Download Primary vagally mediated decelerations in heart rate during tonic

Primary vagally mediated decelerations in heart rate
during tonic rapid eye movement sleep in cats
RICHARD L. VERRIER,1,2 T. RERN LAU,3,4 UMESHA WALLOOPPILLAI,1 JAMES
QUATTROCHI,2,3 BRUCE D. NEARING,1,2 RICARDO MORENO,1,2 AND J. ALLAN HOBSON2,3
1Institute for Prevention of Cardiovascular Disease, Beth Israel Deaconess Medical Center;
2Harvard Medical School; 3Laboratory of Neurophysiology, Department of Psychiatry,
Massachusetts Mental Health Hospital, Boston 02215; and 4Harvard College,
Cambridge, Massachusetts 02139
phasic rapid eye movement sleep; pause; asystole
that sleep results in profound
state-dependent alterations in heart rate (2, 9, 12, 19,
29, 32). Slow-wave sleep (SWS) is associated with a
relatively stable pattern of reduced heart rate characterized by respiratory sinus arrhythmia. Rapid eye movement (REM) sleep results in more labile heart rate and
is characterized by abrupt fluctuations (2, 8, 9, 14–16,
23). The most common is a surge in heart rate that is
generally accompanied by the baroreflex-mediated deceleration in rate in response to the initial tachycardia
(2, 8, 9, 23).
The REM sleep-induced increases in heart rate are
accompanied by a striking increase in coronary arterial
blood flow that, in canines, achieves 35% over baseline
and lasts for 15–20 s (15). These heart rate surges occur
mainly during phasic REM sleep (8) and appear to be
mediated by the sympathetic nervous system because
they are abolished by chronic stellectomy (15). In
canines with coronary stenosis, the surge in heart rate
IT HAS LONG BEEN KNOWN
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results in a decrease in coronary flow through the stenosed
vessel (16). REM sleep may have an important impact on
arrhythmogenesis clinically, because ventricular arrhythmias (6, 32, 33) and angina (19, 21) are more pronounced during this phase of sleep. The importance of
changing autonomic tone to cardiac vulnerability during sleep is further underscored by the recent clinical
evidence of a nonuniform distribution of atrial fibrillation (25), sudden death, myocardial infarction, and
implantable cardioverter/defibrillator discharge (18).
In the present study, we describe a novel phenomenon of a primary deceleration in heart rate that occurs
predominantly during tonic REM sleep. This pattern is
distinct from the previously described baroreflexmediated decelerations in that it is characterized by an
abrupt decrease in heart rate without antecedent or
subsequent changes in rate.
The main goals of our study were to characterize the
primary decelerations in heart rate and to shed light on
the underlying central and peripheral autonomic mechanisms. These objectives were accomplished by recording from several CNS structures and by administration
of selective autonomic blocking agents that do not cross
the blood-brain barrier.
METHODS
The study was conducted according to National Institutes
of Health standards, and protocols were approved by the
Harvard Medical Area Standing Committee on Animal Use.
The animals were housed in 1.2 3 1.2-m cages, and food and
water were provided ad libitum. A 12:12-h light-dark cycle
was maintained.
Surgical preparation. Seven adult male cats weighing
between 2 and 2.5 kg were anesthetized with halothane
(1–2%) and chronically implanted with electrodes to monitor
electroencephalogram (EEG), pontogeniculooccipital (PGO)
wave activity in lateral geniculate nucleus (LGN) [6.5 anterior (A), 10.0 lateral (L), 112.0 ventral (V)], hippocampal CA1
theta activity (3.3 A, 5.5 L, 117.0 V), electromyogram (EMG),
electrooculogram (EOG), respiration, and electrocardiogram
(ECG). The stereotaxic coordinates are according to Berman
(4). EMG and EOG were monitored from electrodes placed in
the nuchal muscle and posterior wall of the orbit, respectively.
