J. Sleep Res. (1998) 7, 282–287

Heart rate variability and apnea during sleep in Down’ssyndrome

R A F F A E L E F E R R I 1 , 2 , L I L I A C U R Z I - D A S C A L O VA 4 , S T E F A N O D E LG R A C C O 2 , M A U R I Z I O E L I A 2 , S E B A S T I A N O A . M U S U M E C I 2 andS A LVAT O R E P E T T I N AT O 3

1 Sleep Research Center, 2 Department of Neurology and 3 Department of Neurophysics, Oasi Institute for Research on Mental Retardationand Brain Aging (IRCCS), Troina, Italy and 4 INSERM, Laboratoire de Physiologie-EF, Hopital Robert Debre, Paris, France

Accepted in revised form 17 April 1998; received 14 November 1997

SUMMARY Autonomic system dysfunction has been reported to occur frequently in patients withDown’s syndrome (DS) and is constituted mainly by an imbalance between thesympathetic and vagal systems. The analysis of heart rate variability (HRV) duringsleep is a quantitative reliable method for studying such a mechanism, but it has notyet been extensively and adequately applied in DS. In this study, HRV during sleepwas evaluated in seven DS patients and in six normal controls, by also controllingfor the presence of sleep apnea or arousal. The main results were an increasedsympathetic function (low-frequency component of HRV) and a decreased vagalactivity (high-frequency component of HRV) in DS with respect to normal controls,during apnea-free periods. Moreover, the presence of apnea, in DS, induced a furthersignificant increase in low-frequency and very low-frequency components of HRVduring sleep Stage 2. This study provides additional evidence of a brainstemdysfunctioning in DS, responsible for the abnormal imbalance between the sympatheticand vagal systems and confirms the brainstem involvement already suggested in theliterature in order to explain brainstem-auditory evoked potential abnormalities andcentral sleep apnea in these patients.

Down’s syndrome, heart rate variability, spectral analysis, central sleepapnea, obstructive sleep apnea, brainstem, autonomic function

INTRODUCTION centers) and peripheral (oscillation in arterial pressure andrespiratory movements) oscillators (Malliani et al. 1991).

Autonomic system dysfunction has been reported to be aSpectral analysis of heart rate variability (HRV) is a

common problem in Down’s syndrome (DS) and seems to bequantitative reliable method for analyzing the modulatory

responsible for fatal idiosyncrasy to atropine-related drugseffects of neural mechanisms on the sinus node (Task Force(McKusick 1957), hyperreactivity to atropine (Berg et al. 1959;of the European Society of Cardiology and the NorthMir and Cumming 1971) and to the anticholinergic agentAmerican Society of Pacing and Electrophysiology, 1996)tropicamide (Sacks and Smith 1989), and of abnormaland two main components are currently considered, high-sympathetic enzyme levels and response to noradrenaline (Lakefrequency (HF) and low-frequency (LF). The vagal activityet al. 1979) in these patients.is the major contributor to the HF component while theHeart rate is under the control of efferent sympatheticLF component is considered by some authors as a markerand vagal activities directed to the sinus node, which areof sympathetic modulation and by others as a parametermodulated by central brainstem (vasomotor and respiratoryincluding both vagal and sympathetic influences.

To our knowledge, the only previous study on HRV duringsleep in DS is that by Sei et al. (1995) who reported changesCorrespondence: Dr Raffaele Ferri, Department of Neurology, Oasiin autonomic control of the cardiac activity, mostly constitutedInstitute, Via Conte Ruggero,73, 94018 Troina, Italy.

Fax+39–935–653327, e-mail: rferri@oasi.en.it by an increase in HR during REM sleep. However, in this

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Heart rate variability and sleep apnea in DS 283

paper little attention was paid to other sleep-related factors by means of an Oxford MPA-II recorder: electrocardiogram,which could influence the results, the most important of which peripheral oxygen saturation, chest wall movement by thoracicis the presence of sleep apnea episodes, frequent in DS (Southall impedance, and oro-nasal airflow with thermistors. All signalset al. 1987; Marcus et al. 1991; Stebbens et al. 1991; Ferri were also reproduced on paper by means of a Siemenset al. 1997). In fact, respiratory pauses are accompanied by a Mingograf EEG 21 polygraph.significant change in heart rate sympathovagal balance(Vanninen et al. 1996) and by an important increase in very

Sleep and respiration analysislow frequency component of HRV in adults as well as in

