Br Heartj_ 1995;74:390-396

Heart rate and respiratory rhythm dynamics on

ascent to high altitude

Lewis A Lipsitz, Fred Hashimoto, Lawrence P Lubowsky, Joseph Mietus,George B Moody, Otto Appenzeller, Ary L Goldberger

Hebrew RehabilitationCenter for AgedResearch and TrainingInstitute, Boston,Massachusetts, USAL A LipsitzL P LubowskyUniversity ofNewMexico School ofMedicine,Albuquerque, NewMexico, USAF HashimotoDepartment ofMedicine, Beth IsraelHospital, Boston,Massachusetts, USAL A LipsitzJ MietusG B MoodyA L GoldbergerNew MexicoEnhancement andMarathon ClinicsResearch Foundation,Albuquerque, NewMexico, USA0 AppenzellerCorrespondence to: Dr L ALipsitz, HebrewRehabilitation Center forAged Research and TrainingInstitute, 1200 Centre Street,Roslindale MA 02131, USA.Accepted for publication7 March 1995

AbstractObjective-To investigate the alterationsin autonomic control of heart rate at highaltitude and to test the hypothesis thathypoxaemic stress during exposure tohigh altitude induces non-linear, periodicheart rate oscillations, simnilar to thoseseen in heart failure and the sleep apnoeasyndrome.Subjects-l1 healthy subjects aged 24-64.Main outcome measures-24 hour ambu-latory electrocardiogram records ob-tained at baseline (1524 m) and at 4700 m.Simultaneous heart rate and respiratorydynamics during 2-5 hours of sleep by fastFourier transform analysis of beat to beatheart rate and of an electrocardiographi-cally derived respiration signal.Results-All subjects had resting hypox-aemia at high altitude, with an averageoxyhaemoglobin saturation of 81% (5%).There was no significant change in meanheart rate, but low frequency (0-01-0.05Hz) spectral power was increased (P <0*01) at high altitude. Time series analysisshowed a complex range of non-linearsinus rhythm dynamics. Striking low fre-quency (0-04-0.06 Hz) heart rate oscilla-tions were observed during sleep in eightsubjects at high altitude. Analysis of theelectrocardiographically derived respira-tion signal indicated that these heart rateoscillations correlated with low frequencyrespiratory oscillations.Conclusions-These data suggest (a) thatincreased low frequency power duringhigh altitude exposure is not simplyattributable to increased sympatheticmodulation of heart rate, but relates todistinctive cardiopulmonary oscillationsat -0 05 Hz and (b) that the emergence ofperiodic heart rate oscillations at highaltitude is consistent with an unstablecardiopulmonary control system that maydevelop on acute exposure to hypoxaemicstress.

(Br HeartJ_ 1995;74:390-396)

Keywords: heart rate; respiratory rhythm; high altitude

Perturbation of the non-linear physiologicalmechanisms regulating cardiopulmonary func-tion may result in the emergence of highlyperiodic behaviour in heart rate and ventila-tory dynamics. 13 Perhaps the best describedexamples of such pathological oscillations areCheyne-Stokes breathing in heart failure and

the obstructive sleep apnoea syndrome. Eachof these conditions is associated not only withperiodic ventilatory dynamics but also withcyclic alterations in heart rate.46 We hypothe-sised that hypoxaemic stress during exposureto high altitude would also induce non-linear,periodic heart rate dynamics.

Subjects and methodsWe studied 11 healthy subjects (nine men andtwo women) aged 24 to 64 years. All werephysically well trained in long distance run-ning, but they were not accustomed to moun-tain climbing. Two lived at sea level and ninelived at 1524 m. Twenty four hour ambulatoryelectrocardiograms were recorded withCardioData Dura-Lite cassette recorders(Model 2011) at low (1524 m) and high(4000-4700 m) altitude.The lower altitude ambulatory electrocar-

diographic recordings were conducted duringa usual work day and overnight sleep at1524 m. The high altitude recordings wereperformed during an expedition in theHimalayas at 4700 m. Electrodes from theambulatory monitors were attached to eachsubject during the first day at MountKhachenjunga base camp (4700 m) after athree day trek ascending 3400 m. The electro-cardiographic recording was obtained over 24hours and was divided into three time andactivity segments (a) eight hours of quiet activ-ity from 1400 to 2200, (b) eight hours of sleepfrom 2200 to 0600, and (c) eight hours ofextreme exertion from 0600 to 1400. All sub-jects had resting oxyhaemoglobin saturationmeasurements obtained during the first day atbase camp (4700 m only), using a Finapresoxygen saturation monitor (model 2300,Ohmeda, Louisville, Colorado, USA).Tape recorded electrocardiographic signals