Respiration was monitored with a pair of diaphragmatic
electrodes inserted through a midline incision in the peritoneum and sutured directly onto the costal margin of the
muscle. Precordial ECG electrodes were placed subcutaneously. The noncephalic electrode leads were tunnelled subcutaneously to emerge with the cephalic leads in an amphenol
pin connector at the top of the head. In three animals, a
jugular intravenous catheter was inserted subcutaneously for
later autonomic blockade. In two additional animals, a cath-
0363-6119/98 $5.00 Copyright r 1998 the American Physiological Society
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Verrier, Richard L., T. Rern Lau, Umesha Wallooppillai, James Quattrochi, Bruce D. Nearing, Ricardo
Moreno, and J. Allan Hobson. Primary vagally mediated
decelerations in heart rate during tonic rapid eye movement
sleep in cats. Am. J. Physiol. 274 (Regulatory Integrative
Comp. Physiol. 43): R1136–R1141, 1998.—Rapid eye movement (REM) sleep results in profound state-dependent alterations in heart rate. The present study describes a novel
phenomenon of a primary deceleration in heart rate that is
not preceded or followed by increases in heart rate or arterial
blood pressure and occurs primarily during tonic REM sleep.
The goals were to characterize the primary decelerations and
to provide insights on the underlying central and peripheral
autonomic mechanisms. Cats were chronically implanted
with electrodes to record electroencephalogram, pontogeniculooccipital wave activity in lateral geniculate nucleus, hippocampal theta rhythm, electromyogram, electrooculogram,
respiration (diaphragm), and electrocardiogram. Arterial blood
pressure was monitored from a carotid artery catheter. R-R
interval fluctuations were continuously tracked using customized software. The muscarinic blocking agent glycopyrrolate
(0.1 mg/kg iv) and the b-adrenergic blocking agent atenolol
(0.3 mg/kg iv) were administered in alternating sequence
with a 90- to 120-min interval. Glycopyrrolate immediately
eliminated the decelerations during REM sleep. Atenolol
alone had no effect on their frequency. These findings suggest
that a change in the centrally induced pattern of autonomic
activity to the heart is responsible for the primary decelerations, namely, a bursting of cardiac vagal efferent fiber activity.
HEART RATE DECELERATIONS DURING TONIC REM SLEEP
Statistical methods. The two-way ANOVA was used to
calculate differences in the relative incidence of events by sleep
stage. Bonferroni post-test was used to compare the results
among the sleep states. Values are means 6 SE (P , 0.05).
RESULTS
Our findings demonstrate that tonic REM sleep is
associated with marked, transient reductions in heart
rate that are not preceded by increases in heart rate
(Fig. 1). This event is characterized as an R-R interval
increase .20% over the R-R mean value for the preceding 6 s. A second criterion was a duration of $1.4 s. The
44 h of control records analyzed yielded 27.4 h of sleep,
with 18.5 h of SWS and 8.8 h of REM sleep. There were
179 heart rate events during sleep that satisfied the
deceleration criteria. The mean R-R increase was 34 6
9%, and the greatest increase was 58%. The return to
normal rhythm after the deceleration episode was
unremarkable, showing no significant alteration in
rate compared with the predeceleration rate (Fig. 2).
The great majority (86%) of all decelerations lasted
between 1.5 and 3 s, with a mean duration of 2.25 6 0.7 s.
In the two cats instrumented for arterial blood
pressure measurement, we found that this parameter
was relatively stable before and after the heart rate
decelerations of tonic REM (Fig. 3). On cessation of
PGO activity and concomitant with the heart rate
deceleration, there was a moderate but statistically
significant reduction in arterial blood pressure, which
returned to the predeceleration value on resumption of
PGO wave firing. The fact that the pressure change was
relatively minor probably accounts for the absence of
an appreciable reflex compensatory heart rate increase.
All heart rate decelerations included in this analysis
are distinct from respiratory sinus arrhythmia. Examination of respiratory-linked decelerations detected
through the diaphragmatic tracing during both REM
and SWS revealed that the mean R-R increase for sinus
Fig. 1. Representative polygraphic recording of a primary heart rate
deceleration during tonic rapid eye movement sleep (T-REM). During
this deceleration, heart rate decreased from 150 to 105 beats/min, or
30%. Deceleration occurred during a period devoid of pontogeniculooccipital (PGO) spikes in lateral geniculate nucleus (LGN) or theta
rhythm in hippocampal (CA1) leads. Deceleration is not a respiratory
arrhythmia, because it is independent of diaphragmatic movement.
Abrupt decreases in amplitude of CA1, PGO waves (LGN), and
respiratory amplitude and rate (DIA) are typical of transitions from
phasic to tonic REM. EKG, electrocardiogram; EMG, electromyogram; DIA, diaphragm.