Sleep stages were scored on paper recordings, followingchildren (Shiomi et al. 1996; Aldjadeff et al. 1997).For this reason, in the present study, we evaluated HRV standard criteria (Rechtschaffen and Kales 1968). Subsequently,

during sleep in a group of seven DS patients and compared respiratory pauses and oxygen desaturations werethe results with those obtained in six normal controls, by also automatically detected by the software provided with thecontrolling for the presence of sleep apnea. Our hypothesis is Oxford Medilog 9200 System; however, all episodes detectedthat an autonomic system imbalance in DS should be reflected were checked and visually controlled examining the tracingsby an increase in LF and a decrease in HF component of HRV on screen.during sleep, this imbalance being not a simple consequence Respiratory episodes were classified as apneas if theof the presence of apnea but dependent on primarily autonomic amplitude of the airflow (and thoracic movement, duringchanges. central pauses) was reduced to less than 20% of baseline

breaths, for at least 10 s, or as hypopneas if the reduction wasbetween 20 and 50% of baseline. Finally the apnea/hypopneaSUBJECTS AND METHODSindex (AHI) was calculated for both central and obstructive

Patients events, in each subject and during each sleep stage, as thenumber of episodes per hour of sleep. Desaturation eventsSeven DS patients (diagnosis confirmed by karyotyping), werewere defined as a decrease in oxygen saturation percentage ofincluded in this study; their mean age was 13.9 years (rangeat least 4% from baseline values; these events were considered8.6–16.5 years). The height and weight of each patient wereas depending from a respiratory pause when they occurredmeasured and the corresponding body mass index calculatedwithin 30 s after the latter. Also the desaturation index (DeI),(weight/height2). Body mass index ranged between 15.1 andi.e. number of desaturation dips per hour, was calculated for25.8 with an average value of 21.4.each subject.None of the patients presented with acute or chronic

respiratory illness; also, a severe degree of macroglossia orglossoptosis, tonsillar and adenoidal encroachment, and other Heart rate variability analysismalformative abnormalities of the upper airways were absent.

HRV was studied on the recording night for each 10-min periodNone of the subjects showed gross neurologic deficit. Five hadin the following stages located within the first or second sleepnormal cardiovascular function; the remaining two presentedcycle: W+S1 (sleep Stage 1, including wake around sleepmitral valve prolapse or arching not causing significant changesonset), S2 (sleep Stage 2), SWS (sleep Stages 3 and/or 4), andof the circulatory dynamics. None of them presented atlanto-REM sleep. For DS patients, these epochs were subdividedaxial instability or luxation. None of the patients was receivinginto epochs without sleep apnea episodes and in epochs withdrugs acting at the level of the central or peripheral nervoussleep apnea episodes, containing at least five apnea events (assystems.defined above) each. In normal controls, only epochs withoutsleep apnea were found. Arousal events were also visually

Control subjects detected and counted in all epochs without apnea, followingthe criteria established by the American Sleep DisordersThe control group included six subjects (mean age 12.8 years,Association (1992)). In each 10-min epoch, ECG signals wererange 8.0–17.5 years). All of them were carefully evaluatedanalyzed for automatic detection of Rwaves with a self-madefrom the neurological, otorhinolaryngoiatric andprogram utilizing a simple threshold plus first derivativecardiovascular points of view and failed to show significantalgorithm; however, careful visual inspection for possible errorsabnormalities.was performed on all epochs. In order to overcome the problemof the low sampling rate of our recorders (128 Hz) which might

Recordinghave caused a jitter in the estimation of the R-wave fiducialpoint (Task Force of the European Society of Cardiology andAll subjects slept in the laboratory for two consecutive nights;the North American Society of Pacing and Electrophysiologythe recording of data was carried out during the second night.1996) and a consequent alteration of the spectrum, a parabolicFor determination of sleep stages, the electroencephalograminterpolation was used to refine its evaluation (Merri et al.(6 channels), the electro-oculogram, and the mental1990; Bianchi et al. 1993). A series of time domain measureselectromyogram were recorded by means of an Oxford Medilog

9000-II recorder. Other physiological variables were recorded were calculated: mean R-R-value, SDNN (standard deviation

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284 R. Ferri et al.

