％AHI, events/h

0.08
0.09
0.36＊＊－0.03
0.00

SWS, ％REM, ％
Arousal index, events/h

－0.07
－0.22
0.51＊＊

－0.02
0.03
0.32＊

CT90, ％

0.32＊

0.34＊

3 ％ODI, events/h

0.30

LF/HF ratio-

HF amplitude, ms

0.28＊

＊

－0.53

0.36＊＊
0.34＊＊＊－0.40＊＊

P＜0.05 and ＊＊P＜0.01.
Abbreviations : JESS, Japanese version of the Epworth sleepiness scale ; EM, early in themorning ; LF, low frequency ; HF, high frequency ; BMI, body mass index ; SBP, systolic
BP ; DBP, diastolic BP ; AHI, apnea hypopnea index ; SWS, slow wave sleep ; REM, rapid
eye movement ; CT90, cumulative ％ time with SpO2＜90 ％ ; 3 ％ODI, cumulative number＊of desaturation events with SpO2 ≥ 3 ％/h ; SDB, sleep disordered breathing.
Table 5

Criterion Variables

Results of multiple linear regression analysis in all subjects (n＝153)
Explanatory Variables

stdβ

P values

SBP early in the morning (Model 1 : r＝0.555, P＜0.0001)
Age

0.37

＜0.0001

0.21
－0.11
0.10
0.13
0.04

0.00340.11180.23010.10810.6379

0.40
0.21
0.18
－0.11

＜0.0001
0.00330.0136
0.1094

BMI
Sleep efficiency
Arousal index
CT90
LF/HF ratio
SBP early in the morning (Model 2 : r＝0.547, P＜0.0001)
Age
BMI
CT90
Sleep efficiency

Abbreviations : SBP, systolic blood pressure ; BMI, body mass index ; CT90, cumulative ％ time with
SpO2＜90 ％ ; LF, low frequency ; HF, high frequency.

HF and arousal index showed poor associations, andsleep efficiency were significantly and independently

were therefore excluded. Finally, a significant re­associated with increased SBP early in the morning.

gression model was proposed consisting of age, BMI,
CT90, and sleep efficiency (Table 5 lower panel).
These findings indicated that age, BMI, CT90, andNo. 4, 2019

Ⅳ

Discussion

PSG and PRV were examined simultaneously and247

Uematsu・Fujimoto

analyzed in 153 male employees. The SN activity

demodulation (CD) method used in the present study

showed the order REM sleep＞light sleep＞SWS inenabled measurement of transitional changes in in­

all groups. The SN activity in each sleep stage andstantaneous amplitude of the target frequency do­

the BP both before going to bed and early in themain from short-time recordings lasting for 6.7 s,

morning were higher in subjects with moderate-to-corresponding to approximately seven beats19）20）.

severe obstructive SDB than in the normal and mild

Therefore, instantaneous time-frequency analysis

SDB groups. The increased SN activity was closelyusing the CD method could allow analysis of PRV

correlated with age (r＝0.53) and arousal index (r＝for each 30-s epoch.

0.51). Multiple linear regression analysis indicated

It has been reported that SN activity changes ac­that age, BMI, hypoxemia during sleep represented

cording to sleep stage in the order REM sleep＞lightby CT90, and decreased sleep efficiency were signifi­

sleep＞SWS in normal subjects11）14）. In subjects withcantly and independently associated with SBP earlymoderate-to-severe SDB, the SN activity was ele­in the morning. These findings suggested that thevated at all sleep stages compared to normal sub­frequent cortical arousal due to SDB may contributejects, and also showed the order REM sleep＞lightto the increased SN activity, and that hypoxemia

sleep＞SWS. The SN activity during REM was sig­

during sleep in addition to age and obesity may benificantly higher than those in light sleep and SWS.

associated with the increased SBP early in the

The SN activity evaluated by microneurography has

morning in moderate-to-severe SDB.

also been shown to be increased during sleep, espe­

In this study, an electric photoplethysmographcially during stage 2 of non-REM sleep and REM

was used to evaluate HRV instead of ECG. This has

sleep, when apnea severity and oxygen desaturation

been proposed as a surrogate for ECG in analysis ofare greatest26）. Liang et al.27） recently reported AN

HRV due to its ease of application. The pulse fre­function in each sleep stage evaluated by HRV in

quency demodulation technique using the same elec­

patients with sleep apnea-hypopnea syndrome withtric photoplethysmograph used in this study has

AHI ≥ 10 events/h. The LF/HF ratio was increased

22）

been validated previously against traditional HRV

in all stages, consistent with the observations of theand provided a reliable assessment of PRV.

present study, and subjects with coexisting respira­The method for direct measurement of SN activity

tory events and cortical arousals showed the highest

involves measurement of muscle SN activity by mi­values at all stages. They concluded that respiratory

