Guidelines Heart Rate Variability FT 1996 PDF

European Heart J ournal (1996) 17, 354381
Guidelines
Heart rate variability
Standards of measurement, physiological interpretation, and
clinical use
Task Force of The European Society of Cardiology and The North American
Society of Pacing and Electrophysiology (Membership of the Task Force listed in
the Appendix)
Introduction
Thelast two decadeshavewitnessedtherecognitionof a
signicant relationship between the autonomic nervous
system and cardiovascular mortality, including sudden
cardiac death
[14]
. Experimental evidence for an associ-
ation between a propensity for lethal arrhythmias and
signs of either increased sympathetic or reduced vagal
activity hasencouraged thedevelopment of quantitative
markers of autonomic activity.
Heart rate variability (HRV) represents one of
the most promising such markers. The apparently easy
derivation of this measure has popularized its use. As
many commercial devices now provide automated
measurement of HRV, the cardiologist has been pro-
videdwithaseeminglysimpletool for bothresearchand
clinical studies
[5]
. However, thesignicanceandmeaning
of the many dierent measures of HRV are more
complex than generally appreciated and there is a
potential for incorrect conclusions and for excessive or
unfounded extrapolations.
Recognition of theseproblems led theEuropean
Society of Cardiology and theNorth American Society
of Pacing and Electrophysiology to constitute a Task
Force charged with the responsibility of developing
appropriate standards. The specic goals of this Task
Force were to: standardize nomenclature and develop
denitions of terms; specify standard methods of
measurement; dene physiological and pathophysio-
logical correlates; describecurrently appropriateclinical
applications, and identify areas for futureresearch.
I n order to achieve these goals, the members of
theTask Forceweredrawnfromtheeldsof mathemat-
ics, engineering, physiology, and clinical medicine. The
standards and proposals oered in this text should
not limit further development but, rather, should
allow appropriate comparisons, promote circumspect
interpretations, and lead to further progress in theeld.
Thephenomenon that is thefocus of this report
is the oscillation in the interval between consecutive
heart beats as well as theoscillations between consecu-
tive instantaneous heart rates. Heart Rate Variability
hasbecometheconventionallyacceptedtermto describe
variations of both instantaneous heart rate and RR
intervals. I n order to describeoscillation in consecutive
cardiac cycles, other terms havebeen used in thelitera-
ture, for example cycle length variability, heart period
variability, RR variability and RR interval tachogram,
andtheymoreappropriatelyemphasizethefact that it is
the interval between consecutive beats that is being
analysed rather than the heart rate per se. However,
thesetermshavenot gainedaswideacceptanceasHRV,
thus wewill usethetermHRV in this document.
Background
The clinical relevance of heart rate variability was rst
appreciatedin1965whenHonandLee
[6]
notedthat fetal
distresswasprecededbyalterationsininterbeat intervals
beforeanyappreciablechangeoccurredintheheart rate
itself. Twenty years ago, Sayers and others focused
attention on the existence of physiological rhythms
imbedded in the beat-to-beat heart rate signal
[710]
.
Key Words: Heart rate, electrocardiography, computers,
autonomic nervous system, risk factors.
The Task Force was established by the Board of the European
Society of Cardiology and co-sponsored by the North American
Society of Pacing and Electrophysiology. I t was organised jointly
by the Working Groups on Arrhythmias and on Computers of
Cardiology of the European Society of Cardiology. After ex-
changes of written views on the subject, the main meeting of a
writing coreof theTask Forcetook placeon May 810, 1994, on
Necker I sland. Following external reviews, the text of this report
wasapprovedbytheBoardof theEuropeanSocietyof Cardiology
on August 19, 1995, and by the Board of the North American
Society of Pacing and Electrophysiology on October 3, 1995.
Published simultaneously in Circulation.
Correspondence: Marek Malik, PhD, MD, Chairman, Writing
Committee of the Task Force, Department of Cardiological
Sciences, St. Georges Hospital Medical School, Cranmer Terrace,
London SW17 0RE, U.K.
0195-668X/96/030354+28 $18.00/0 1996 American Heart Association I nc.; European Society of Cardiology
During the 1970s, Ewing et al.
[11]
devised a number of
simple bedside tests of short-term RR dierences to
detect autonomic neuropathy in diabetic patients. The
association of higher risk of post-infarction mortality
with reduced HRV was rst shown by Wolf et al. in
1977
[12]
. I n 1981, Akselrod et al. introduced power
spectral analysis of heart rate uctuations to quantita-
tively evaluatebeat-to-beat cardiovascular control
[13]
.
