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From the Departments of Internal Medicine (K.N., P.J.H. v. d. B., V.K.S.)
and Neurology (M.E.D.), Cardiovascular Division, University of Iowa, Iowa
City, and Centro L.I.T.A.-Vialba (N.M., C.C.), Centro Ricerche
Cardiovascolari, CNR, Medicina Interna II, Ospedalè "L.
Sacco", Università degli Studi di Milano (Italy).
Correspondence to Virend Somers, MD, PhD, Department of Internal Medicine, Cardiovascular Division, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242. E-mail virend-somers{at}uiowa.edu
Methods and Results—Spectral analysis of variability of
muscle sympathetic nerve activity, RR interval, and blood pressure were
obtained during undisturbed supine rest in 15 patients with
moderate-to-severe OSA, 18 patients with mild OSA, and 16 healthy
control subjects in whom sleep disordered breathing was excluded by
complete overnight polysomnography. Patients with OSA were newly
diagnosed, never treated for OSA, and free of any other known diseases.
Patients with moderate-to-severe OSA had shorter RR intervals (793±27
ms) and increased sympathetic burst frequency (49±4 bursts/min)
compared with control subjects (947±42 ms; 24±3 bursts/min;
P=0.008 and P<0.001, respectively). In
these patients, total variance of RR was reduced
(P=0.01) and spectral analysis of RR variability
showed an increase in low frequency normalized units, a decrease
in high frequency normalized units, and an increase in the ratio of low
to high frequency (all P<0.05). Even though blood
pressure was similar to that of the control subjects, blood pressure
variance in patients with moderate-to-severe OSA was more than double
the variance in control subjects (P=0.01). Patients with
mild OSA also had a reduction in RR variance (P=0.02) in
the absence of any significant difference in absolute RR interval. For
all patients with OSA, linear regression showed a positive correlation
(r=0.40; P=0.02) between sleep apnea
severity and blood pressure variance.
Conclusions—Cardiovascular variability is altered
in patients with OSA. This alteration is evident even in the absence of
hypertension, heart failure, or other disease states and may be linked
to the severity of OSA. Abnormalities in cardiovascular
variability may be implicated in the subsequent development of overt
cardiovascular disease in patients with OSA.
In patients with overt cardiovascular disease, altered
autonomic regulation, manifesting as abnormalities in
cardiovascular variability, may be linked to adverse
cardiovascular outcomes. Heart rate variability is
markedly reduced in patients with heart
failure12 13 14 and in patients after myocardial
infarction.15 Decreased heart rate variability in
patients with idiopathic dilated cardiomyopathy
independently predicts the risk of cardiac death or heart
transplantation.16 After myocardial infarction,
depressed heart rate variability is a powerful prognostic indicator of
both arrhythmic complications and death.15 17 18
Increased blood pressure variability in hypertension is linked
independently to target organ damage.19 20 21 There
are no studies of the heart rate, blood pressure, and sympathetic nerve
variability in awake, otherwise normal patients with OSA in comparison
with matched control subjects.
Spectral analysis of heart rate variability is a widely
used noninvasive technique for the assessment of autonomic indexes of
neural cardiac control.22 23 24 In normal humans,
short-term RR interval variability occurs predominantly at a low
frequency (LF) (0.04 to 0.14 Hz) and a high frequency (HF) (±0.25 Hz,
synchronous with the respiratory frequency).18 33
Similar variability profiles are present in direct
recordings of sympathetic nerve traffic25
and blood pressure.25 26
Whether patients with sleep apnea have abnormalities in
cardiovascular variability, in the absence of existing
cardiovascular disease, is not known. We tested the
hypothesis that cardiovascular variability is
altered in patients with OSA and that the severity of
cardiovascular variability derangement is linked to the
severity of OSA. We therefore compared variability characteristics of
simultaneous recordings of MSNA, RR interval, blood
pressure, and respiration in patients with mild OSA, patients with
moderate-to-severe OSA, and matched normal control subjects in whom OSA
was excluded by complete overnight polysomnographic monitoring.