were digitised at 128 Hz using a MarquetteSeries 8000 Holter analysis system (MarquetteElectronics, Milwaukee, Wisconsin, USA).The digitised data were then annotatedaccording to an automated arrhythmia detec-tion algorithm, and the beat annotations wereverified by visual inspection. Cardiac rhythmanalysis has been described previously in thesesubjects, who showed only infrequent ectopicactivity.7

Spectral analysis of sinus rhythm heart ratewas performed for sequential 15 minute sec-tions of each 24 hour period according to thestandard fast Fourier transform technique.8Total heart rate power, a measure of overallheart rate variability, was computed for the

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Heart rate and respiratory rhythm dynamics on ascent to high altitude

Mean (SD) oxygenation and heart rate measurements at low and high altitude

Low altitude (1524 m) High altitude (4700 m)

Resting Oxyhaemoglobin saturation (%) N/A 81 (5)Heart rate during sleep (beats/minute) 60 (12) 65 (16)Heart rate power during sleep

Total (0-050 Hz) 21 (12) 38 (14)*Low frequency (001-0-15 Hz) 11 (6) 18 (7)*High frequency (0-15-0-50 Hz) 1-4 (1-0) 1-6 (0 6)

N/A, not available.*P < 0-01.

0-0 50 Hz band. Relatively low frequencyheart rate power was computed for the0 01-0 15 Hz band and high frequency heartrate power for the 0O15-0 50 Hz band.The heart rate time series and spectral plots

were carefully examined by the investigatorsfor evidence of non-linear dynamics, includingoscillatory bursts and sudden changes in thefrequency of oscillations (bifurcations)."Episodes of low frequency heart rate oscilla-tions (0-04-0-06 Hz) lasting 15 minutes or

longer were identified by two observers, whoindependently examined each subject's 24hour heart rate time series from low and highaltitude.To determine the relation between heart

rate and respiratory oscillations, we derived a

respiratory signal from the body surface elec-trocardiographic recording by measuring fluc-tuations in the mean cardiac electrical axis thataccompany respiration.9 This technique isbased on the observation that the body surfaceelectrocardiogram is influenced by electrodemotion relative to the heart and by changes inthoracic electrical impedance as the lungs filland empty. By interpolating between axismeasurements for each normal QRS interval a

continuous electrocardiographically derivedrespiration signal is obtained. The relationbetween this signal and respiration has beenconfirmed by comparing the changes in axisdirection with simultaneous measurements ofchest circumference taken with a mercurystrain gauge or pneumatic respiration trans-ducer.9 In a small sample of patients with andwithout sleep apnoea on polysomnography theelectrocardiographically derived respirationtechnique had a sensitivity of 75% for detect-ing apnoeic episodes, and gave no false posi-tive results among 10 normal subjects withoutsleep apnoea.10 This method has also beenused to examine the effect of respiratory rateand amplitude on heart rate variability inpatients with congestive heart failure.5Although noisy signals may limit the sensitivityof this method, the electrocardiographicallyderived respiration technique was particularlywell suited for the measurement of respiratoryrate in the field when lightweight portablemonitors for both heart rate and respirationwere not available. Since we did not aim tomeasure precisely ventilatory dynamics at highaltitude, the electrocardiographically derivedrespiration signal provided a practical means

to determine whether low frequency heart rateoscillations were associated with respiration.

Each 24 hour electrocardiographicallyderived respiration signal was scanned visuallyfor evidence of abnormal breathing periodici-ties (see examples in figures 1 and 2). A fast

Fourier transform analysis was also computedfor continuous segments of the electrocardio-graphically derived respiration signal to com-pare the frequencies of respiratory and heartrate oscillations.

Changes in total, high, and low frequencyheart rate power from low to high altitudewere analysed by means of paired t tests. Heartrate power is expressed in arbitrary units. Alldata are presented as means (SD). Statisticalsignificance is defined as P < 0-05.

ResultsAll subjects had evidence of hypoxaemia whileresting at high altitude, with an average oxy-haemoglobin saturation of 81% (5%) (table).None of the subjects had any signs or symp-toms of high altitude pulmonary oedema.