Thesefrequencydomainanalysescontributedto
theunderstandingof theautonomic background of RR
interval uctuations in the heart rate record
[14,15]
. The
clinical importanceof HRV becameapparent in thelate
1980swhenit wasconrmedthat HRV wasastrongand
independent predictor of mortality following an acute
myocardial infarction
[1618]
. Withtheavailabilityof new,
digital, high frequency, 24-h multi-channel electro-
cardiographic recorders, HRV has the potential to
provide additional valuable insight into physiological
and pathological conditions and to enhance risk
stratication.
Measurement of heart rate variability
Timedomain methods
Variations in heart ratemay beevaluated by a number
of methods. Perhapsthesimplest toperformarethetime
domain measures. With these methods either the heart
rate at any point in time or the intervals between
successive normal complexes are determined. I n a con-
tinuous electrocardiographic (ECG) record, each QRS
complexisdetected, andtheso-callednormal-to-normal
(NN) intervals (that is all intervals between adjacent
QRS complexes resulting from sinus node depolariza-
tions), or the instantaneous heart rate is determined.
Simple timedomain variables that can be calculated
includethemean NN interval, themean heart rate, the
dierencebetween thelongest and shortest NN interval,
the dierence between night and day heart rate, etc.
Other timedomain measurements that can beused are
variations in instantaneous heart rate secondary to
respiration, tilt, Valsalva manoeuvre, or secondary to
phenylephrine infusion. These dierences can be de-
scribed aseither dierencesin heart rateor cyclelength.
Statistical methods
From a series of instantaneous heart rates or cycle
intervals, particularly those recorded over longer
periods, traditionally 24h, more complex statistical
time-domain measures can be calculated. These may be
divided into two classes, (a) those derived from direct
measurements of the NN intervals or instantaneous
heart rate, and (b) those derived from the dierences
between NN intervals. These variables may be derived
fromanalysisof thetotal electrocardiographicrecording
or may be calculated using smaller segments of the
recording period. Thelatter method allows comparison
of HRV to be made during varying activities, e.g. rest,
sleep, etc.
Thesimplest variableto calculateis thestandard
deviationof theNN interval (SDNN), i.e. thesquareroot
of variance. Since variance is mathematically equal to
total power of spectral analysis, SDNN reects all the
cyclic components responsible for variability in the
period of recording. I n many studies, SDNN is calcu-
lated over a 24-h period and thus encompasses both
short-term high frequency variations, as well as the
lowest frequency components seen in a 24-h period. As
the period of monitoring decreases, SDNN estimates
shorter andshorter cyclelengths. I t shouldalso benoted
that thetotal varianceof HRV increaseswith thelength
of analysed recording
[19]
. Thus, on arbitrarily selected
ECGs, SDNN is not a well dened statistical quantity
because of its dependence on the length of recording
period. Thus, in practice, it is inappropriateto compare
SDNN measures obtained fromrecordings of dierent
durations. However, durationsof therecordingsused to
determine SDNN values (and similarly other HRV
measures) should bestandardized. As discussed further
in this document, short-term 5-min recordings and
nominal 24h long-term recordings seem to be
appropriateoptions.
Other commonly used statistical variables calcu-
lated from segments of the total monitoring period
includeSDANN, thestandard deviation of theaverage
NN interval calculatedover short periods, usually5min,
which is an estimateof thechanges in heart ratedueto
cycleslonger than5min, andtheSDNN index, themean
of the 5-min standard deviation of the NN interval
calculated over 24h, which measures thevariability due
to cycles shorter than 5min.
Themost commonlyusedmeasuresderivedfrom
interval dierences includeRMSSD, thesquareroot of
themeansquareddierencesof successiveNN intervals,
NN50, the number of interval dierences of successive
NN intervals greater than 50ms, and pNN50 the pro-
portion derived by dividing NN50 by thetotal number
of NN intervals. All these measurements of short-term
variation estimate high frequency variations in heart
rateand thus arehighly correlated (Fig. 1).