The decision to divide the patients with OSA into two groups
(mild and moderate to severe) was prospective and was based on the AHI
(number of apneas or hypopneas per hour of sleep). Patients with an AHI
of <20 were classified as the mild group, and those with an AHI of
>20 were classified as the moderate-to-severe group. This
classification followed earlier studies showing that mortality rates in
patients with OSA and an AHI of >20 was markedly increased in
comparison with patients with OSA and an AHI of
<20.9
The 16 healthy control subjects were closely matched for age and body
mass index (Table 1
Informed written consent was obtained from all subjects. The study was
approved by the institutional human subjects review committee.
Measurements
All subjects were studied during the daytime (in the morning or the
early afternoon). Studies were conducted in the same room and
Data Analysis
Analog-to-digital conversion was performed in real time at 600
samples/s/channel. The data then were analyzed off-line with a
personal computer (Aptiva, IBM). The principles of the software for
data acquisition and spectral analysis have been described
elsewhere.25 This method allows spectral
analysis of respiration, RR interval, beat-to-beat blood
pressure, and sympathetic nerve activity. In brief, a
derivative-threshold algorithm provided the continuous series of RR
intervals (tachogram) derived from the ECG. Isolated artifacts were
detected and removed. From the arterial pressure signal,
beat-to-beat systolic (systogram) and diastolic
(diastogram) values were calculated. A specially designed interpolation
program was used to minimize any effects of occasional calibration
signals on spectral analysis of the Finapres
recordings. The signals of sympathetic nerve activity and
respiratory activity were sampled once every cardiac cycle, thus
obtaining a neurogram and a respirogram synchronized with the
tachogram. Before sampling, the neurogram was preprocessed to provide,
for each cardiac cycle, the time-integrated value of the signal.
All variability series were analyzed by means of autoregressive
parametric spectral and cross-spectral algorithms that
automatically provide the number, center frequency, and power of each
oscillatory component.23 25
The LF and HF spectral components of RR interval, SBP, and MSNA were
expressed in absolute and normalized units (NU). The NU were obtained
by calculating the percentage of LF and HF variability with respect to
the total power after subtracting the power of the very low frequency
component (frequencies of <0.03 Hz).18 23 31 The
HF oscillation in each subject was related to the
respiratory signal. Occasionally, a small amount of power was detected
at frequencies higher than the respiratory frequency. This amount of
variance was not taken into account in the calculation of the
normalized HF power. Therefore, the sum of the normalized LF and HF
powers did not equal 100% in all subjects. A coherence
(K2) function then was used to determine
the amount of linear coupling among the series of RR interval,
sympathetic nerve activity, systolic blood pressure (SBP), and
respiration.25 31 This measure has the same
meaning as the squared correlation coefficient (explained variance) in
a linear regression equation and allows a determination of the amount
of linear coupling between the oscillations present in
different time series.
The presence of LF components in respiration prevents interpretation of
the LF and HF components of cardiovascular
variabilities because of overlap of the respiratory
oscillation with the LF
oscillation.32 33 The respiratory
variability had a significant LF component in 4 normal control
subjects, 5 patients with mild OSA, and 4 patients with
moderate-to-severe OSA. Consequently, we obtained meaningful data on
the LF and HF components of cardiovascular variability
in 12 control subjects, 13 patients with mild OSA, and 11 patients with
moderate-to-severe OSA.
Statistical Analysis
Although blood pressure was similar in the three groups (Table 1
Whether expressed in absolute burst frequency or bursts per 100 heart
beats, MSNA was markedly elevated in both patients with mild OSA (46±3
bursts/min; 64±4 bursts per 100 heart beats) and patients with
moderate-to-severe OSA (49±4 bursts/min; 63±4 bursts per 100 heart
beats) compared with the control subjects (24±3 bursts/min; 38±4
bursts per 100 heart beats) (P<0.001 for each
comparison).
Patients with moderate-to-severe OSA had an increased normalized LF
variability of RR interval (P=0.045) and a decreased
normalized HF variability of RR interval (P=0.04) compared
with the control subjects (Table 2
The center frequencies of the LF and HF components of the patients with
OSA did not differ from those of the control subjects. The coherence
among the LF variability of RR, SBP, and MSNA in the patients with
sleep apnea was similar to that in the control subjects (>0.5 in all
three subject groups). The linear coupling among the HF components of
RR interval variability, MSNA, and respiration were similar and
correlated significantly for the control subjects, the patients with
mild OSA, and the patients with moderate-to-severe OSA.