23）

croneurography . However, this method is invasive

events break the parasympathetic/sympathetic bal­and requires specialized skill to perform. HRV analy­

ance, and subsequent arousal enhances this imbal­

sis is a simple and non-invasive method, but it isance. In the present study, a significant correlation

subject to a number of problems, including poor

was observed between SN activity and arousal

time resolution and the effects of differences in sleep

index. SN activity has been shown to be highest atarchitecture on AN function. Generally, HRV has

the end of an episode of apnea, and a large increase

been evaluated by classical power spectrum analysis,in blood pressure is observed together with corticalincluding the fast Fourier transform algorithm or

arousal after reopening of the upper airway28）. In thethe autoregressive approach. However, the time res­present study, the BP in the moderate-to-severe

olution is low and requires at least 100 heart beats,

SDB group was significantly higher and weakly

so it requires approximately 2 minutes to obtain thecorrelated with hypoxemia during sleep, intermittent

data necessary for definitive analysis of the frequen­

desaturation, arousal index, SN activity, and sup­cy domains contained in the R-R intervals of thepressed PN activity in addition to age. The age, BMI,

24）
25）

. On the other hand, the sleep stage ishypoxemia during sleep due to SDB, and decreased

judged by each 30-s epoch. Therefore, HRV cannot

sleep efficiency were independently associated with

be analyzed using the classical method. The complex

the increased SBP early in the morning in all sub­heartbeat248

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67

Autonomic nerve function and morning blood pressure in SDB

jects. It has been suggested that hypoxemia, hyper­

creased SN activity and hypertension early in thecapnia, changes in cardiohemodynamics by marked

morning. Second, all subjects were male because

negative intrathoracic pressure, and frequent arousal

most of the company employees were male, so

due to apnea and hypopnea may cause increases indifferences related to sex could not be evaluated.

SN activity, and thus contribute to the risk of devel­

Third, the distribution of SDB severity was skewed

oping hypertension, especially masked hypertension,

toward mild SDB, with only 16 subjects showing

29）
30）

.

severe SDB ≥ 30 events/h. However, it may be mean­

In the present study, a strong correlation between

ingful to determine the significance of differences

increased SBP early in the morning and SN activity

according to severity and relationships with BP evenwas not observed. Both the SN activity and SBP

in a population relatively skewed toward mild-to-

were strongly correlated with age, and may mask

moderate SDB. Finally, BP was only evaluatedthe relationship. However, the hypoxemia and sleep

before and after PSG examination. The diagnosis of

disturbance due to SDB were independently associ­early morning hypertension should be performed

ated with increased SBP. These findings suggest

based on the mean of at least 5 days31）, but this could

that the cortical arousals due to apnea and hypopnea

not be accomplished in the present study.

such as midnight surge and morning surge types

cause the burst of SN, and that hypoxemia and sleep

Ｖdisturbance may contribute to the increase in SBP

Conclusion

early in the morning. However, a close relationshipFrequent arousal due to SDB may contribute to

between SN activity and SBP was not observed asincreased SN activity, and hypoxemia during sleep

these variables may be strongly affected by age andand sleep disturbance in addition to age and obesity

BMI.

may be associated with the increased SBP early inThis study had several limitations. First, the mod­the morning in moderate-to-severe SDB.

erate-to-severe SDB group showed higher age andAcknowledgments

BMI because the SDB is usually affected by age
and BMI. Age is an important factor affecting AN
function, which also affects BP together with obesity.

We thank the polysomnography technicians for
performing the examinations and analyses.

These factors may have affected the results of the

Conflict of Interest

present study. Therefore, further age- and BMImatched studies or a longitudinal approach would
be required to clarify the relationship between in­

The authors declare no conflicts of interest associ­ated with this report.

References
1） Somers VK : Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 96 : 1897-1904, 1995
2） Carlson JT, Hedner J, Elam M, Ejnell H, Sellgren J, Wallin BG : Augmented resting sympathetic activity in awake
patients with obstructive sleep apnea. Chest 103 : 1763-1768, 1993
3） Abboud F, Kumar R : Obstructive sleep apnea and insight into mechanisms of sympathetic overactivity. J Clin
Invest 124 : 1454-1457, 2014
4） Peppard PE, Young T, Palta M, Skatrud J : Prospective study of the association between sleep-disordered breathing
and hypertension. N Engl J Med 342 : 1378-1384, 2000
5） Peker Y, Carlson J, Hedner J : Increased incidence of coronary artery disease in sleep apnoea : a long-term follow-up.
Eur Respir J 28 : 596-602, 2006
6） Arzt M, Young T, Finn L, Skatrud JB, Bradley TD : Association of sleep-disordered breathing and the occurrenceof stroke. Am J Respir Crit Care Med 172 : 1447-1451, 2005
7） Marin JM, Carrizo SJ, Vicente E, Agusti AG : Long-term cardiovascular outcomes in men with obstructive sleep
No. 4, 2019249