Geometrical methods
Theseries of NN intervals can also beconverted into a
geometric pattern, such as the sample density distribu-
tion of NN interval durations, sample density distribu-
tion of dierences between adjacent NN intervals,
Lorenz plot of NN or RR intervals, etc., and a simple
formulaisusedwhichjudgesthevariabilitybasedonthe
geometric and/or graphic properties of the resulting
pattern. Threegeneral approachesareused in geometric
methods: (a) a basic measurement of the geometric
pattern (e.g. the width of the distribution histogramat
the specied level) is converted into the measure of
HRV, (b) the geometric pattern is interpolated by a
mathematicallydenedshape(e.g. approximationof the
distribution histogramby a triangle, or approximation
of the dierential histogram by an exponential curve)
and then theparameters of this mathematical shapeare
used, and(c) thegeometricshapeisclassiedintoseveral
Standards of heart ratevariability 355
Eur Heart J , Vol. 17, March 1996
pattern-based categories which represent dierent
classesof HRV (e.g. elliptic, linear andtriangular shapes
of Lorenz plots). Most geometric methods require the
RR (or NN) interval sequence to be measured on or
converted to adiscretescalewhich isnot too neor too
coarseand which permits theconstruction of smoothed
histograms. Most experience has been obtained with
bins approximately 8ms long (precisely 78125ms=
1/128s) which corresponds to the precision of current
commercial equipment.
The HRV triangular index measurement is the
integral of thedensitydistribution(i.e. thenumber of all
NN intervals) divided by the maximum of the density
distribution. Usingameasurement of NN intervalson a
discretescale, themeasureisapproximatedbythevalue:
(total number of NN intervals)/
(number of NN intervals in themodal bin)
which is dependent on thelength of thebin, i.e. on the
precision of thediscretescaleof measurement. Thus, if
the discrete approximation of the measure is used with
NN interval measurement on a scale dierent to the
most frequent sampling of 128Hz, the size of the bins
should be quoted. The triangular interpolation of NN
100
100 000
1
0.001
pNN50 (%)
N
N
5
0

(
c
o
u
n
t
s
/
2
4

h
)
1000
100
10
0.01 0.1 1 10
(b)
10 000
120
100
0.001
0
RMSSD (ms)
p
N
N
5
0

(
%
)
1
0.01
20 40 60 80
(a)
10
100
0.1
Figure 1 Relationship between the RMSSD and pNN50 (a), and pNN50 and
NN50(b)measuresof HRVassessedfrom857nominal 24-hHoltertapesrecorded
insurvivorsof acutemyocardial infarctionprior tohospital discharge. TheNN50
measureusedinpanel (b) wasnormalizedinrespect tothelengthof therecording
(Dataof St. GeorgesPost-infarctionResearchSurveyProgramme.)
356 Task Force
interval histogram(TI NN) is the baseline width of the
distribution measured as a base of a triangle, approxi-
mating the NN interval distribution (the minimum
squaredierenceis used to nd such atriangle). Details
of computing theHRV triangular index and TI NN are
shown in Fig. 2. Both these measures express overall
HRV measured over 24h and are more inuenced by
the lower than by the higher frequencies
[17]
. Other
geometric methods are still in the phase of exploration
and explanation.
The major advantage of geometric methods lies
in their relativeinsensitivity to theanalytical quality of
theseries of NN intervals
[20]
. Themajor disadvantageis
the need for a reasonable number of NN intervals to
construct thegeometric pattern. I n practice, recordings
of at least 20min (but preferably 24h) should be used
to ensure the correct performance of the geometric
methods, i.e. the current geometric methods are in-
appropriateto assess short-termchanges in HRV.
Summary and recommendations
The variety of timedomain measures of HRV is sum-
marizedinTable1. Sincemanyof themeasurescorrelate
closelywithothers, thefollowingfour arerecommended
for timedomain HRV assessment: SDNN (estimateof
overall HRV); HRV triangular index(estimateof overall
HRV); SDANN (estimate of long-termcomponents of
HRV), and RMSSD (estimate of short-term compo-
nents of HRV). Two estimates of the overall HRV are
recommended because the HRV triangular index
permits only casual pre-processing of the ECG signal.
TheRMSSD method is preferred to pNN50and NN50
becauseit has better statistical properties.
The methods expressing overall HRV and its
long- and short-term components cannot replace each
other. The method selected should correspond to the
aimof eachstudy. Methodsthat might berecommended
for clinical practices are summarized in the Section
entitled Clinical useof heart ratevariability.
Distinction should be made between measures
derived from direct measurements of NN intervals or
instantaneous heart rate, and from the dierences
between NN intervals.
I t is inappropriate to compare timedomain
measures, especially those expressing overall HRV,
obtained fromrecordings of dierent durations.
Other practical recommendations are listed in
the Section on Recording requirements together with
suggestions related to thefrequency analysis of HRV.