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eter was placed in the carotid artery for blood pressure
measurement, tunnelled subcutaneously, and affixed by acrylic
to the headcap. Postsurgical antibiotic treatment was administered as needed after consultation with a veterinarian.
Recording procedures. Monitoring was initiated 10–14 days
after surgery as the cats slept spontaneously in a soundattenuated, darkened, 1 3 1 3 1.2-m recording chamber at
room temperature (23°C) with a window for behavioral observation. Data from the 4-h afternoon sessions were recorded on
a Grass 78 multichannel polygraph with 7P511 amplifiers for
alternating current channels and 7P1/7DA amplifiers for
direct current channels (Grass Instruments, Quincy, MA). The
cable from the amphenol pin connector allowed 360° of rotation so that the animal could move freely in the chamber.
Peripheral autonomic blockade. After control recording of at
least one REM episode, the b1-adrenergic blocker atenolol (0.3
mg/kg iv) and the muscarinic blocker glycopyrrolate (0.1 mg/kg
iv) were administered in alternating sequence with a 90- to
120-min interval through the jugular catheter without disturbing the animals. Six repetitions of the protocol were carried out
in each of the three cats. The blood-brain barrier is impermeable to these two compounds (11, 17). Dosages were selected to
achieve a relatively high degree of receptor blockade without
disrupting sleep state.
Data analysis. The criteria for selecting a heart rate deceleration were 1) 20% increase in the R-R interval over the mean
for the preceding 6 s and 2) duration $1.4 s. A paper printout
was used for visual scanning and reference, and an optical disk
copy was analyzed on a Compaq DeskPro Pentium 90 MHz
computer under Windows 95. Our customized software provides color-coded plots of the R-R intervals, which make it
feasible to identify decelerations that fit the criteria. The
thresholds for the decelerations were entered before analysis.
Any increase in R-R interval .20% was plotted by the
computer in a different color from baseline R-R intervals. The
program could highlight a set time surrounding the deceleration so that heart rate preceding and after the event could be
measured. For each animal, the number of control and peripherally blocked decelerations during quiet waking, SWS, and
phasic and tonic REM sleep was totaled and the duration of
each deceleration was measured. The mean R-R intervals for
the 6 s immediately preceding and after the deceleration were
evaluated. The effects of respiration and of normal sinus
arrhythmia were eliminated from the analysis by discarding
the decelerations that coincided with diaphragmatic inflections and those that appeared in rhythmic series with respiration rate. In addition, typical decelerations linked to respiration were found to have a duration ,1.4 s and were thus
excluded by our criterion of duration $1.4 s.
Sleep stages were hand scored as SWS, REM sleep, and
quiet waking for each 15-s episode, according to current
practice (31). SWS was marked by high-voltage, low-frequency
synchronized EEG activity, delta waves, and spindle activity.
The transition from SWS to REM sleep was identified by the
appearance of $3 PGO waves/15 s in addition to SWS characteristics. REM sleep was characterized by low-voltage, highfrequency desynchronized EEG activity, atonia, PGO wave
activity, bursting of EOG activity, and an absence of delta and
spindle activity. The presence of EMG activity distinguished
quiet waking from REM sleep. PGO activity from LGN electrode recordings occurring as unclustered waves at intervals of
,300 ms defined phasic periods of REM sleep (20, 24). Periods
of REM containing EEG desynchronization with no PGO
waves or theta rhythm, although preceded and followed by
PGO or theta activity, were defined as tonic. The state
dependency and central nervous system (CNS) correlates of
heart rate decelerations were identified.
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HEART RATE DECELERATIONS DURING TONIC REM SLEEP
B
arrhythmia was 18%, with a mean duration ,1.4 s.
Furthermore, heart rate decelerations coinciding with
expiratory diaphragmatic inflections or appearing in
close rhythmic series were excluded from the analyses.
The criteria used in selecting decelerations thus excluded most heart rate decelerations linked to respiratory sinus arrhythmia.
The relationship between heart rate decelerations
and sleep states was also explored. SWS composed 42%
of the total recording time and 68% of the total sleep
period. REM sleep composed 20% of the total recording
time and 32% of the total sleep period. The mean
proportion of REM sleep spent in tonic activity was
,30%. SWS averaged 1 deceleration per 43.5 min;
phasic REM sleep averaged 1 deceleration per 16 min.
