Cardiac changes during arousals from non-REM sleep in healthy volunteers

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Cardiac changes during arousals from non-REM sleep in healthy volunteers.

Eugene Nalivaiko1, Peter G. Catcheside3, Amanda Adams3, Amy S. Jordan3, Danny J. Eckert3 and R. Doug McEvoy2,3

1Department of Human Physiology and Centre for Neuroscience, 2Department of Medicine, Flinders University and 3Adelaide Institute for Sleep Health, Repatriation

General Hospital, Adelaide, Australia

Running head: ECG changes during arousal from sleep

Contact information: Dr Eugene Nalivaiko Department of Human Physiology Flinders Medical Centre Bedford Park SA 5042 Australia tel +61 8 8204-4107 fax +61 8 8204-5768

e-mail:[email protected]

of 29Articles in PresS. Am J Physiol Regul Integr Comp Physiol (November 16, 2006). doi:10.1152/ajpregu.00642.2006

Copyright © 2006 by the American Physiological Society.

mailto:[email protected]

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ABSTRACT

Our aim was to evaluate cardiac changes evoked by spontaneous and sound-induced

arousals from sleep. Cardiac responses to spontaneous and auditory-induced arousals

were recorded during overnight sleep studies in 28 young healthy subjects (14 males, 14

females) during non-REM sleep. Computerised analysis was applied to assess beat-to-

beat changes in heart rate, atrio-ventricular conductance and ventricular repolarisation

from 30 s prior to 60 s after the auditory tone. During both types of arousals, the most

consistent change was the increase in the heart rate (in 62% of spontaneous and in 89% of

sound-induced arousals). This was accompanied by an increase or no change in PR

interval and by a decrease or no change in QT interval. The magnitude of all cardiac

changes was significantly higher for tone-induced vs. spontaneous arousals (mean±SD

for heart rate: +9±8 vs. +13±9 beats per min; for PR prolongation: 14±16 vs. 24±22 ms;

for QT shortening: -12±6 vs. -20±9 ms). The prevalence of transient tachycardia and PR

prolongation was also significantly higher for tone-induced vs. spontaneous arousals

(tachycardia: 85% vs. 57% of arousals, p<0.001; PR prolongation: 51% vs. 25% of

arousals, p<0.001). All cardiac responses were short-lasting (10-15 s). We conclude that

cardiac pacemaker region, conducting system and ventricular myocardium may be under

independent neural control. Prolongation of atrio-ventricular delay may serve to increase

ventricular filling during arousal from sleep. Whether prolonged atrio-ventricular

conductance associated with increased sympathetic outflow to the ventricular

myocardium contributes to arrhythmogenesis during sudden arousal from sleep remains

to be evaluated.

Key words: arousal, autonomic, atrio-ventricular node, QT, sympathetic.

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INTRODUCTION

Arousal from sleep is associated with profound and almost instantaneous cardiovascular

and respiratory changes. Sudden arousal may precipitate cardiac arrhythmias in subjects

with a susceptible myocardium; arousal is a recognised trigger of potentially fatal

polymorphic ventricular tachycardia (torsades de points) in patients with congenital long

QT syndrome (26, 30). Numerous arousals occurring in obstructive sleep apnea (OSA)

sufferers likely contribute to the development of accompanying cardiac pathology (11,

13, 16).

Surprisingly, human studies of cardiac changes during arousal from sleep rarely extend

beyond measuring heart rate. In a number of such studies (5, 7, 8, 15, 17, 19), a modest

and short-lasting tachycardia has been reported several seconds after an arousing

stimulus. Heart rate, however, is a poor index of potentially proarrhythmic changes that

may occur in the cardiac conduction system or in the atrial or ventricular myocardium.

We thus sought to characterize arousal-induced changes in atrio-ventricular conductance

and ventricular repolarization via a more detailed analysis of PR and QT ECG intervals in

healthy volunteers. Arousal-induced cardiac changes are short-lasting and require

dynamic, beat-to-beat detection of ECG intervals. To this end, we developed an

automated ECG analysis algorithm that could be applied to arousal responses.