When the two groups of patients with OSA were pooled together (n=33),
AHI correlated negatively with RR interval (r=-0.37,
P=0.04) and positively with both MSNA (r=0.44,
P=0.01) and SBP variability (r=0.40,
P=0.02). MSNA was correlated negatively with RR interval
(r=-0.56, P=0.001) and RR variability
(r=-0.44, P=0.01) and positively with SBP
variability (r=0.38; P=0.03). In patients with
sleep apnea in whom frequency domain analysis was feasible
(n=24), AHI correlated positively with the normalized LF component of
the RR interval (r=0.42, P=0.04) and negatively
with the normalized HF component of the RR interval
(r=-0.41, P=0.047).
Altered cardiovascular variability affects
predominantly patients with moderate-to-severe sleep apnea. In addition
to faster heart rate and increased sympathetic burst frequency, RR
variability is decreased and blood pressure variability is markedly
increased in these patients. Normalized LF variability of RR and
LF-to-HF ratio of RR variability are increased, and normalized HF
variability of RR is decreased. In patients with mild sleep apnea,
these abnormalities are less pronounced, with significant differences
from normal control subjects evident only in a decreased RR variability
and an increase in MSNA burst frequency. It is intriguing that mild
sleep apneics also manifest decreased RR variability even in the
absence of both the significant RR shortening and increased blood
pressure variability seen in moderate-to-severe sleep apneics. It may
be that abnormalities in control mechanisms regulating RR variability
precede the development of abnormalities in blood pressure variability
and absolute heart rate.
The reason for the absence of a clear increase in LF-to-HF ratio of
MSNA variability is not known. It may be that in this particular
context, the LF-to-HF ratio is a less sensitive index of sympathetic
drive. Alternatively, it may be that the progression of changes in
autonomic drive in OSA first affects heart rate and absolute MSNA,
before changes in MSNA variability become evident.
Previous studies of cardiovascular variability in sleep
apnea have analyzed mainly measurements obtained during
sleep.34 35 Repetitive apneas trigger marked
fluctuations in both blood pressure and heart rate with consequent
effects on the estimates of cardiovascular
variability.11 The validity of spectral measures
during repetitive apneas and consequent respiratory irregularity also
has been questioned.32 Data for the present
study therefore were obtained during wakefulness and in the absence of
either apneas or hypoxemia.
Prior studies have reported that patients with OSA have increases in
direct intraneural measurements of sympathetic nerve
traffic.10 11 However, there have been no
previous comparisons of sympathetic activity in patients with sleep
apnea compared with subjects without sleep apnea who have similar body
mass index and blood pressure. Thus, the contribution of obesity and
blood pressure to high sympathetic traffic in patients with sleep apnea
was uncertain. The present study shows that obesity and
hypertension do not account for the high sympathetic neural traffic in
patients with OSA.
This study had several strengths. First, all participants were
free of medications. Second, normal control subjects were matched for
age and body mass index, thus ruling out any potential confounding
influence of age or obesity on our data. Third, given the high
prevalence of OSA in asymptomatic, apparently normal obese
subjects27 and the lack of reliable screening
tests for sleep apnea,36 we ruled out
sleep-related breathing disorders in our control subjects by complete
overnight polysomnographic recordings. Fourth, all patients
with sleep apnea were normotensive, free of other known diseases, newly
diagnosed, and never treated for sleep apnea. Last, all measures were
obtained in the absence of potential confounding influences such as
apneas, oxygen desaturation, or sleep.