During tonic REM sleep, decelerations occurred at a
rate of 1 per 74 s, a 13-fold increase over phasic REM
sleep (P 5 0.0002) (Fig. 4). Significantly more decelerations occurred during tonic REM compared with either
phasic REM or SWS (P , 0.001, Bonferroni multiplecomparison test). The difference between the number of
decelerations during phasic REM and SWS was not
significant (P . 0.05).
Peripheral autonomic blockade with the mixed muscarinic antagonist glycopyrrolate both alone (Fig. 5)
and 90–120 min after b-blockade with atenolol immediately abolished heart rate decelerations during REM
sleep. At the dosage used, glycopyrrolate produced a
mean rate elevation of 49% and atenolol caused a mean
heart rate depression of 16%. The effect of glycopyrrolate at this dose also persisted beyond one half-life of
the drug. Administration of the b-adrenergic antagonist atenolol did not affect the frequency of decelera-
Fig. 3. A: representative polygraphic recording of decrease in arterial blood pressure during a primary heart rate deceleration during
T-REM. During this deceleration, heart rate decreased 20% from 175
to 138 beats/min and then recovered to 180 beats/min. As shown on
blood pressure channel (BP), there is no rise in arterial blood
pressure before onset of deceleration, indicating that deceleration is
due to central nervous system activation of vagus nerve and is not a
reflexly mediated compensatory phenomenon. Deceleration occurred
during a period devoid of PGO spikes in LGN. B: mean arterial blood
pressure before, during, and after 2 T-REM-induced heart rate
decelerations in each of 2 felines. Arterial blood pressure decreased
from 65.67 6 0.58 and 65.72 6 0.73 mmHg, at 20–11 and 10–1 beats
before the deceleration, respectively, to 58.53 6 0.96 mmHg (* P ,
0.001) during deceleration. Blood pressure returned to 64.65 6 1.00
mmHg (P , 0.001 compared with deceleration BP). Arterial pressure
before and after the event did not differ significantly (means 6 SE).
tions (Fig. 6). In two cats, we compared the proportion
of recording time spent in REM sleep and the mean
duration of REM epochs during 2 h before and after
glycopyrrolate and/or atenolol administration. These
Fig. 4. Number of heart rate decelerations per minute as a function
of sleep state. There were 0.023 6 0.007 decelerations/min in SWS
and 0.063 6 0.030 decelerations/min in P-REM (NS). Number of
decelerations/min in T-REM (0.806 6 0.100) is significantly greater
compared with other sleep states (P , 0.001).
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Fig. 2. Heart rates before, during, and after decelerations as a
function of sleep state. For all sleep states, heart rates during
decelerations are statistically different from heart rates for the 6 s
preceding and after decelerations (P , 0.001). For all states, there
was no statistical difference between heart rates 6 s before and 6 s
after each deceleration. During decelerations within slow-wave sleep
(SWS), heart rate decreased from 145.6 6 3.9 before to 102.7 6 4.4
during decelerations and then recovered to 142.8 6 1.9 beats/min. In
phasic REM sleep (P-REM), heart rate decreased from 140.8 6 3.1
before to 89.1 6 2.7 during deceleration and then recovered to
141.0 6 6.8 beats/min. For T-REM sleep, heart rate decreased from
144.1 6 3.7 before to 97.3 6 4.2 during deceleration and then
recovered to 137.7 6 2.6 beats/min. NS, not significant.
HEART RATE DECELERATIONS DURING TONIC REM SLEEP
parameters were not significantly different (P . 0.05),
indicating that sleep structure had not been disrupted,
perhaps due to the remote intravenous access and the
lack of lipophilicity of the two agents.