Many cardiovascular-autonomic variables are gender dependent. Gender differences in

the basal HR and QT intervals during sleep have been reported (18), and susceptibility to

some types of cardiac arrhythmias appears to differ between the genders (21). Since in a

previous study we found greater ventilatory and peripheral vasoconstriction responses to

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arousal in men compared to women (15), our second aim was to compare arousal-induced

cardiac responses between healthy men and women.

METHODS

Subjects

In total, 14 males and 14 females participated. All subjects were non-smokers, non-

snorers, took no regular medications, and had no auditory, cardiovascular, respiratory or

sleeping problems. All females were studied in the follicular menstrual phase. The study

conformed with the principles outlined in the Declaration of Helsinki, and was approved

by the Repatriation General Hospital Research and Ethics Committee. All volunteers

provided written consent after being fully informed regarding the nature and risks of the

study. Subjects attended the laboratory approximately 2 hours prior to their normal

reported bedtime (range 9:30 to 12:30 pm) having abstained from caffeine for at least 8

hours.

Data collection, experimental protocol and data analysis

Sleep parameters including 2 electroencephalograms (EEG; C4-A1, C3-A2), left and

right electrooculograms and submental electromyograms (from the skin area under the

chin) were continuously recorded via a Compumedics S-series system (Abbotsford,

Victoria Australia). In each subject a ECG signal (lead II) was amplified and band-pass

filtered (0.3-30 Hz, Compumedics S series) and recorded using a 1 kHz sample rate.

To elicit sound-induced arousals, auditory tones (0.5s, 1kHz, range 55-90 dB) were

administered throughout the night via ear-insert headphones. Tones were presented

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during the expiratory phase of ventilation following at least 5-min of sleep after any

period of wakefulness (EEG defined wake lasting >15-sec) and at least 2-min of stable

sleep without arousal (spontaneous or tone-induced EEG changes lasting 3-15 sec). Tone

intensity was adjusted in 5-dB increments to achieve as many 3-15 sec EEG defined

arousals as practical.

A single skilled technician, blinded to all but the conventional sleep recordings (EEG,

EOG and EMG) determined sleep stage in 30-sec epochs according to standard criteria

(25). The same technician identified all 3-15 sec EEG defined arousal events according to

American Sleep Disorders Association criteria (1).

ECG analysis

For each subject, 3 spontaneous and 3 tone-induced arousal events recorded during stable

stage 2 sleep were selected at random for detailed ECG analysis. Digital ECG recordings

from 30-sec before to 60-sec after the point of onset of EEG-defined arousal event were

analysed using custom-written software in IgorPro (WaveMetrics, OR, USA). Our

algorithm for ECG wave detection consisted of the following steps (Fig. 1A): a) manual

setting of the threshold - above the peak of T-wave but below the peak of the R-wave; b)

manual setting of time points for computing the baseline before P-wave (b1) and after T-

wave (b2); c) detection of R-wave peak of the first ECG cycle; d) detection of Q-wave

peak; e) computing the baseline voltage before P-wave; f) detection of the P-wave peak;

g) detection of the P-wave onset (computed as a time when the voltage exceeded 5% of

the P-wave amplitude); h) detection of the baseline after T-wave; i) detection of the T-

wave peak; k) detection of the T-wave end (computed as a time when the voltage

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dropped to 5% of the T-wave amplitude); l) shift to the next ECG cycle. On the

termination of the computation, the software returned the text values for the

instantaneous HR and for each PR and QT interval, X and Y values (amplitude and time)

for each T-wave, and raw ECG trace with the markers superimposed on it (Fig. 1B). This

allowed visual inspection (performed on each trace), with manual correction of markers if

necessary, prior to calculation of HR and PR and QT intervals. QT interval corrected for