Uematsu・Fujimoto
apnoea-hypopnoea with or without treatment with continuous positive airway pressure : an observational study. Lancet
365 : 1046-1053, 2005
8） Young T, Finn L, Peppard PE, Szkio-Coxe M, Austin D, Nieto FJ, Stubbs R, Hla KM : Sleep disordered breathing
and mortality : eighteen-year follow-up of the Wisconsin sleep cohort. Sleep 31 : 1071-1078, 2008
9） Malliani A, Pagani M, Lombardi F, Cerutti S : Cardiovascular neural regulation explored in the frequency domain.
Circulation 84 : 482-492, 1991
10） Tobaldini E, Nobili L, Strada S, Casali KR, Braghiroli A, Montano N : Heart rate variability in normal and pathologicalsleep. Front Physiol 4 : 294, 201311） Szollosi I, Krum H, Kaye D, Nauqhton MT : Sleep apnea in heart failure increases heart rate variability and sympathetic
dominance. Sleep 30 : 1509-1514, 200712） Silvani A, Dampney RA : Central control of cardiovascular function during sleep. Am J Physiol Heart Circ Physiol
305 : H1683-1692, 201313） Boudreau P, Yeh WH, Dumont GA, Boivin DH : Circadian variation of heart rate variability across sleep stages.
Sleep 36 : 1919-1928, 201314） Scholz UJ, Bianchi AM, Cerutti S, Kubicki S : Vegetative background of sleep : spectral analysis of the heart ratevariability. Physiol Behav 62 : 1037-1043, 199715） Herzig D, Eser P, Omlin X, Riener R, Wilhelm M, Achermann P : Reproducibility of Heart Rate Variability Is Parameterand Sleep Stage Dependent. Front Physiol 8 : 1100, 2018 eCollection 201716） Agatsuma T, Fujimoto K, Komatsu Y, Urushihata K, Honda T, Tsukahara T, Nomiyama T : A novel device (SD-101)with high accuracy for screening sleep apnoea-hypopnoea syndrome. Respirology 14 : 1143-1150, 200917） Iber C, Ancoli-Israel S, Chesson AL, Quan SF : The American academy sleep medicine manual for the scoring of sleep
and associated events, rules, terminology and technical specifications. Westchester, IL : American Academy Sleep
Medicine ; 200718） EEG arousals : scoring rules and examples : a preliminary report from the Sleep Disorders Atlas Task Force of theAmerican Sleep Disorders Association. No authors listed Sleep 15 : 173-184, 1992
19） Hayano J, Taylor JA, Yamada A, Mukai S, Hori R, Asakawa T, Yokoyama K, Watanabe Y, Takata K, Fujinami T :Continuous assessment of hemodynamic control by complex demodulation of cardiovascular variability. Am J
Physiol 264 : H1229-1238, 199320） Hayano J, Taylor JA, Mukai S, Okada A, Watanabe Y, Takata K, Fujinami T : Assessment of frequency shifts in R-R
interval variability and respiration with complex demodulation. J Appl Physiol 77 : 2879-2888, 199421） Hayano J, Barros AK, Kamiya A, Ohte N, Yasuma F : Assessment of pulse rate variability by the method of pulse
frequency demodulation. Biomed Eng Online 4 : 62, 200522） Berger RD, Saul JP, Cohen RJ : Transfer function analysis of autonomic regulation, 1 : canine atrial rate response.
Am J Physiol 256 : H142-152, 198923） Goya TT, Silva RF, Guerra RS, Lima MF, Barbosa ER, Cunha PJ, Lobo DM, Buchpiguel CA, Busatto-Filho G, Negrão
CE, Lorenzi-Filho G, Ueno-Pardi LM : Increased Muscle Sympathetic Nerve Activity and Impaired Executive Per­
formance Capacity in Obstructive Sleep Apnea. Sleep 39 : 25-33, 201624） Akselrod S, Gordon D, Ubel FA, Shannon DC, Berger AC, Cohen RJ : Power spectrum analysis of heart rate
fluctuation : a quantitative probe of beat-to-beat cardiovascular control. Science 213 : 220-222, 1981
25） Task Force of the European Society of Cardiology and the North American Spociety of Pacing Electrophysiology.
Circulation 93 : 1043-1065, 1996
26） Somers VK, Dyken ME, Clary MP, Abboud FM : Sympathetic neural mechanisms in obstructive sleep apnea. J Clin
Invest 96 : 1897-1904, 1995
27） Liang J, Zhang X, He X, Ling L, Zeng C, Luo Y : The independent and combined effects of respiratory events and250

Shinshu Med J

67

Autonomic nerve function and morning blood pressure in SDB
cortical arousals on the autonomic nervous system across sleep stages. Sleep Breath 22 : 1161-1168, 201828） Narkiewicz K, Somers VK : Cardiovascular variability characteristics in obstructive sleep apnea. Auton Neurosci 90 :89-94, 2001
29） Kario K : Obstructive sleep apnea syndrome and hypertension : mechanism of the linkage and 24-h BP control.
Hypertens Res 32 : 537-541, 200930） Shirasaki O, Yamashita S, Kawara S, Tagami K, Ishikawa J, Shimada K, Kario K : A new technique for detecting
sleep apnea-related “midnight” surge of BP. Hypertens Res 29 : 695-702, 200631） The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2014). Hypertens Res
37 : 253-392, 2014（2018. 10. 25 received；2019. 4. 10 accepted）

No. 4, 2019251