DISCUSSION
This study describes a novel phenomenon of a primary, abrupt deceleration in heart rhythm that occurs
predominantly during tonic REM sleep. It is distinct
from previously reported sleep state-dependent perturbations in heart rhythm inasmuch as it occurs in the
absence of antecedent acceleration or subsequent change
in heart rate or arterial blood pressure. In earlier
reports by Baust and Bohnert (2) and Dickerson and
co-workers (7), decelerations were almost invariably
accompanied by prior accelerations in rate, with the
likely involvement of baroreceptor activation. Another
distinctive feature is that the deceleration occurs pri-
Fig. 6. b-Adrenergic blockade with atenolol (0.3 mg/kg iv) did not
affect frequency of deceleration events (P . 0.05). Three repetitions of
this protocol were performed in each of three cats. Sleep architecture
was not affected by atenolol administration. Data analysis was
initiated 30 min after cats were placed in sleep chamber. By this time,
animals were uniformly asleep.
marily during tonic REM sleep. This differs from the
previously observed baroreceptor-mediated decelerations, which occur mainly during transition from SWS
to desynchronized sleep and more frequently during
phasic REM than any other stage of REM sleep (7). It is
surprising that this phenomenon of a primary deceleration has not been previously described. This omission
may have been in part due to the fact that previous
investigations have relied predominantly on ECG recordings with a highly compressed time scale or on
tachograph recordings, which have a relatively long
time constant and do not provide accurate representation of beat-to-beat changes. In the present study, the
customized software, with preprogrammed, objective
criteria for acceleration and deceleration, made it possible to track in exquisite detail the subtle dynamics of
beat-to-beat fluctuations throughout the recording period.
Comparison of new observations with previous reports of cardiac decelerations in REM. This phenomenon appears to be distinct from the reductions in heart
rate observed by Dickerson and co-workers (7). They
found heart rate pauses accompanied by increases in
coronary blood flow that were concentrated during
transition from SWS to desynchronized sleep and in
REM sleep, where they occurred more frequently during phasic than tonic REM sleep. Because the heart
rhythm pause was almost invariably preceded by tachycardia and elevations in arterial blood pressure, it is
likely that the deceleration in rate was the result of
reflex vagal activation secondary to baroreceptor stimulation. This differs from the present findings of decelerations that occur primarily during tonic REM sleep and
are not associated with any preceding or subsequent
change in heart rate or arterial blood pressure. The
only point of similarity is that the phenomena appear to
have a common mediator, namely enhanced vagal
activity. In the heart rhythm pauses described by
Dickerson and co-workers (7), however, vagal activity
appears to be due to a reflex response after sinus
tachycardia and hypertension. In the present study, the
involvement of the vagus appears to be directly initiated by central influences, because there is no antecedent or subsequent change in resting heart rate or
arterial blood pressure. The REM sleep-related decelerations reported by Baust and Bohnert (2) in their classic
study were also heralded by rate accelerations and
were therefore likely to have been part of a reflex
response. The heart rate decelerations in the present
study were not preceded by a rise in arterial blood
pressure, and therefore the present phenomenon does
not appear to be attributable to baroreflex phenomenon. Rather, the main mechanism appears to be
central activation of the vagus nerve, which slows the
heart directly. This surmise is further supported by the
fact that the decelerations were completely eliminated
by muscarinic blockade with glycopyrrolate.
The phenomenon that we have observed is more akin
to the primary, vagally mediated deceleration in heart
rhythm described by Guilleminault and co-workers (13)
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Fig. 5. Blockade with a single dose of the M2 muscarinic antagonist
glycopyrrolate (0.1 mg/kg iv) resulted in immediate elimination of
REM sleep-induced heart rate decelerations in all 3 repetitions of this
protocol in each of 3 cats. Pretreatment with atenolol did not alter
this effect in 3 repetitions in each of 3 cats (data not shown). Sleep
architecture was not affected by glycopyrrolate administration. Data
analysis was initiated 30 min after cats were placed in sleep chamber.
By this time, animals were uniformly asleep.
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HEART RATE DECELERATIONS DURING TONIC REM SLEEP
activity to the heart. This could be the result of a
decrease in sympathetic activity or an enhancement of
vagal tone, either alone or in combination. We found
that cardioselective b1-adrenergic blockade with atenolol did not affect the incidence or magnitude of decelerations but muscarinic blockade with glycopyrrolate completely abolished the phenomenon. These observations
suggest that the tonic REM sleep-induced decelerations are primarily mediated by bursting of cardiac
vagal efferent fiber activity. It is well known that
enhanced vagal activity can abruptly and markedly
affect sinus node firing rate (22). The quaternary
ammonium structure of glycopyrrolate limits its passage through the blood-brain barrier, thus minimizing
possible confounding CNS effects (11). The agent did
not affect REM sleep structure. Therefore, it is unlikely
that indirect effects of the drug on brain state contributed to this effect. Because b-adrenergic blockade exerted no effect on the frequency or magnitude of decelerations, it does not appear that withdrawal of cardiac
sympathetic tone is an important factor in the observed
rate changes. Rather, a primary surge in vagal activity
is implicated. This does not preclude the fact that
cardiorespiratory interactions may moderate heart rate,
because this influence operates throughout sleep (14).