HR (QTcorr) was computed according to Bazett’s formula (3): QTcorr =QT/RR0.5. We also

computed two indices reflecting transmural dispersion of repolarization, according to

(32): Tpeak-Tend (time from the prak to the end of each T-wave) and late T-wave area (an

area under the falling phase of each T-wave). The latencies of cardiac responses for

sound-induced arousals were calculated as time between the onset of an auditory tone and

the peak changes in the HR or PR or QT intervals. Beat-by-beat HR, PR and QT interval

measurements were then converted to a beat-interval independent time-base using linear

interpolation at 0.1 sec intervals. Replicate trial data within each arousal type (tone-

induced and spontaneous) were averaged within each subject.

Statistical analysis

Gender, arousal type and time-dependent effects on heart rate, PR and QT intervals were

examined using 2-way ANOVA for repeated measures using values recorded at 2-sec

intervals between arousal onset (time zero) and 20-sec post arousal, with arousal type and

time as repeated factors within subjects. A 2-sec interval was chosen to allow time-effects

to be examined over the 20-sec post-arousal period whilst keeping the number of

replicate measures within limits compatible with ANOVA for repeated measures.

Greenhouse-Geisser adjusted p-values < 0.05 were considered significant.

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In addition to ANOVA of group data we used the cumulative sum method (10) to detect

statistically significant deviations from baseline within each individual data trace. By

examining each ECG trace in this way the incidence and magnitude of the post arousal

changes in ECG parameters were computed. Linear regression was used to assess

dependence between the amplitudes of arousal-induced changes in the ECG interval, and

Chi-square tests were used to examine differences in their incidence. Data were analysed

using StatView 5.0 (SAS Institute Inc., USA). Group data are reported as means±SD.

P<0.05 was considered significant.

RESULTS

Subject and EEG arousal characteristics

The subjects were young and of normal weight for height and did not differ in age or

body mass index between genders (Table 1). The tone intensity associated with all tone-

induced arousals was 63±10 dB (range 58-69 dB) and was not different between genders

(p=0.846). The duration of arousal-related EEG changes was nearly identical for tone-

induced versus spontaneous arousals (7.0±1.1 vs. 6.9±1.0 sec), and there were no gender

or gender by arousal type interaction effects (p=0.254 and p=0.717 respectively).

Basal ECG parameters

Values for the basal HR and for the PR and QT intervals are presented in Table 2.

Females had higher heart rate, longer QTcorr interval and shorter Tpeak-Tend duration

compared to males but PR and QT intervals did not differ between males and females.

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Changes in ECG indices associated with arousals

As shown graphically in Fig. 2, there were strong time-dependent effects of arousal on

heart rate (p<0.001), PR (p=0.006) and QT (p<0.001) interval responses in the 20-sec

post arousal. There were also significant arousal type x time dependent interaction effects

for heart rate (p<0.001) and QT interval (p=0.014) and a trend for a similar interaction for

PR interval (p=0.093), with generally smaller responses for spontaneous compared to

tone-induced arousals. The effect of gender was not significant, and there was no gender

x arousal-type interaction. Arousals had no effect on Tpeak-Tend or late T-wave area.

Histograms showing the distribution of arousal-related ECG changes are shown in Fig. 3.

For both types of arousal, the predominant HR response was transient increase in the HR

(62% of spontaneous arousals and 89% of tone-induced arousals). When PR intervals

changed (27% of spontaneous arousals and 44% of tone-induced arousals), the

predominant direction of this change was prolongation. When QT intervals changed,

(31% of spontaneous arousals and 40% of tone-induced arousals), this was predominantly

shortening. Of 54 arousals where QT interval shortened, this shortening started on the

same cardiac cycle (n=6), one cycle after (n=32) or one cycle prior (n=4) to the beginning

of changes in the RR interval. The magnitude of changes in ECG intervals are presented

in Table 2 and individual examples of arousal-induced ECG changes are illustrated in

Fig. 4.