Frequency domain methods
Various spectral methods
[23]
for the analysis of the
tachogramhavebeenappliedsincethelate1960s. Power
N
N
u
m
b
e
r

o
f

n
o
r
m
a
l

R
R

i
n
t
e
r
v
a
l
s
Y
Durati on of normal RR i nterval s
X M
Sampl e
densi ty
di stri buti on
D
Figure 2 To performgeometrical measures on the NN interval
histogram, thesampledensity distributionD is constructedwhich
assigns thenumber of equally longNN intervals to eachvalueof
theirlengths. ThemostfrequentNNinterval lengthX isestablished,
that isY =D(X) isthemaximumof thesampledensitydistribution
D. TheHRV triangular index isthevalueobtainedbydividingthe
area integral of D by the maximumY. When constructing the
distributionD withadiscretescaleonthehorizontal axis, thevalue
isobtainedaccordingtotheformula
HRV index=(total number of all NN intervals)/Y.
For thecomputationof theTINN measure, thevaluesN andM
are established on the time axis and a multilinear function q
constructedsuchthat q(t)=0for tcN andtdM andq(X)=Y, and
suchthat theintegral
#
0
+`
(D(t)q(t))
2
dt
is theminimumamongall selections of all values N andM. The
TINN measure is expressed in ms and given by the formula
TINN=MN.
spectral density (PSD) analysis provides thebasic infor-
mation of how power (i.e. variance) distributes as a
function of frequency. I ndependent of the method
employed, only an estimate of the true PSD of the
signals can be obtained by proper mathematical
algorithms.
Methods for the calculation of PSD may be
generally classied as non-parametric and parametric. I n
most instances, both methods provide comparable
results. Theadvantages of thenon-parametric methods
are: (a) the simplicity of the algorithmemployed (Fast
Fourier TransformFFT in most of thecases) and
(b) the high processing speed, whilst the advantages of
parametric methods are: (a) smoother spectral compo-
nents which can bedistinguished independently of pre-
selectedfrequencybands, (b) easypost-processingof the
spectrumwith an automatic calculation of lowand high
frequency power components and easy identication of
the central frequency of each component, and (c) an
accurateestimation of PSD even on a small number of
samples on which the signal is supposed to maintain
stationarity. The basic disadvantage of parametric
methods is the need to verify the suitability of the
chosen model and its complexity (i.e. the order of the
model).
Spectral components
Short-termrecordings Three main spectral components
are distinguished in a spectrum calculated from short-
term recordings of 2 to 5min
[7,10,13,15,24]
: very low fre-
quency (VLF), lowfrequency (LF), and high frequency
(HF) components. Thedistributionof thepower andthe
central frequency of LF and HF arenot xed but may
varyinrelationto changesinautonomicmodulationsof
the heart period
[15,24,25]
. The physiological explanation
of the VLF component is much less dened and the
existenceof a specic physiological process attributable
to theseheart period changes might even bequestioned.
The non-harmonic component which does not have
coherent properties and which is aected by algorithms
of baselineor trend removal is commonly accepted as a
major constituent of VLF. Thus VLF assessed from
short-termrecordings (e.g. c5min) is a dubious meas-
ureandshouldbeavoidedwheninterpretingthePSD of
short-termECGs.
Measurement of VLF, LF and HF power com-
ponents is usually made in absolute values of power
(ms
2
), but LF and HF may also bemeasured in normal-
ized units (n.u.)
[15,24]
which represent the relative value
of each power component in proportion to the total
power minustheVLF component. Therepresentationof
LF and HF in n.u. emphasizes the controlled and
balanced behaviour of the two branches of the auto-
nomic nervous system. Moreover, normalization tends
to minimize the eect on the values of LF and HF
components of the changes in total power (Fig. 3).
Nevertheless, n.u. should always be quoted with abso-
lutevalues of LF and HF power in order to describein
total thedistribution of power in spectral components.
Long-term recordings Spectral analysis may also be
used to analyse the sequence of NN intervals in the
entire24-h period. Theresult then includes an ultra-low
frequency component (ULF), in addition to VLF, LF
andHF components. Theslopeof the24-hspectrumcan
also be assessed on a loglog scale by linear tting the
spectral values. Table2 lists selected frequencydomain
measures.
Table1 Selected time-domain measures of HRV
Variable Units Description
Statistical measures
SDNN ms Standard deviation of all NN intervals.
SDANN ms Standard deviation of theaverages of NN intervals in all 5min segments of theentirerecording.
RMSSD ms The square root of the mean of the sum of the squares of dierences between adjacent NN
intervals.
SDNN index ms Mean of thestandard deviationsof all NN intervalsfor all 5min segmentsof theentirerecording.