However, our results suggest that respiratory interplay
is not an essential component of the deceleration,
because the phenomenon often occurred in the absence
of a temporal association with inspiratory effort, as is
evident in Fig. 3.
Perspectives
The present observations carry important clinical as
well as scientific implications. They underscore the
principle that sleep state-dependent CNS activity is
integrally coupled to cardiac-bound autonomic pathways. Improved understanding of the neuroanatomical
and functional linkage between the brain and the heart
during sleep may provide important information regarding the adaptive control of cardiovascular function in
normal subjects. Clinically, the growing realization of
the magnitude of sleep-related cardiovascular risk motivates further exploration of control of cardiac function
during sleep in patients with heart disease. It has been
estimated that 250,000 myocardial infarctions and
38,000 sudden deaths occur at night (18). The nonrandom distribution of these events implicates triggering
by autonomic activity. In addition, ,40% of episodes of
atrial fibrillation, for a total of one million events in the
United States alone, are precipitated at night (25).
Atrial tissue is particularly sensitive to the profibrillatory influences of acetylcholine, and pronounced surges
in vagal activity could be an important factor in the
prevalent but poorly understood phenomenon of nocturnal atrial fibrillation. Thus intense vagal activity, as
may occur during either tonic REM sleep, as in the
present study, phasic REM sleep (7, 13), or SWS has the
potential for precipitating not only pause-dependent
ventricular arrhythmias and asystole but also atrial
arrhythmias.
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in human subjects. They observed striking periods of
sinus arrest during REM sleep in young adults who
were apparently normal with respect to cardiac function. Two of the four subjects studied had infrequent
syncope while ambulatory at night and experienced
periods of asystole of up to 9 s during REM sleep.
Administration of muscarinic blockers, either atropine
or protriptyline, significantly reduced the duration of
the nocturnal asystoles but did not prevent them. The
authors concluded that the nocturnal asystoles were
the result of exaggerated, if not abnormally elevated,
vagal tone. However, given the present observations of
significant increases in vagal tone during sleep, the
patients may have represented an extreme portion of a
continuum of vagal activation during REM sleep. An
important difference between the phenomena reported
by Guilleminault (13) and the present findings in cats is
that in the human subjects, the decelerations were
concentrated during phasic, rather than tonic, REM
sleep. Thus it remains to be determined whether the
phenomena differ fundamentally or are species specific.
Although the predominant number of decelerations in
the cats occurred during tonic REM sleep, nevertheless
14% occurred during phasic REM sleep. Thus it is
possible that the distribution of decelerations in humans may favor phasic rather than tonic REM sleep.
Autonomic pathology, as suggested by Guilleminault
(13), may also impact on the magnitude and presentation of the phenomenon in human subjects.
Probable CNS origins of heart rate decelerations in
tonic REM. The primary involvement of CNS activation
is demonstrated by the consistent, antecedent abrupt
cessation of PGO activity and concomitant interruption
of hippocampal theta rhythm, which are salient features of the tonic REM sleep decelerations. This finding
had been anticipated based on the established positive
relationship between PGO activity and hippocampal
theta activity in cats (5, 26). How these changes in CNS
activity lead to the tonic REM sleep-induced increase in
vagal tone to suppress sinus node activity remains
unknown. The literature on the relationship between
PGO activity during sleep and cardiac function is
sparse. Baust and colleagues (3) found only a relatively
minor, baseline rate-dependent, variable response in
heart rate (,80 ms R-R interval change) to PGO
activity in cats. In normal human volunteers, Taylor
and colleagues (30) observed heart rate decelerations
during REM sleep that preceded eye bursts by 3 s and
suggested that the phenomenon reflects an orienting
response at the onset of dreaming. However, because
the decelerations were not illustrated nor their magnitude described, their similarity to those we characterize is debatable. Notwithstanding extensive studies of
the physiological and anatomic basis for PGO activity,
little is known about the conductivity and functional
relationship to heart rhythm control during sleep (1,
10, 27, 28).