Heart rate time series showed many differ-ent types of complicated oscillatory dynamicsat various times of day. Examples of thesedynamics are shown in figure 1 and includebursting activity, abrupt changes in frequency,spike-like oscillations, flutter-like (saw tooth)oscillations, and more complex oscillatory pat-terns. As these could represent non-stationari-ties resulting from different activities,environmental conditions, or measurementartifacts, we limited the analysis to comparable2-5 hour periods of sleep at low and high alti-tude while all subjects were under similarsteady state conditions. During these periodsof sleep at high altitude there were striking lowfrequency heart rate oscillations (0 04 to 0-06Hz) with relatively abrupt onset and cessationin eight of the 11 subjects (figures 1 and 2).The peak to trough amplitude of these oscilla-tions ranged from 12-40 beats/minute. Similarlow frequency heart rate oscillations occurredat lower altitude in only two subjects (aged 61and 44) during sleep. The presence or absenceof low frequency oscillations was not related tothe age, sex, or other identifiable characteris-tics of the subjects. There was no significantchange in mean heart rate with altitude, butthere was a significant increase in low and totalheart rate spectral power during sleep at highaltitude (P < 0-01, table).

Analysis of the electrocardiographicallyderived respiration signal indicated that inseven out of eight subjects with low frequencyheart rate oscillations, these oscillations wereassociated with alternating periods of apnoeaand hyperpnoea at the same frequency (figures2 and 3). Evidence of this breathing patternfrom the electrocardiographically derived res-piration signal was not noted in the absence oflow frequency heart rate oscillations. Crossspectrum and coherence plots derived fromthe power spectral' (figure 4) confirmed thatthe heart rate and electrocardiographicallyderived respiration signals oscillate at the samedominant frequency (0-04-006 Hz) and have aconstant phase relation.

Figure 3 shows details of the relationbetween heart rate and respiratory oscillationsin one subject. The oscillations were charac-terised by periods of hyperpnoea alternatingwith apnoea at a cycle length of approximately

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Figure 1 Complicated heart rate dynamics at high altitude in six subjects, with the time of day in parentheses. These are examples of the types ofbehavioural patterns consistent with perturbations of a highly non-linear control system. The classification of these sinus rhythm patterns is descriptive andintended to convey the wide variety of interbeat interval dynamics

20 s. There was a consistent phase lagbetween the respiratory and heart rate cycles,such that periods of hyperpnoea preceded themaximum heart rate. Furthermore, the heartrate oscillations were not purely sinusoidal buthad a more complex form.

DiscussionAlthough several previous studies have exam-

ined alterations in ventilatory dynamics at highaltitude,'2-"5 little attention has been paid to

alterations in heart rate dynamics under thesehypoxic conditions. A few previous investiga-tors have commented on cyclical variations inheart rate during sleep at actual13 and simu-lated'6 17 high altitude. However, to our knowl-edge, the spectral characteristics of this heartrate variability and the possibility of more

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Figure 2 Representative sinus rhythm heart rate-time series (left hand column) and electrocardiographically derived respiratory signals in arbitrary units(EDR; right hand column) both with power spectra shown as inserts in a subject at high altitude, in a patient with obstructive sleep apnoea, and in a

patient with congestive heart failure and Cheyne-Stokes breathing. The electrocardiographically derived respiratory signal is low pass filtered using a

sliding window average of 10 data points. Note the different cardiopulmonary frequencies in the three clinical conditions. In each condition, however, theheart rate and electrocardiographically derived respiratory power spectra show a spike at the same frequency.

complicated non-linear dynamics have notbeen fully studied, particularly under actualhigh altitude conditions. We found the emer-

gence of a wide range of oscillatory heart ratedynamics at high altitude, including periods ofprominent low frequency heart rate oscilla-tions at around 0-05 Hz, in eight of the 11subjects during sleep. These low frequencyheart rate oscillations corresponded to alter-nating cycles of hyperpnoea and apnoea at thesame frequency. Therefore, our findings indi-cate that increased low frequency heart rate

power is not simply related to heightened sym-pathetic tone but to distinctive cardiopul-monary oscillations.We emphasise that the low frequency heart

rate oscillations we observed are distinct fromphysiological respiratory sinus arrhythmia,which is associated with breath to breathchanges in heart rate at the relatively high fre-quency of about 9-15 per minute (0-15-0-25Hz). Instead, the heart rate oscillationsinduced by exposure to high altitude representmuch lower frequency cycles at about 3 per