Thus, the variability derangements in moderate-to-severe sleep apneics
are not explained by factors such as age, body mass index, or, in
particular, blood pressure. Tachycardia, decreased heart
rate variability,37 increased blood pressure
variability,38 and an increase in the LF-to-HF
ratio of RR variability37 are characteristic
abnormalities of patients with hypertension. Increased blood pressure
variability in hypertensive patients is associated with an increased
likelihood of target organ damage,19 20
independent of the absolute blood pressure level. Thus, an excessive
blood pressure variability may constitute an independent risk factor
for cardiovascular disease. In our study, however,
these abnormalities of heart rate and blood pressure variability were
manifest in normotensive sleep apneic patients, in whom absolute blood
pressure levels were similar to those of the control subjects. Patients
with sleep apnea are at increased risk for
hypertension.2 In epidemiological studies of
normotensive subjects, reduced heart rate variability is predictive of
the subsequent development of new-onset
hypertension.39 We therefore speculate that
abnormalities in cardiovascular variability may
precede, and possibly predispose to, the development of hypertension in
patients with sleep apnea. The fast heart rates, increased LF-to-HF
ratio of RR variability, and increased sympathetic burst frequency are
consistent with a state of heightened sympathetic
cardiovascular drive in sleep apnea. Increased
sympathetic drive may be implicated in the pathogenesis of a number of
cardiovascular risk factors, including insulin
resistance, hypertension, and the evolution of
cardiovascular
hypertrophy.40
Heart rate variability in sleep apnea is reduced, an abnormality that
predicts morbidity and mortality rates in patients with
diabetes41 or heart
failure42 or after myocardial
infarction.15 17 Blood pressure variability in
sleep apneics is increased (about twice that of normal subjects), an
abnormality that is linked to end-organ damage in patients with
hypertension.19 20 These abnormalities are
evident in sleep apnea even in the absence of diabetes or detectable
cardiovascular disease. Why should
cardiovascular variability be deranged in otherwise
normal patients with moderate-to-severe sleep apnea? MSNA in patients
with OSA was positively correlated with blood pressure variability.
Although the mechanism underlying increased blood pressure variability
in patients with OSA will require further investigation, the increased
sympathetic drive may be implicated in increased daytime blood pressure
variability in these patients. It may be that repetitive sympathetic
activation and blood pressure surges that occur in response to apneic
episodes during sleep11 cause an impairment of
baroreflex and other cardiovascular reflex functions
that carry over even into daytime wakefulness.
In conclusion, we demonstrated that cardiovascular
variability is altered in patients with OSA. This alteration is evident
even in the absence of hypertension, heart failure, or other disease
states. The degree of alteration in cardiovascular
variability may be linked to the severity of OSA. Abnormalities in
cardiovascular variability may be implicated in the
subsequent development of overt cardiovascular disease
in patients with OSA.
Received February 2, 1998;
revision received April 29, 1998;
accepted May 4, 1998.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Altered Cardiovascular Variability in Obstructive Sleep Apnea
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Altered
cardiovascular variability is a prognostic indicator
for cardiovascular events. Patients with obstructive
sleep apnea (OSA) are at an increased risk for
cardiovascular disease. We tested the hypothesis that
OSA is accompanied by alterations in cardiovascular
variability, even in the absence of overt cardiovascular
disease.
Key Words: nervous system, autonomic • nervous system, sympathetic • sleep • blood pressure • heart rate
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Obstructive sleep
apnea (OSA) has been linked to hypertension,1 2
heart failure,3 myocardial
ischemia,4 myocardial
infarction,5 stroke,6 and
vascular complications.7 Patients with OSA
may have increased mortality rates.8 9 The
mechanisms underlying the association between OSA and
cardiovascular disease are not known. Sympathetic drive
is increased in OSA10 11 ; therefore,
abnormalities in autonomic cardiovascular regulation
may be implicated.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Subjects
Measurements were obtained in three groups of subjects: normal
control subjects (n=16), patients with mild OSA (n=18), and patients
with moderate-to-severe OSA (n=15). The three groups were similar in
age, body mass index, blood pressure, and gender distribution (Table 1
). The patients with sleep apnea were
newly diagnosed, normotensive, free of any other known diseases, and
receiving no medications; had never been treated for sleep apnea; and
were otherwise healthy. All patients with sleep apnea also were free of
any cardiac history, limitation or changes in exercise tolerance, and
symptoms or signs suggestive of congestive heart failure. Mean
apnea-hypopnea index (AHI) was 15±1 events/h for the 18 patients with
mild OSA and 61±8 events/h for the 15 patients with
moderate-to-severe OSA.