Possible mechanisms of heart rate decelerations in
tonic REM. The most likely basis for the abrupt deceleration in heart rate during tonic REM sleep is a
change in the centrally induced pattern of autonomic
HEART RATE DECELERATIONS DURING TONIC REM SLEEP
We thank Sandra Verrier for editorial assistance and Katherine
Rowe for technical assistance.
This work was supported by Grant HL-50078 from the National
Heart, Lung, and Blood Institute. J. A. Hobson is a Merit Awardee of
the National Institutes of Mental Health (MH-13923); his work is
also supported by the Mind-Body Network of the MacArthur Foundation.
Address for reprint requests: R. L. Verrier, Institute for Prevention
of Cardiovascular Disease, Beth Israel Deaconess Medical Center,
One Autumn St., Boston, MA 02215.
Received 18 September 1997; accepted in final form 23 December
1997.
REFERENCES
15. Kirby, D. A., and R. L. Verrier. Differential effects of sleep
stage on coronary hemodynamic function. Am. J. Physiol. 256
(Heart Circ. Physiol. 25): H1378–H1383, 1989.
16. Kirby, D. A., and R. L. Verrier. Differential effects of sleep
stage on coronary hemodynamic function during stenosis. Physiol.
Behav. 45: 1017–1020, 1989.
17. Kostis, J. B., and R. C. Rosen. Central nervous system effects
of beta-adrenergic blocking drugs: the role of ancillary properties. Circulation 75: 204–212, 1987.
18. Lavery, C. E., M. A. Mittleman, M. C. Cohen, J. E. Muller,
R. L. Verrier. Nonuniform nighttime distribution of acute
cardiac events: a possible effect of sleep states. Circulation 96:
3321–3327, 1997.
19. Macwilliam, J. A. Blood pressure and heart action in sleep and
dreams: their relation to haemorrhages, angina, and sudden
death. Br. Med. J. 22: 1196–1200, 1923.
20. McCarley, R. W., and J. A. Hobson. Discharge patterns of cats
pontine brainstem neurons during desynchronized sleep. J.
Neurophysiol. 38: 751–766, 1975.
21. Nowlin, J. B., W. G. Troyer, Jr., W. S. Collins, G. Silverman,
C. R. Nichols, H. D. McIntosh, E. H. Estes, Jr., and M. D.
Bogdonoff. The association of nocturnal angina pectoris with
dreaming. Ann. Intern. Med. 63: 1040–1046, 1965.
22. Pappano, A. J. Modulation of the heartbeat by the vagus nerve.
In: Cardiac Electrophysiology: from Cell to Bedside, edited by
D. P. Zipes and J. Jalife. Philadelphia, PA: Saunders, 1995, p.
411–422.
23. Parmegianni, P. L. The autonomic nervous system in sleep.
In: The Principles and Practice of Sleep Medicine, edited by
M. H. Kryger, T. Roth, and W. C. Dement. Philadelphia, PA:
Saunders, 1994, p. 194–203.
24. Raetz, S. L., C. A. Richard, A. Garfinkel, and R. M. Harper.
Dynamic characteristics of cardiac R-R intervals during sleep
and wake states. Sleep 14: 526–533, 1991.
25. Rostagno, C., T. Taddei, B. Paladini, P. A. Modesti, P. Utari,
and G. Bertini. The onset of symptomatic atrial fibrillation and
paroxysmal supraventricular tachycardia is characterized by
different circadian rhythms. Am. J. Cardiol. 71: 453–455, 1993.
26. Sakai, K., K. Sano, and S. Iwahara. Eye movements and
hippocampal theta activity in cats. Electroencephalogr. Clin.
Neurophysiol. 34: 547–549, 1973.
27. Sieck, G. C., and R. M. Harper. Discharge of neurons in the
parabrachial pons related to the cardiac cycle: changes during
different sleep-waking states. Brain Res. 199: 385–399, 1980.
28. Siegel, J. M. Brainstem mechanisms generating REM sleep. In:
Principles and Practice of Sleep Medicine, edited by M. H.
Kryger, T. Roth, and W. C. Dement. Philadelphia, PA: Saunders,
1994, p. 125–144.
29. Snyder, F., J. A. Hobson, D. F. Morrison, and F. Goldfrank.
Changes in respiration, heart rate, and systolic blood pressure in
human sleep. J. Appl. Physiol. 19: 417–422, 1964.