Table 1 Comparison between sleep parameters of DS and normal subjects

DS subjects Normal subjectsMann-Whitney

Mean S.D. n Mean S.D. n P-level

TIB (min) 470.8 74.349 7 484.7 26.561 6 N.S.SPT (min) 439.3 67.596 7 457.3 22.322 6 N.S.TST (min) 407.6 65.736 7 443.2 21.255 6 N.S.SEI 0.867 0.0478 7 0.916 0.0589 6 N.S.SOL (min) 21.57 32.659 7 22.50 23.445 6 N.S.AW/h 1.270 0.6840 7 0.638 0.2673 6 N.S. (0.086)SS/h 7.011 1.3481 7 6.053 1.0545 6 N.S.FRL (min) 215.3 35.537 7 126.3 32.605 6 0.003WASO% 7.161 5.3269 7 3.057 2.6861 6 N.S. (0.063)S1% 6.497 1.6330 7 4.933 1.9868 6 N.S. (0.086)S2% 55.48 9.1068 7 58.20 4.8744 6 N.S.SWS% 18.53 3.8684 7 18.90 4.4556 6 N.S.REM% 12.75 2.4480 7 14.80 2.1652 6 N.S.

TIB: Time in bed; SPT: sleep period time; TST: total sleep time; SEI: sleep efficiency index; SOL: sleep onset latency; AW/h: awakenings/h;SS/h: stage shifts/h; FRL: first REM latency; WASO: wakefulness after sleep onset; S1: sleep Stage 1; S2: sleep Stage 2; SWS: sleep Stages 3and 4; REM: rapid eye movement sleep.

of all R-R intervals), RMSSD (the square root of the mean of controls. Only the latency of REM sleep (FRL) resultedsignificantly delayed in DS patients (P<0.003) while there werethe sum of the squares of differences between adjacent R-Rnon-significant changes in some other parameters (increase inintervals), NN50 (number of pairs of adjacent R-R intervalsnumber of awakenings, in wakefulness after sleep onset and indiffering by more than 50 ms in the entire epoch), pNN50sleep Stage 1%; decrease in REM sleep percentage.(NN50%). The first 512 R-R intervals from each epoch were

As expected, DS patients showed, on average, 11.1 centralutilized for all subsequent analysis steps. Subsequently, the R-sleep apnea/hour, 1.4 obstructive sleep apnea (total sleep apneaR interval tachograms were analyzed by means of a FFT12.5/h, range 0.85–19.6) and an average oxygen desaturationalgorithm and the following spectral parameters were obtained:index of 7.0 (range 0–17.1). Normal controls only showed rareVLF (power in very low-frequency range, <0.04 Hz), LF (powerisolated central pauses usually following sighs, not causingin low-frequency range, 0.04–0.15 Hz), HF (power in high-peripheral oxygen desaturation.frequency range, 0.15–0.4Hz), total power (VLF+LF+HF),

The average number of arousal events during each stageLF% (LF power in normalized units: LF/(totalconsidered in this study was very low and similar in DS patientspower−VLF)×100), HF% (HF power in normalized units:(epochs without apnea) and normal controls (0.83 vs. 0.80HF/(total power−VLF)×100), LF/HF (ratio LF/HF), VLFduring W+S1, 0.75 vs. 0.71 during sleep Stage 2, 0.08 vs.peak (frequency of highest peak in the VLF range), LF peak0.14 during SWS, and 1.16 vs. 1.78 during REM sleep); the(frequency of highest peak in the LF range), HF peakdifferences were not statistically significant.(frequency of highest peak in the HF range).

Heart rate variability during epochs without sleep pneaStatistical analysisThe results of the comparison between DS and normal subjectsThe comparison between sleep parameters and HRV-relatedof HRV during stages W+S1 and SWS, in absence of sleepmeasurements obtained from epochs without sleep apnea eventsapnea, are shown in Tables 2 and 3.and in each sleep stage, in the group DS patients and in normal

During stage W+S1, DS patients showed significantlycontrols, was performed by means of the Mann–Whitney test.

increased LF% and LF/HF, and decreased HF% (Table 2).In the group of DS subjects, the statistical comparison between

During sleep Stage 2, all parameters were not significantlyHRV parameters obtained from epochs without and from those

different, between the two groups. On the contrary, duringwith sleep apnea events in each sleep stage was performed by

sleep Stages 3 and/or 4, most of the frequency domainmeans of the Wilcoxon test for paired data sets (Siegel 1956).

parameters showed a statistically significant difference:increased VLF, LF, LF% and LF/HF, and decreased HF% in

RESULTS DS, as well as a significantly higher frequency of the peak inthe VLF range in the same group (Table 3). During REMSleep structure and sleep apneasleep, the increase in VLF absolute power did not reach

Table 1 shows the comparison between sleep structure statistical significance while the frequency of the peak in theLF range was significantly decreased in DS patients.parameters found in both groups of subjects, DS and normal

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Heart rate variability and sleep apnea in DS 285

Table 2 Comparison between HR findings in DS and normal subjects during stage W+S1 without sleep apnea