View this table:
[in a new window]
Table 1. Demographics of Normal Subjects and Patients With
Sleep Apnea 
). Because of the high prevalence of occult OSA in
apparently normal, asymptomatic obese
subjects,27 sleep-disordered breathing was
excluded in all control subjects by complete overnight polysomnographic
studies.
MSNA was recorded continuously by obtaining multiunit
recordings of postganglionic sympathetic activity to muscle
circulation, measured from a nerve fascicle in the peroneal nerve
posterior to the fibular head, as described
previously.28 Electrical activity in the nerve
fascicle was measured using tungsten microelectrodes (shaft diameter of
200 µm, tapering to an noninsulated tip of 1 to 5 µm). A
subcutaneous reference electrode first was inserted 2 to 3 cm from the
recording electrode, which was inserted into the nerve
fascicle. The neural signals were amplified, filtered, rectified, and
integrated to obtain a mean voltage display of sympathetic nerve
activity. 
3 hours
after the last meal. After the placement of electrodes and monitoring
equipment, subjects were allowed to rest in the supine position for
15 minutes before measurements were obtained.
Simultaneous measurements of the ECG, respiration
(pneumograph), oxygen saturation (Nellcor pulse oximeter),
arterial pressure (Finapres system), and MSNA
were recorded on a Gould 2800 S recorder and a Pentium PC.
These measurements were obtained while subjects were awake, during 10
minutes of undisturbed supine rest. None of the subjects or patients
had apneas, hypopneas, or oxygen desaturation during the study.
Sympathetic bursts were identified by a single observer (K.N.).
The intraobserver and interobserver variabilities in our laboratory
have been reported to be 4.3±0.3%29 and
5.4±0.5%,30 respectively. Sympathetic activity
was calculated as bursts/min and bursts per 100 heartbeats after
careful inspection of the mean voltage neurogram.
Results are expressed as mean±SEM, except for the demographics
presented in Table 1, for which values represent
mean±SD. Statistical analysis consisted of one-way ANOVA,
followed by Scheffé's test for multiple comparisons, to allow
pairwise testing for significant differences between the groups.
Because of a skewed distribution, we used the ln transform of the
LF-to-HF ratios. Correlations were estimated with use of the Pearson
coefficient. A value of P<0.05 was considered
significant.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
The RR interval was significantly shorter in patients with
moderate-to-severe OSA (793±27 ms) than in the normal subjects
(947±42 ms; P=0.008) (Figures 1 and 2).
Variance of RR interval was reduced significantly in both patients with
mild OSA (P=0.02) and patients with moderate-to-severe OSA
(P=0.01) (Figure 1).
View larger version (27K):
[in a new window]
Figure 1. RR interval, SBP, and their variances in control
subjects (n=16), patients with mild OSA (n=18), and patients with
moderate-to-severe OSA (n=15). RR interval was reduced in the patients
with moderate-to-severe OSA compared with the control subjects.
Patients with mild OSA and patients with moderate-to-severe OSA had an
attenuated RR variance in comparison with that in the control subjects.
SBP variance was markedly increased in patients with moderate-to-severe
OSA compared with either control subjects or patients with mild OSA.
*P<0.05 versus control subjects.
P<0.05 versus mild OSA. Data are mean±SEM.
View larger version (31K):
[in a new window]
Figure 2. ECG, blood pressure, sympathetic neurograms, and
respiration in a control subject (left) and in a patient with severe
OSA (right), showing faster heart rate (HR), increased blood pressure
(BP) variability, and markedly elevated MSNA in the patient with OSA.
Spectral analysis recordings for these subjects are
shown in Figure 3 .,
Figure 1), SBP variance in patients with moderate-to-severe OSA
(22±3 mm Hg) was greater than that in the control subjects
(9±3 mm Hg; P=0.01) and greater than that in
patients with mild OSA (12±3 mm Hg; P=0.03). ,
Figures 3 and 4). The LF-to-HF ratio of RR variability,
but not of SBP variability or MSNA variability, was increased
significantly in the patients with moderate-to-severe OSA (Table 2)
compared with the control subjects and patients with mild OSA (both
P=0.04). The normalized LF and HF components of RR, SBP, and
MSNA variability in patients with mild OSA were not different from
those observed in the control subjects (Table 2).