30. Taylor, W. B., H. Moldofsky, and J. J. Furedy. Heart rate
deceleration in REM sleep: an orienting reaction interpretation.
Psychophysiology 22: 110–115, 1985.
31. Ursin, R., and M. B. Sterman. A Manual for the Standardized
Scoring of Sleep and Waking States in the Adult Cat. Los Angeles,
CA: Brain Information Service/Brain Research Institute, University of California, 1981.
32. Verrier, R. L., J. E. Muller, and J. A. Hobson. Sleep, dreams,
and sudden death: the case for sleep as an autonomic stress test
for the heart. Cardiovasc. Res. 31: 181–211, 1996.
33. Verrier, R. L., P. H. Stone, E. F. Pace-Schott, and J. A.
Hobson. Sleep-related cardiovascular risk: new home-based
monitoring technology for improved diagnosis and therapy. Ann.
Noninvasive Electrocardiol. 2: 158–175, 1997.
Downloaded from http://ajpregu.physiology.org/ by 10.220.33.5 on June 15, 2017
1. Baghdoyan, H. A., B. X. Carlson, and M. T. Roth. Pharmacological characterization of muscarinic cholinergic receptors in cat
pons and cortex. Pharmacology 48: 77–85, 1994.
2. Baust, W., and B. Bohnert. The regulation of heart rate during
sleep. Exp. Brain Res. 7: 169–180, 1969.
3. Baust, W., E. Holzbach, and O. Zechlin. Phasic changes in
heart rate and respiration correlated with PGO-spike activity
during REM sleep. Pflügers Arch. 331: 113–123, 1972.
4. Berman, A. L. The Brain Stem of the Cat. Madison, WI:
University of Wisconsin, 1968.
5. Bizzi, E., and D. C. Brooks. Functional connections between
pontine reticular formation and lateral geniculate nucleus during deep sleep. Arch. Ital. Biol. 101: 666–680, 1963.
6. Brodsky, M., D. Wu, P. Denes, C. Kanakis, and K. M. Rosen.
Arrhythmias documented by 24-hour continuous electrocardiographic monitoring in 50 male medical students. Am. J. Cardiol.
39: 390–395, 1977.
7. Dickerson, L. W., A. H. Huang, B. D. Nearing, and R. L.
Verrier. Primary coronary vasodilation associated with pauses
in heart rhythm during sleep. Am. J. Physiol. 264 (Regulatory
Integrative Comp. Physiol. 33): R186–R196, 1993.
8. Dickerson, L. W., A. H. Huang, M. M. Thurnher, B. D.
Nearing, and R. L. Verrier. Relationship between coronary
hemodynamic changes and the phasic events of rapid eye movement sleep. Sleep 16: 550–557, 1993.
9. Gassel, M. M., B. Ghelarducci, P. L. Marchiafava, and O.
Pompeiano. Phasic changes in blood pressure and heart rate
during the rapid eye movement episodes of desynchronized sleep
in unrestrained cats. Arch. Ital. Biol. 102: 530–544, 1964.
10. Gilbert, K. A., and R. Lydic. Pontine cholinergic reticular
mechanisms cause state-dependent changes in the discharge of
parabrachial neurons. Am. J. Physiol. 266 (Regulatory Integrative Comp. Physiol. 35): R136–R150, 1994.
11. Gilman, A. G., T. W. Rall, A. S. Nies, and P. Taylor (Editors).
Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York: Pergamon, 1990.
12. Guazzi, M., and A. Zanchetti. Blood pressure and heart
rate during natural sleep of the cat and their regulation by
carotid sinus and aortic reflexes. Arch. Ital. Biol. 103: 789–817,
1965.
13. Guilleminault, C. P., P. Pool, J. Motta, and A. M. Gillis.
Sinus arrest during REM sleep in young adults. N. Engl. J. Med.
311: 1006–1010, 1984.
14. Harper, R. M., R. C. Frysinger, J. Zhang, R. B. Trelease, and
R. R. Terreberry. Cardiac and respiratory interactions maintaining homeostasis during sleep. In: Clinical Physiology of Sleep,
edited by R. Lydic and J. F. Biebuyck. Bethesda, MD: Am.
Physiol. Soc., 1988.
R1141