DS subjects Normal subjectsMann–Whitney

Mean S.D. n Mean S.D. n P-level

Mean R-R-value (s) 0.882 0.2003 5 0.836 0.2358 6 N.S.SDNN 0.111 0.0527 5 0.079 0.0462 6 N.S.RMSSD 0.094 0.0690 5 0.079 0.0582 6 N.S.NN50 204.0 111.25 5 156.8 114.03 6 N.S.pNN50 39.92 21.771 5 30.69 22.315 6 N.S.VLF abs. (s2/beat) 4.347 3.9002 5 2.247 2.5202 6 N.S.LF abs. (s2/beat) 3.089 3.5850 5 0.997 1.0500 6 N.S. (0.068)HF abs. (s2/beat) 2.787 4.3901 5 1.281 1.3328 6 N.S.Total abs. (s2/beat) 10.22 11.778 5 4.525 4.8002 6 N.S.LF% 61.36 10.258 5 45.93 10.074 6 0.028HF% 38.64 10.258 5 54.07 10.074 6 0.028LF/HF 1.733 0.6921 5 0.907 0.3781 6 0.028VLF peak (cycles/beat) 0.013 0.0112 5 0.009 0.0088 6 N.S.LF peak (cycles/beat) 0.063 0.0322 5 0.086 0.0418 6 N.S.HF peak (cycles/beat) 0.234 0.0746 5 0.248 0.0783 6 N.S.

SDNN: standard deviation of all R-R intervals; RMSSD: square root of the mean of the sum of the squares of differences between adjacentR-R intervals; NN50: number of pairs of adjacent R-R intervals differing by more than 50 ms in the entire epoch; pNN50: NN50%; VLF:power in very low-frequency range, <0.04 Hz; LF: power in low-frequency range, 0.04–0.15 Hz; HF: power in high-frequency range,0.15–0.4Hz; total power: VLF+LF+HF; LF%: LF power in normalized units, LF/(total power−VLF)×100: HF%: HF power in normalizedunits, HF/(total power−VLF)×100; LF/HF: ratio LF/HF; VLF peak: frequency of highest peak in the VLF range; LF peak: frequency ofhighest peak in the LF range; HF peak : frequency of highest peak in the HF range.

Effects of sleep apnea in DS higher than that of our patients, the sleep structure wassignificantly altered in patients, as compared to controls, the

Table 4 shows the effects of the presence of sleep apnea byfrequency range for LF (0.05–0.15 cycles/beat) was different

comparing HRV findings in DS during sleep Stage 2 withoutand their standardized values were obtained on the whole

or with apnea episodes. This comparison was possible only inspectrum (and not only considering HF and LF). These last

sleep Stages 2 and REM and in a low number of subjectstwo points do not comply with the guidelines of the Task Force

because we could not find in all subjects epochs fulfilling theof the European Society of Cardiology and the North American

criteria explained in Methods for the other sleep stages. TheSociety of Pacing and Electrophysiology (1996) which were

effects of the presence of sleep apnea episodes (at least 5)carefully followed in our work.during sleep Stage 2 were: increase in SDNN, VLF, LF and

Our results constitute evidence of an altered balance betweentotal spectral power, LF% and LF/HF, and decrease in HF%.the sympathetic and vagal systems at a brainstem level in DS;During REM sleep, the presence of sleep apnea did not producea brainstem dysfunctioning was already demonstrated by earlierstatistically significant changes in HRV.studies on brainstem auditory evoked potentials (BAEPs) inDS (Squires et al. 1980; Gigli et al. 1984). More recently,we observed an age-related enhancement of the characteristic

DISCUSSION BAEP abnormalities in these patients (Ferri et al. 1995) similarto the probable age-related increase in central sleep apneaFrom our results, it is evident that DS patients show reducedseverity (Ferri et al. 1997). The studies on BAEPs providedHF and increased LF (in both absolute and standardizedevidence of the presence of an altered excitability at the levelvalues) during sleep, as compared to normal controls, and suchof the brainstem, probably based on a deficit of inhibitorya difference is not consequent to the presence of apnea orprocesses, leading to a faster neural conduction of the auditoryarousal. These data suggest an imbalance between thepotentials (Gigli et al. 1984; Ferri et al. 1995). Similarly, oursympathetic and vagal systems with a prevalent sympatheticprevious study on respiration during sleep in DS demonstratedactivity in DS patients, especially during slow-wave NREMthe presence of an abnormal control of the peripheralsleep.chemoreceptor reflex, probably constituted by an increase ofOur results differ from those reported by Sei et al. (1995);the gain of the control system (Ferri et al. 1997).these authors found increased HR% and decreased LF% in

Finally, the demonstration of an altered balance betweenDS patients, mostly during REM sleep. These differences mightthe sympathetic and vagal systems can be discussed also inbe partially due to methodologically different approaches; inpsychophysiological terms, following the ideas of the so-calledfact, Sei et al. (1995) did not control for the eventual presence

of sleep apnea episodes, the age range of their subjects was ‘Polyvagal Theory’ (Porges 1995). This theory states that the

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286 R. Ferri et al.