SDSD ms Standard deviation of dierences between adjacent NN intervals.
NN50 count Number of pairs of adjacent NN intervals diering by more than 50ms in the entire recording.
Threevariants arepossiblecountingall such NN intervals pairs or only pairs in which therst or
thesecond interval is longer.
pNN50 % NN50 count divided by thetotal number of all NN intervals.
Geometric measures
HRV triangular index Total number of all NN intervals divided by the height of the histogram of all NN intervals
measured on a discretescalewith bins of 78125ms (1/128s). (Details in Fig. 2)
TI NN ms Baselinewidthof theminimumsquaredierencetriangular interpolationof thehighest peak of the
histogramof all NN intervals (Details in Fig. 2.)
Dierential index ms Dierence between the widths of the histogram of dierences between adjacent NN intervals
measured at selected heights (e.g. at thelevels of 1000 and 10000 samples)
[21]
.
Logarithmic index Coecient of the negative exponential curve k e
t
which is the best approximation of the
histogramof absolutedierences between adjacent NN intervals
[22]
.
358 Task Force
The problem of stationarity is frequently dis-
cussed with long-term recordings. I f mechanisms
responsible for heart period modulations of a certain
frequency remain unchangedduringthewholeperiodof
recording, the corresponding frequency component of
HRV maybeusedasameasureof thesemodulations. I f
the modulations are not stable, interpretation of the
results of frequency analysis is less well dened. I n
particular, physiological mechanisms of heart period
modulations responsiblefor LF and HF power compo-
nents cannot be considered stationary during the 24-h
period
[25]
. Thus, spectral analysisperformedintheentire
24-h period as well as spectral results obtained from
shorter segments (e.g. 5min) averaged over the entire
24-h period (the LF and HF results of these two
computationsarenot dierent
[26,27]
) provideaveragesof
themodulations attributableto theLF and HF compo-
nents (Fig. 4). Such averages obscuredetailed informa-
tion about autonomic modulation of RR intervals
available in shorter recordings
[25]
. I t should be remem-
bered that the components of HRV provide measure-
ments of the degree of autonomic modulations rather
than of the level of autonomic tone
[28]
and averages of
modulations do not represent an averaged level of tone.
Technical requirements and recommendations
Because of the important dierences in the interpreta-
tion of the results, the spectral analyses of short- and
long-term electrocardiograms should always be strictly
distinguished, as reported in Table2.
The analysed ECG signal should satisfy several
requirements in order to obtain a reliable spectral esti-
mation. Any departurefromthefollowingrequirements
may lead to unreproducible results that are dicult to
interpret.
I n order to attribute individual spectral compo-
nents to well dened physiological mechanisms, such
mechanisms modulating the heart rate should not
change during the recording. Transient physiological
phenomena may perhaps be analysed by specic meth-
ods which currently constitute a challenging research
topic, but which arenot yet ready to beused in applied
research. To check thestability of thesignal in terms of
certain spectral components, traditional statistical tests
may beemployed
[29]
.
Thesampling ratehas to beproperly chosen. A
lowsamplingratemay produceajitter in theestimation
of the R wave ducial point which alters the spectrum
considerably. Theoptimal rangeis 250500Mz or per-
haps even higher
[30]
, whilealower samplingrate(in any
case d100Hz) may behave satisfactorily only if an
algorithm of interpolation (e.g. parabolic) is used to
renetheR waveducial point
[31,32]
.
Baseline and trend removal (if used) may aect
thelower componentsin thespectrum. I t isadvisableto
check thefrequency responseof thelter or thebehav-
iour of the regression algorithmand to verify that the
spectral components of interest are not signicantly
aected.