The pattern of arousal-related ECG changes varied between subjects, but for a given type

of arousal, the pattern remained consistent within subjects. Linear regression analysis

revealed that in females, but not in males, magnitude of tachycardic responses correlated

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with QT interval shortening, as illustrated in Fig. 5. This was true for both types of

arousals. For both genders, there was no dependence between changes in HR and PR

interval or between PR and QT intervals changes.

In some instances, PR interval prolongation was associated with transient changes in P-

wave morphology (inversion, increase or decrease in amplitude), as illustrated in Fig. 6.

This happened during 11 sound-induced arousals and during 3 spontaneous arousal

episodes. P-wave changes were of different duration (sometimes lasting just 2-3 beats),

and clearly were not accompanied by changes in R- or T-wave morphology. In 3 cases,

inversion or decrease of P-wave amplitude was associated with a small transient fall in R-

wave amplitude (Fig. 6D).

The mean latency to QT shortening (3.6±0.9 s) did not differ from the mean latency to

HR increase (4.1±0.9 s). The latency to PR interval change was longer (5.2±1.3 s), and

was significantly different from both HR and QT latency responses (p<0.01) (Table 2).

Spontaneous vs. tone-induced arousals

The incidence of transient tachycardia and PR prolongation was significantly higher

during tone-induced compared to spontaneous arousals (increase in HR: p<0.001; PR

prolongation: p<0.05). The incidence of QT interval shortening was not different between

the two arousal types (p=0.277).

HR changes during tone-induced arousals were larger compared to spontaneous arousals

(+13±9 vs. +9±8 BPM, p<0.05, n=28) when measured for the whole experimental group.

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A small number of bradycardic responses did not affect this relationship. For all cases

where PR interval transiently increased, this increase was larger for tone-induced

compared to spontaneous arousals (+25±17 vs. +14±11 ms, p<0.05). The magnitude of

QT interval shortening was also substantially larger during tone-induced than

spontaneous events (-20±8 vs. -12±5 ms, p<0.01).

DISCUSSION

This is the first study with a detailed beat-to-beat analysis of changes in atrio-ventricular

conductance and ventricular repolarization (as detected by PR and QT interval duration)

during arousal from sleep in humans. Our major aim was to test whether arousal

provokes any changes in these parameters. The most important and novel observation is

that arousal-induced transient tachycardia often was associated either with a paradoxical

prolongation of the PR interval, or with a rate-independent shortening of the QT interval,

or with both. These results suggest that the cardiac pacemaker region, conducting system

and ventricular myocardium may be under independent neural control (see below).

Mechanisms of arousal-induced cardiac changes

Several previous studies have examined cardiovascular changes during stimulus-evoked

and spontaneous arousal from sleep in healthy humans (5, 7, 8, 17, 19, 22), and our

observation of transient tachycardia shortly after an arousal stimulus is in full agreement

with these reports. The short latency of cardiac changes observed in this and previous

studies clearly indicates that these are neurally-mediated responses.

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In many instances increases in HR were associated with a transient QT interval

shortening. QT interval is known to depend on HR, and shortens as HR increases. This

rate-dependent shortening is not instantaneous, and requires at least several cardiac cycles

to develop. In our study, QT shortening occurred during the same or the subsequent

cardiac cycle as an increase in HR, indicating that transient tachycardia was not the cause

of QT alterations. Most likely, QT shortening reflects a genuine decrease in myocardial

repolarisation time elicited by sympathetically-released noradrenaline.