View this table:
[in a new window]
Table 2. LF and HF Variabilities of RR Interval, SBP, and
MSNA in Subjects Without an LF Component in
Respiration
View larger version (19K):
[in a new window]
Figure 3. Power spectral analysis of
simultaneous recordings of RR variability, SBP
variability, MSNA variability, and respiration (Resp) in the control
subject (left) and in the patient with OSA (right) shown in Figure 2 .
RR variance is decreased and SBP variance is increased in the patient
with OSA compared with the control subject. There is a relative
predominance of the LF component over the HF component of RR interval
in the patient with OSA. LF components are clearly present in the
MSNA variability profiles of both subjects. PSD indicates power
spectral density; au, arbitrary units. The vertical axes for MSNA and
respiration are not numbered because these show arbitrary units.
View larger version (26K):
[in a new window]
Figure 4. Normalized LF and HF components of RR interval in
control subjects (n=12), patients with mild OSA (n=13), and patients
with moderate-to-severe OSA (n=11). The mean LF power of RR interval
variability was higher and the mean HF power was lower in the patients
with OSA compared with the control subjects. *P<0.05
versus control subjects. Data are mean±SEM.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The novel findings in this study are that (1)
cardiovascular variability is altered in patients with
OSA, and this alteration occurs even in the absence of hypertension,
heart failure, or other disease states; and (2) the degree of
derangement in cardiovascular variability may be linked
to the severity of OSA.
Acknowledgments
Dr Narkiewicz, a visiting scientist from the Department of
Hypertension and Diabetology, Medical School of Gdansk, Poland, is the
recipient of a Fogarty Fellowship (NIH 3F05-TW-05200) and a Perkins
Memorial Award from the American Physiological
Society. This study also was supported by an American Heart Association
Grant-in-Aid, NIH HL-14388, and an NIH Sleep Academic Award (Dr
Somers). We thank Diane Davison, RN, MA, for technical assistance.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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 S. M. Caples, A. S. Gami, and V. K. Somers Obstructive Sleep Apnea Ann Intern Med, February 1, 2005; 142(3): 187 - 197. [Full Text] [PDF]
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C. Cogliati, S. Colombo, T. G. Ruscone, D. Gruosso, A. Porta, N. Montano, A. Malliani, and R. Furlan Acute {beta}-Blockade Increases Muscle Sympathetic Activity and Modifies Its Frequency Distribution Circulation, November 2, 2004; 110(18): 2786 - 2791. [Abstract] [Full Text] [PDF]
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 S. Rey, R. Del Rio, J. Alcayaga, and R. Iturriaga Chronic intermittent hypoxia enhances cat chemosensory and ventilatory responses to hypoxia J. Physiol., October 15, 2004; 560(2): 577 - 586. [Abstract] [Full Text] [PDF]
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 F. Iellamo, F. Placidi, M. G. Marciani, A. Romigi, M. Tombini, S. Aquilani, M. Massaro, A. Galante, and J. M. Legramante Baroreflex Buffering of Sympathetic Activation During Sleep: Evidence From Autonomic Assessment of Sleep Macroarchitecture and Microarchitecture Hypertension, April 1, 2004; 43(4): 814 - 819. [Abstract] [Full Text] [PDF]
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 K. Dingli, T. Assimakopoulos, P.K. Wraith, I. Fietze, C. Witt, and N.J. Douglas Spectral oscillations of RR intervals in sleep apnoea/hypopnoea syndrome patients Eur. Respir. J., December 1, 2003; 22(6): 943 - 950. [Abstract] [Full Text] [PDF]
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R. Wolk, A. S.M. Shamsuzzaman, and V. K. Somers Obesity, Sleep Apnea, and Hypertension Hypertension, December 1, 2003; 42(6): 1067 - 1074. [Abstract] [Full Text] [PDF]
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