0.5
10
Hz
P
S
D

(
m
s
e
c
2

1
0
3
/
H
z
)
0
LF HF
0.5
Hz
0
LF
HF
LF
HF
LF
HF
Rest Ti l t
Figure 3 Spectral analysis(autoregressivemodel, order
12) of RR interval variabilityinahealthysubject at rest
andduring90 head-uptilt. Atrest, twomajorcomponents
of similar power aredetectableat lowandhighfrequen-
cies. During tilt, the LF component becomes dominant
but, astotal varianceisreduced, theabsolutepower of LF
appearsunchangedcomparedtorest. Normalizationpro-
cedureleadstopredominant LF andsmaller HF compo-
nents, whichexpressthealterationof spectral components
dueto tilt. Thepiecharts showtherelativedistribution
together withtheabsolutepower of thetwo components
representedbythearea. Duringrest, thetotal varianceof
the spectrumwas 1201ms
2
, and its VLF, LF, and HF
componentswere586ms
2
, 310ms
2
, and302ms
2
, respec-
tively. Expressedinnormalizedunits, theLFandHFwere
4895n.u. and4778n.u., respectively. TheLF/HF ratio
was102. Duringtilt, thetotal variancewas671ms
2
, and
itsVLF, LF, andHF componentswere265ms
2
, 308ms
2
,
and95ms
2
, respectively. Expressedinnormalizedunits,
the LF and HF were 7596n.u. and 2348n.u., respec-
tively. The LF/HF ratio was 334. Thus note that, for
instance, the absolute power of the LF component was
slightlydecreasedduringtiltwhilstthenormalizedunitsof
LF weresubstantiallyincreased
1
100
0.00001
0.0001
Frequency (Hz)
P
o
w
e
r

(
m
s
2
)
0
.
0
4
0.1
10
1
0.01
0.001
0.0001
0.001
0
.
0
0
3
0.01 0.1
0
.
1
5
0.4
VLF ULF LF HF
Figure 4 Example of an estimate of power spectral
density obtainedfromtheentire24-hinterval of along-
termHolter recording. OnlytheLF andHF components
correspondtopeaksof thespectrumwhiletheVLF and
ULF can be approximated by a line in this plot with
logarithmicscalesonbothaxes. Theslopeof suchaline
isthe measureof HRV.
Thechoiceof QRSducial point maybecritical.
I t is necessary to use a well tested algorithm (i.e.
derivative+threshold, template, correlation method,
etc.) in order to locate a stable and noise-independent
reference point
[33]
. A ducial point localized far within
the QRS complex may also be inuenced by varying
ventricular conduction disturbances.
Ectopic beats, arrhythmic events, missing data
and noiseeects may alter theestimation of thePSD of
HRV. Proper interpolation (or linear regression or simi-
lar algorithms) on preceding/successive beats on the
HRV signals or on its autocorrelation function may
reduce this error. Preferentially, short-term recordings
which arefreeof ectopy, missingdata, and noiseshould
beused. I n somecircumstances, however, acceptanceof
only ectopic-free short-term recordings may introduce
signicant selection bias. I n such cases, proper inter-
polationshouldbeusedandthepossibilityof theresults
beinginuenced by ectopy should beconsidered
[34]
. The
relative number and relative duration of RR intervals
which were omitted and interpolated should also be
quoted.
Algorithmic standards and recommendations
The series of data subjected to spectral analysis can be
obtained in dierent ways. A useful pictorial represen-
tation of thedataisthediscreteevent series(DES), that
is the plot of R
i
-R
i1
interval vs time (indicated at R
i
occurrence) which is an irregularly time-sampled signal.
Nevertheless, spectral analysis of the sequence of
instantaneous heart rates has also been used in many
studies
[26]
.
The spectrum of the HRV signal is generally
calculated either fromthe RR interval tachogram(RR
durations vs number of progressive beatssee Fig.
5a,b) or by interpolating the DES, thus obtaining a
continuoussignal asafunctionof time, or bycalculating
the spectrumof the countsunitary pulses as a func-
tion of time corresponding to each recognised QRS
complex
[35]
. Such achoicemay haveimplicationson the
morphology, the measurement units of the spectra and
themeasurement of therelevant spectral parameters. I n
order to standardize the methods, the use of the RR
interval tachogramwith the parametric method, or the
regularly sampled interpolation of DES with the non-
parametric method may be suggested; nevertheless,
regularly sampled interpolation of DES is also suitable
for parametric methods. The sampling frequency of
interpolation of DES has to besuciently high that the
Nyquist frequency of the spectrum is not within the
frequency rangeof interest.
Standards for non-parametric methods (based
upon the FFT algorithm) should include the values
reported in Table2, theformula of DES interpolation,
the frequency of sampling the DES interpolation, the
number of samples used for the spectrum calculation,
and the spectral window employed (Hann, Hamming,
and triangular windows are most frequently used)
[36]
.
The method of calculating the power in respect of the
window should also be quoted. I n addition to require-
ments described in other parts of this document, each
study employingthenon-parametric spectral analysisof
HRV should quoteall theseparameters.
Standards for parametric methods should
include the values reported in Table 2, the type of the
model used, the number of samples, the central fre-
quency for each spectral component (LF and HF) and
the value of the model order (numbers of parameters).