Tachycardia is usually associated with a speeding in atrio-ventricular (AV) conductance

that is reflected by PR interval shortening. Lack of such shortening in our subjects could

mean that either relevant neural pathways were not activated, or that PR changes were

too small for detection. Our most interesting finding is that in many instances arousal-

induced transient tachycardia was associated with PR interval prolongation which was

sometimes quite substantial. PR prolongation could not be attributed to software

detection artefacts as each ECG record was inspected visually following automatic

processing. It is possible that PR prolongation was secondary to the rise in heart rate, a

phenomenon well documented in humans during rapid atrial pacing (6, 20, 23). However,

in this case one would expect a correlation between the increase in HR and PR interval

prolongation and this was not observed in our study. Another possibility, albeit

speculative, is that heart rate and atrio-ventricular conductance are under independent

neural control (see last section).

Differences between spontaneous and induced arousals, and gender differences.

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The intensity and incidence of cardiac changes were substantially higher during tone-

induced arousals, which is possibly indicative of their adaptive role: while spontaneous

awakening may or may not be associated with the onset of physical activity, forced

arousal may indicate immediate threat. During the brief period after arousal from sleep

the normal baroreflex is suspended (31), perhaps in preparation for a flight or fight

response. Horner (14) presents a view that the process of arousal represents a distinct

physiological state, with reduced gating of sensory information. In this regard, it is

interesting to note that auditory stimuli presented to awake volunteers habituate and

produce much smaller cardiovascular effects compared to the situation when these same

subjects are asleep (22).

Given that arousal-induced ventilatory changes followed a similar time-course and were

also larger following tone-induced compared to spontaneous arousals (15), it is possible

that cardiac arousal responses are partly mediated by intrathoracic pressure and more

delayed chemoreflex changes associated with the ventilatory arousal response. However,

the very short latencies to cardiac changes as reported here indicate that they were

unlikely to be secondary to ventilatory effects.

In full accord with a previous report by Lanfranchi (18), we found that basal HR was

higher, and basal QTcorr was longer in females compared to males. Interestingly, females

had slightly shorter basal Tpeak-Tend interval. As it is currently unknown whether this

parameter is rate-dependent (like QT-interval), meaning of this our finding is difficult to

interpret. The only gender-related difference in arousal-induced cardiac responses was

that in females, but not in males, the amplitude of tachycardic response correlated with

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QT-interval shortening, for both spontaneous and induced arousals. The reasons for such

differences are unclear and may at least in part reflect other cardiovascular influences

unrelated to gender (e.g. differences in cardiovascular fitness). These data further support

the growing evidence of gender differences in cardiovascular reactivity (9).

Relevance to mechanisms of arrhythmogenesis

Several types of cardiac arrhythmias are clearly associated with the sleep state (see (28)

for review). Sudden arousal from sleep by an alarm clock may precipitate potentially fatal

polymorphic ventricular tachyarrhythmias (“torsades de pointes”) in patients with

congenital long QT syndrome (29, 30). Sound-induced arousal from sleep is now a

recognised arrhythmia trigger for the subjects with the LQT3 subtype of this syndrome

(as opposed to LQT1 subtype where physical exercise is a major trigger), and it is even

recommended that they remove alarm clocks and phones from their bedrooms (26). Our

present results indicate that sudden arousals possibly enhance myocardial noradrenaline

release – a prerequisite for arrhythmogenesis (27).

Several previous studies have also reported an association between obstructive sleep

apnoea and cardiac arrhythmias (11, 13, 16). It may be that these arrhythmias are related,

at least in part, to numerous arousals occurring during sleep in OSA patients. Such

arousals are accompanied with changes in HR, albeit under quite different hemodynamic

and ventilatory conditions.

It is unknown whether the changes in AV conductance reported here during arousal

represent an additional pro-arrhythmic factor. We speculate that during increased

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sympathetic outflow to the ventricular myocardium, prolonged AV delay may potentially

contribute to arrhythmogenesis by retarding the arrival of the normal ventricular

excitation wave, thereby extending the "vulnerable" diastolic period.

We did not find any arousal-induced changes in Tpeak-Tend and late T-wave area, an ECG

indices of transmural dispersion of repolarization in the ventricular myocardium(32).

This may indicate that either these changes are too small to be detected by our method, or

that in healthy individuals sound-induced arousals from sleep do not affect transmural

dispersion of repolarization.