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minute (0 05 Hz), associated with alternatingperiods of hyperpnoea and apnoea (figure 3).Although normal breathing is by nature peri-odic, the lower frequency cycles represent anabnormal respiratory pattern conventionallyreferred to as periodic breathing. During peri-ods of hyperpnoea, breath by breath respira-tory cycles at 0-1-0-2 Hz are also present (seeelectrocardiographically derived respirationspectra in figures 2 (top) and 4). The interac-tion of multiple respiratory cycles at differentfrequencies is in part responsible for the com-plex structure of the electrocardiographicallyderived respiration signal and heart rate timeseries.Our finding of increased low frequency

heart rate power during the first day of ascentto high altitude is consistent with the observa-tions of Hughson et al in three men duringdays 4-5 of acclimatisation at 4300 m.'8 Theseinvestigators found that an increased ratio oflow to high frequency power at high altitudewas prevented by propranolol, suggesting that itwas related to heightened activity of the sym-pathetic nervous system. Furthermore, theratio of low to high frequency power decreasedby 11-12 days of acclimatisation, possiblybecause of, receptor desensitisation. Unfortu-nately, they were unable to evaluate the effectsof respiration on their findings.Hughson et al also reported that the ratio of

high frequency to total heart rate power (usedas an index of parasympathetic nervous systemactivity) was reduced during days 4-5 andrestored to its sea level value by 11-12 days inthree subjects at altitude. 18 We did not observea significant change in the absolute value ofhigh frequency power. If reported as a ratio of

high frequency to total heart rate power, ourdata would also show a decline during earlyaltitude exposure because of an increase intotal power. However, our finding that theincrease in total power was due primarily tolow frequency respiratory oscillations seriouslychallenges the use of this ratio as a measure ofparasympathetic nervous system activity underhigh altitude conditions.Our observation of low frequency heart rate

and ventilatory oscillations with a cycle time of20 s (0 05 Hz) at 4700 m agrees remarkablywell with findings of other investigators whostudied breathing patterns at high altitude.Using a mathematical model of the respiratorycontrol system, Khoo et al predicted the onsetof abnormal breathing periodicities with amean cycle time of about 20 s at an altitudeof 14 000 feet (approximately 4267 M).'5Waggener et al observed periodic breathingwith a mean cycle length of 20 s at 4270 m,Yand West et al reported a cycle length of 20-5 sat 6300 m.'3 The phase relation betweenhyperpnoea and the peak heart rate responseillustrated in figure 3 is also similar to thatreported by West et al.'3Abnormal cyclical breathing patterns are

also associated with concordant heart rateoscillations in congestive heart failure withCheyne-Stokes respiration,45 and in the sleepapnoea syndrome.6 As illustrated in figure 2,however, the characteristic cardiopulmonarycycle lengths in these two conditions are typi-cally slower than those observed by us andothers' 13719 at high altitude. For example, inCheyne-Stokes respiration the cardiopul-monary cycle length usually ranges from 40 to65 s (0-015-0-025 Hz).'45 This suggests a

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range of pathological cardiopulmonary oscilla-tions reflecting different underlying mecha-nisms; Cheyne-Stokes breathing presumablyresults from prolongation of circulatory transittime associated with heart failure,20 while peri-odic breathing at high altitude is attributed toincreased feedback gain in central or periph-eral chemoreceptors due to hypoxaemia. "

At various times during the 24 hour heartrate recordings at high altitude we observedthe remarkably rich and complicated range ofdynamic patterns shown in figure 1. Theabrupt changes and switching between states(so called bifurcations) represent non-station-ary behaviours that are characteristic ofdynamic systems.2 3 21-23 Although a precisemodel for these transitions cannot be inferredsolely from the spontaneous cardiopulmonarydatasets available in this study, several new

biological behaviours are suggested. In particu-lar, abrupt switching between periodic andnon-periodic regimens is an anticipated fea-ture of a wide class of non-linear systems dis-playing one or more of the following:bifurcation behaviour,23 intermittency,2' sto-

22chastic resonance, or phase transitions (criti-cal phenomena).23 We applied these conceptsderived from non-linear dynamics and statisti-cal physics to our data because the time serieswere complex and not explained fully by tradi-tional models.