Table 3 Comparison between HR findings in DS and normal subjects during slow-wave sleep (Stages 3 and 4) without sleep apnea

DS subjects Normal subjectsMann–Whitney

Mean S.D. n Mean S.D. n P-level

Mean R-R-value (s) 0.916 0.1733 7 0.934 0.2586 6 N.S.SDNN 0.086 0.0413 7 0.074 0.0677 6 N.S.RMSSD 0.087 0.0593 7 0.097 0.0996 6 N.S.NN50 230.1 138.46 7 214.7 143.95 6 N.S.pNN50 45.04 27.095 7 42.01 28.170 6 N.S.VLF abs. (s2/beat) 1.154 0.8853 7 0.334 0.1841 6 0.032LF abs. (s2/beat) 1.686 1.9205 7 0.653 0.9144 6 0.045HF abs. (s2/beat) 2.304 2.4902 7 4.635 8.9139 6 N.S.Total abs. (s2/beat) 5.144 4.3834 7 5.539 9.9371 6 N.S.LF% 42.96 17.571 7 21.34 11.225 6 0.022HF% 57.04 17.571 7 78.66 11.225 6 0.022LF/HF 1.007 0.7222 7 0.303 0.2183 6 0.022VLF peak (cycles/beat) 0.026 0.0067 7 0.018 0.0064 6 0.038LF peak (cycles/beat) 0.056 0.0081 7 0.071 0.0304 6 N.S.HF peak (cycles/beat) 0.260 0.0399 7 0.246 0.0638 6 N.S.

Abbreviations as in Table 2.

Table 4 Comparison between HR findings in DS during sleep Stage 2 without or with apnea episodes

Sleep Stage 2 (n=5)Without apnea With apnea

Mean S.D. Mean S.D P<

Mean R-R-value (s) 0.913 0.1777 0.904 0.1573 N.S.SDNN 0.106 0.0557 0.151 0.0565 0.05RMSSD 0.099 0.0805 0.099 0.0712 N.S.NN50 216.6 34.44 189.2 93.889 N.S.pNN50 42.38 26.309 37.02 18.373 N.S.VLF abs. (s2/beat) 2.853 1.5544 8.670 4.5300 0.05LF abs. (s2/beat) 3.009 3.5746 5.286 4.8650 0.05HF abs. (s2/beat) 3.600 5.4696 3.148 4.7466 N.S.Total abs. (s2/beat) 9.462 8.6689 17.10 13.374 0.05LF% 48.01 12.824 70.68 16.305 0.1>P>0.05HF% 51.99 12.824 29.32 16.305 0.1>P>0.05LF/HF 1.113 0.6903 4.494 4.7807 0.1>P>0.05VLF peak (cycles/beat) 0.017 0.0104 0.027 0.0107 N.S.LF peak (cycles/beat) 0.059 0.0165 0.043 0.0020 0.1>P>0.05HF peak (cycles/beat) 0.255 0.0282 0.250 0.0369 N.S.

Abbreviations as in Table 2.

vagal system does not represent a unitary dimension and is theory, the detection of changes in vagal activity in DS subjects,together with the already reported changes in central controlformed by two distinct motor systems; one is the vegetative

status originating in the dorsal motor nucleus, associated with of respiration (Ferri et al. 1997), might be in somewhat directphysiopathological connection with the basic mechanisms ofpassive automatic regulation of visceral subdiaphragmatic

functions, the second is the smart vagus, originating in the their developmental psychomotor problems.In conclusion, the results of our study provide furthernucleus ambiguus (NA), associated with the active processes

of attention, motion, emotion, and communication, with evidence of a brainstem dysfunctioning in DS, responsible forthe abnormal imbalance between the sympathetic (increased)supradiaphragmatic target organs. The same theory claims that

the functional output of the NA vagus on the heart can be and vagal (decreased) systems, enhanced by the occurrenceof apnea. They confirm the brainstem involvement alreadymonitored by the respiratory sinus arrhythmia and that there is

a common cardiopulmonary oscillatory network in the nucleus suggested in order to explain BAEP abnormalities and centralsleep apnea, and support our initial hypothesis.tractus solitarius and NA (Porges 1995). Thus, following this

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