We observed quite substantial inter-individual variability in the magnitude of cardiac

responses during arousals. It may be that more reactive individuals are at greater risk of

developing cardiac arrhythmias compared to less reactive individuals. If so, assessment

of cardiac reactivity during arousals from sleep may prove to be a useful approach for

risk stratification.

Perspectives

At present, we can only speculate regarding the mechanisms underlying arousal-related

changes in AV conductance. It is possible that arousal resulted in altered autonomic

neural outflow to the AV node. Two possibilities exist. Firstly, it may be that

sympathetically-activated transient tachycardia and shortening of ventricular

repolarisation were associated with increased vagal outflow to the conducting structures

of the heart, resulting in an increase of the PR interval. Secondly, it is possible that a

transient increase of autonomic outflow to the atria resulted in a spatial shift of the

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pacemaker active site (2, 4), so that the distance from this site to the AV node increased.

Transient changes in P-wave morphology in some of our subjects could represent a

surface ECG manifestation of such a pacemaker shift. In most instances, these P-wave

changes were not associated with any alterations in the shape or amplitude of the QRS

complex or T-wave (Fig. 3A-C), and it is thus unlikely that they were caused by

respiration-related changes in cardiac axis. Clearly, further experiments with

parasympathetic blockade are required to elucidate mechanism of the AV conductance

slowing.

Whether arousal-induced increase in AV delay is a previously unknown adaptive

physiological phenomena or a sign of pathology remains an open question. Auditory-

induced arousals during non-REM sleep are associated with a substantial fall in stroke

volume, so that cardiac output also falls despite tachycardia (22). It thus seems entirely

reasonable to suggest that in the physiologically alarmed state such as the transition from

sleep to wakefulness evoked by potentially dangerous external events, a longer interval

between atrial and ventricular contractions may improve ventricular filling and thus

counteract the decrease in the cardiac output.

The magnitude of the arousal-induced tachycardic response did not correlate with

changes in atrio-ventricular conductance. Also, in males change in heart rate did not

correlate with changes in cardiac repolarization. Furthermore, in many instances increase

in heart rate was the only observable cardiac response to arousal. These results suggest

that the cardiac pacemaker area, conductive system and ventricular myocardium are

controlled independently, possibly with simultaneous increase of sympathetic outflow to

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the pacemaker area and to the myocardium, and of vagal outflow to the conductive

system. This, in turn, may indicate that separate subpopulations of cardiomotor neurons

in the brainstem are responsible for the control of chronotropic, dromotropic and

inotropic function. While such a possibility remains speculative with regard to

sympathetic control, Gatti et al. (12) reported that functionally distinct preganglionic

vagal motoneurons in the nucleus ambiguous independently control cardiac rate and AV

conduction. Importantly, co-activation of vagal and sympathetic outflow to the heart was

noted in several studies, in which the functional significance of such co-activation often

remained unexplained; see review by Paton et al. (24).

Acknowledgements: The authors are grateful to Prof Bill Blessing for the assistance in

developing the software for ECG analysis, and to Dr Kieron Thomson for his comments

regarding the manuscript. This work was supported by funding from the National Health

and Medical Research Council of Australia and by the National Heart Foundation of

Australia.

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FIGURES LEGENDS

Fig. 1. User-assisted automatic detection of ECG indices. A – sequence of steps in the

processing of each cardiac cycle. See text for details. B – raw ECG trace with

automatically generated markers at P-wave onset, Q-, R- and T-peaks and T-wave end.

Fig. 2. Arousals from sleep produce transient increase in heart rate associated with

prolongation of PR interval and shortening of QT interval - averaged group data (14

males and 14 females). Vertical line depicts acoustic stimulus onset for tone-induced

arousals and onset of EEG changes for spontaneous arousals. See text for details.