Furthermore, statistical gures haveto becalculated in
order to test thereliability of themodel. Theprediction
Table2 Selected frequency domain measures of HRV
Variable Units Description Frequency range
Analysis of short-termrecordings (5min)
5min total power ms
2
Thevarianceof NN intervals over the approximately c04Hz
temporal segment
VLF ms
2
Power in very lowfrequency range c004Hz
LF ms
2
Power in lowfrequency range 004015Hz
LF norm n.u. LF power in normalised units
LF/(Total PowerVLF)100
HF ms
2
Power in high frequency range 01504Hz
HF norm n.u. HF power in normalised units
HF/(Total PowerVLF)100
LF/HF Ratio LF [ms
2
]/HF [ms
2
]
Analysis of entire24h
Total power ms
2
Varianceof all NN intervals approximately c04Hz
ULF ms
2
Power in theultra lowfrequency range c0003Hz
VLF ms
2
Power in thevery lowfrequency range 0003004Hz
LF ms
2
Power in thelowfrequency range 004015Hz
HF ms
2
Power in thehigh frequency range 01504Hz
Slopeof thelinear interpolation of the approximately c004Hz
spectrumin a log-log scale
360 Task Force
0.5
0.015
0
Frequency (Hz)
P
S
D

(
s
2
/
H
z
)
0.010
0.005
(e)
0.1 0.2 0.3 0.4
HF
LF
VLF
0.5
0.015
0
Frequency (Hz)
P
S
D

(
s
2
/
H
z
)
0.010
0.005
(c)
0.1 0.2 0.3 0.4
HF
LF
VLF
1.0
0.4
0
Beat #
R
R

(
s
)
0.6
0.5
(a)
100 200
n = 256
0.9
0.8
0.7
Rest
tachogram
Mean = 842.5 ms
2
= 1784 ms
2
Frequency
Hz
Power
ms
2
Power
n.u.
VLF
LF
HF
0.00
0.11
0.24
785
479
450
47.95
45.05
LF/HF = 1.06
PEWT > 3
OOT = 9
p = 9
Frequency
Hz
Power
ms
2
VLF
LF
HF
0.00
0.10
0.25
266
164
214
wi ndow = Hann
0.5
0.015
0
Frequency (Hz)
0.010
0.005
(f)
0.1 0.2 0.3 0.4
HF
LF
VLF
0.5
0.015
0
Frequency (Hz)
0.010
0.005
(d)
0.1 0.2 0.3 0.4
HF
LF
VLF
1.0
0.4
0
Beat #
0.6
0.5
(b)
100 200
n = 256
0.9
0.8
0.7
Ti l t
tachogram
Mean = 564.7 ms
2
= 723 ms
2
Frequency
Hz
Power
ms
2
Power
n.u.
VLF
LF
HF
0.00
0.09
0.24
192
413
107
77.78
20.15
LF/HF = 3.66
PEWT > 11
OOT = 15
p = 15
Frequency
Hz
Power
ms
2
VLF
LF
HF
0.00
0.10
0.25
140
312
59
wi ndow = Hann
Figure5 Interval tachogramof 256consecutiveRRvaluesinanormal subjectatsupinerest(a)andafter
head-uptilt(b). TheHRVspectraareshown, calculatedbyparametricautoregressivemodelling(candd),
andbyaFFT basednon-parametricalgorithm(eandf). Meanvalues(m), variances(s
2
) andthenumber
(n) of samplesareindicated. For (c) and(d), VLF, LF andHF central frequency, power inabsolutevalue
andpower innormalizedunits(n.u.) arealsoindicatedtogether withtheorder pof thechosenmodel and
minimal valuesof PEWT andOOT whichsatisfythetests. In(e)and(f), thepeakfrequencyandthepower
of VLF, LF andHF werecalculatedbyintegratingthePSDinthedenedfrequencybands. Thewindow
typeisalsospecied. Inpanels(c) to(f), theLFcomponentisindicatedbydarkshadedareasandtheHF
component bylight shadedareas.
error whitenesstest (PEWT) providesinformationabout
thegoodness of thetting model
[37]
whiletheoptimal
order test (OOT) checks the suitability of the order of
the model used
[38]
. There are dierent possibilities of
performing OOT which include nal prediction error
and Akaike information criteria. The following opera-
tivecriterion for choosingtheorder p of an autoregres-
sivemodel might beproposed: theorder shall bein the
range820, fulllingthePEWT test andcomplyingwith
theOOT test (p]min(OOT)).