During periods of wakefulness and extremeexertion non-stationarities in the data repre-sent heart rate responses to physical perturba-tions, emotional stresses, and environmentalchanges. Unfortunately, we could not measure

and therefore study these influences in thefield. Therefore, we limited our analysis tosteady state conditions during sleep. Underthese conditions we observed striking low fre-quency oscillations (figure 2). In one of thefirst descriptions of periodic heart rate changesat high altitude, West et al described a similar

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saw toothed pattern of heart rate variability."3Our results extend their observation and we

have used spectral analysis techniques to con-

firm the relation between heart rate and pul-monary oscillations at high altitude.The results of our study are important for

several reasons. Firstly, the oscillatory heartrate patterns we observed indicate an under-lying non-linear mechanism.'"17

Secondly, the patterns are consistent with a

highly unstable cardiopulmonary control sys-

tem that may develop on acute exposure tohigh altitude before acclimatisation.'324

Thirdly, future attempts to model the physi-ological mechanisms underlying cardiopul-monary control should account for differenttypes of periodic patterns. For example, any

successful "unified" explanation of cardiopul-monary oscillations in different pathologicalstates will need to account explicitly for theirdifferential cycle lengths as shown in figure 2.

Fourthly, our analysis shows the use of a

respiratory signal derived solely from ambula-tory electrocardiograms, but independent ofthe respiratory sinus arrhythmia (electrocar-diographically derived respiration) in assessingthe interactions between ventilatory and car-

diac dynamics.910Finally, our data challenge the widespread

assumption that low frequency heart rate spec-tral power measures the activity of the sympa-

thetic nervous system, while high frequencyoscillations represent only parasympathetictone.'72926 Instead, our results show that an

increase in low frequency heart rate power athigh altitude is not simply due to a generalincrease in the 0-01-0-15 Hz frequency bandbut relates specifically to the emergence of a

distinct class of cardiopulmonary oscillationsassociated with a narrow spectral peak (oftenwith higher harmonics). The observation thatatropine blunts the low frequency cyclical vari-ation in heart rate associated with the sleep

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Figure 4 Heart rate andelectrocardiographicallyderived respiration (EDR)autospectra for arepresentative subjectduring sleep at highaltitude (top). Both showdominant low frequencyoscillations at 0-05 Hz.The heart rate andelectrocardiographicallyderived respiration crossspectrum (bottom, left)and heart rate andelectrocardiographicallyderived respirationcoherence spectrum(bottom, right) confirmthat both signals oscillateat identical frequencies(0 05 Hz) with a highcoherence value of > 0 8.11The heart rate andelectrocardiographicallyderived respirationautospectra and crossspectra are normalised tototal amplitude.

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Lipsitz, Hashimoto, Lubowsky, Mietus, Moody, Appenzeller, et al

apnoea syndrome6 also indicates that an

increase in low frequency heart rate power isnot necessarily attributable solely to height-ened sympathetic tone.Our study has several limitations.

Unfortunately, we were unable to study heartrate dynamics after acclimatisation at high alti-tude. Furthermore, the electrocardiographi-cally derived respiration signal did not permitthe measurement of respiratory amplitude andthe calculation of transfer functions betweenrespiration and heart rate. The identificationof periodic breathing in seven out of eight sub-jects with low frequency heart rate oscillationsmay reflect the limited sensitivity of this tech-nique.

Because of the abrupt onset and end of theoscillatory events and the non-stationarity ofthe data, methods derived from non-lineardynamics- for example, Lyapunov exponentcalculation and 1/f modelling-were notapplicable. Future studies of the complexdynamics of heart rate oscillations are neededto elucidate more fully the non-linear mecha-nisms of cardiopulmonary control, as well as

to provide new tools to diagnose pathologicalbreathing states.

This work was supported in part by the Hebrew RehabilitationCenter for the Aged, Boston, Massachusetts; by a NationalInstitute on Aging Teaching Nursing Home Award (AG04390)and by a Claude Pepper Geriatric Research and TrainingCenter Grant (AG08812) from the US Public Health Service,Bethesda, Maryland; by awards from the National Institute on

Drug Abuse (PO1-DA06316), the National Heart, Lung, andBlood Institute (RO1-HL-42172), the National Aeronauticsand Space Administration (NAG9-572), and the G Haroldand Leila Y Mathers Charitable Foundation; by the ClinicalResearch Center at the University of New Mexico School ofMedicine; by CardioData Corporation; and by the Instituto CMondino, University of Pavia, Italy.

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