Fig.3. Histograms showing distribution of cardiac responses that occurred during

spontaneous (A) and tone-induces (B) arousals. Data are presented as a number of trials,

with a total number of trials equal 84 for each graph. As vertical scales are extended for

convenience of comparison, zero bins are truncated; figures at the top of each zero bin

indicate the number of trials with no response. Bin width – 2 BPM (for heart rate) and 2

ms (for PR and QT intervals).

Fig 4. Changes in HR, PR and QT intervals during sound-induced arousals from sleep.

Upper panels (A) illustrate these changes observed in three different subjects (a, b and c).

Dashed lines indicate the time of acoustic stimulus. Bottom panels depict raw ECG traces

from the case Aa. Dashed line in Ba and Bb are the same ECG complex recorded at 28 s,

just prior to the arousal sound. Solid lines – ECG complexes with maximal QT (Ba) and

PR (Bb) changes, recorded at times corresponding to the peaks on PR and QT traces,

respectively, in Aa. Duration of all traces in the panel B – 1 s.

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Fig. 5. Tachycardiac responses correlated with QT intervals shortening in females, but

not in males, for both spontaneous and tone-induced arousals. Data are presented as

deltas. Dashed lines – linear regression fits.

Fig. 6. Changes in P-wave morphology during arousals. A-D: ECG records from four

different subjects during sound-induced arousals from sleep. Dashed lines indicate the

time of acoustic stimulus. Note that arousal was associated with P-wave inversion (A) or

decrease (B) or increase (C and D) in the P-wave amplitude. E: EEG trace during arousal,

with a typical K-complex and transient appearance of alpha rhythm.

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Table 1. Subject characteristics. Males Females p Age (yr) 26.9 ± 7.3 23.6 ± 6.3 0.223 Weight (kg) 78.2 ± 11.2 66.0 ± 11.4 0.008 Height (cm) 184.3 ± 6.2 167.5 ± 5.0 <0.001 BMI (kg·m2) 23.0 ± 2.5 23.4 ± 3.1 0.666Values are mean±SD. n=14 males and 14 females.

Table 2. Values of basal ECG indices and of their changes associated with arousals.

Values are mean±SD Some cells in the table are empty because corresponding parameters do not exist. NS – non-significant; M+F – males plus females.

Spontaneous arousals Tone-induced arousals Males Females p M+F Males Females p M+F

HR basal (BPM) 55±5 59±5 0.04 57±5 54±6 59±6 0.03 56±6HR delta (BPM) 7±9 11±9 NS 9±8 10±8 16±6 NS 13±9HR latency (s) - - - - 4.0±1.0 4.1±0.4 NS 4±0.8 PR basal (ms) 163±24 168±26 NS 165±24 169±27 160±20 NS 165±25 PR delta (ms) 16±15 13±17 NS 14±16 16±21 30 ± 22 NS 24±22 PR latency (s) - - - - 5.1±1.6 5.2±0.7 NS 5.2±1.3 QT basal (ms) 404±23 407±22 NS 405±22 411±26 408 ± 20 NS 410±23 QTcorr basal (ms) 385±13 402±12 0.004 394±16 389±16 409 ± 26 0.02 399±24 QT delta (ms) -10±6 -14±4 NS -12±6 -19±3 -21 ± 8 NS -20±9QT latency (s) - - - - 3.6±1.1 3.7± 0.9 NS 3.7±1Tpeak-Tend (ms) 88±2 79±2 0.018 83±1 87±2 80±2 0.013 83±1LateT-area (mV*ms) 42±2 42±2 NS 42±2 44±2 42±3 NS 43±2

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Fig. 1 160x141mm (72 x 72 DPI)

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Fig. 3 176x170mm (72 x 72 DPI)

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Fig. 4 206x246mm (72 x 72 DPI)

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Fig. 5 179x164mm (72 x 72 DPI)

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Fig. 6 189x203mm (72 x 72 DPI)

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Cardiac changes during arousals from non-REM sleep in healthy volunteers

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