Correlation and dierences between timeand frequency
domain measures
When analysing stationary short-termrecordings, more
experience and theoretical knowledge exists on the
physiological interpretation of the frequencydomain
measures compared to the timedomain measures
derived fromthesamerecordings.
However, many time- and frequency-domain
variables measured over the entire 24-h period are
strongly correlated with each other (Table 3). These
strong correlations exist because of both mathematical
and physiological relationships. I n addition, thephysio-
logical interpretation of thespectral components calcu-
lated over 24h is dicult, for the reasons mentioned
(section entitled Long-term recordings). Thus, unless
special investigations areperformed which usethe24-h
HRV signal to extract information other than theusual
frequencycomponents(e.g. theloglogslopeof spectro-
gram), the results of frequencydomain analysis are
equivalent to those of timedomain analysis, which is
easier to perform.
Rhythmpattern analysis
Asillustrated in Fig. 6
[39]
, thetimedomain and spectral
methodssharelimitationsimposed by theirregularity of
theRR series. Clearlydierent prolesanalysedbythese
techniquesmay giveidentical results. Trendsof decreas-
ingor increasingcyclelengthareinrealitynot symmetri-
cal
[40,41]
as heart rateaccelerations areusually followed
by a faster decrease. I n spectral results, this tends to
reduce the peak at the fundamental frequency, and to
enlarge its basis. This leads to the idea of measuring
blocks of RR intervals determined by properties of the
rhythmandinvestigatingtherelationshipof such blocks
without considering theinternal variability.
Approaches derived fromthe timedomain and
the frequencydomain have been proposed in order to
reducethesediculties. Theinterval spectrumandspec-
trum of counts methods lead to equivalent results (d,
Fig. 6) and arewell suited to investigatetherelationship
between HRV and thevariability of other physiological
measures. Theinterval spectrumis well adapted to link
RR intervalsto variablesdenedonabeat-to-beat basis
Table 3 Approximate correspondence of time domain
and frequency domain methods applied to 24-h ECG
recordings
Timedomain variable
Approximatefrequency
domain correlate
SDNN Total power
HRV triangular index Total power
TI NN Total power
SDANN ULF
SDNN index Mean of 5min total power
RMSSD HF
SDSD HF
NN50 count HF
pNN50 HF
Dierential index HF
Logarithmic index HF
1000
(d)
0 500
(c)
(b)
(a)
Figure 6 Example of four synthesised time series with identical means,
standard deviations, and ranges. Series (c) and (d) also have identical
autocorrelation functions and thereforeidentical power spectra. Reprinted
withpermission
[39]
.
362 Task Force
(e.g. blood pressure). Thespectrumof counts is prefer-
able if RR intervals are related to a continuous signal
(e.g. respiration), or to theoccurrenceof special events
(e.g. arrhythmia).
Thepeak-valley procedures arebased either on
the detection of the summit and the nadir of oscilla-
tions
[42,43]
or on thedetection of trends of heart rate
[44]
.
The detection may be limited to short-termchanges
[42]
but it can beextended to longer variations: second and
third order peaks and troughs
[43]
or stepwiseincreaseof
asequenceof consecutiveincreasingor decreasingcycles
surrounded by opposite trends
[44]
. The various oscilla-
tions can be characterized on the basis of the heart
rate accelerating or slowing, the wavelength and/or the
amplitude. I n a majority of short- to mid-termrecord-
ings, the results are correlated with frequency compo-
nents of HRV
[45]
. The correlations, however, tend to
diminish as the wavelength of the oscillations and the
recording duration increase. Complex demodulation
uses the techniques of interpolation and detrending
[46]
and provides the time resolution necessary to detect
short-term heart rate changes, as well as to describe
the amplitude and phase of particular frequency
components as functions of time.
Non-linear methods
Non-linear phenomena are certainly involved in the
genesis of HRV. They aredetermined by complex inter-
actions of haemodynamic, electrophysiological and
humoral variables, as well as by autonomic and central
nervousregulations. I t hasbeen speculated that analysis
of HRV based on the methods of non-linear dynamics
might elicit valuable information for the physiological
interpretationof HRV andfor theassessment of therisk
of sudden death. Theparameters which havebeen used
to measure non-linear properties of HRV include 1/f
scalingof Fourier spectra
[47,19]
, H scalingexponent, and
CoarseGrainingSpectral Analysis(CGSA)
[48]
. For data
representation, Poincarsections, low-dimension attrac-
tor plots, singular value decomposition, and attractor
trajectories have been used. For other quantitative
descriptions, the D
2
correlation dimension, Lyapunov
exponents, and Kolmogorov entropy have been
employed
[49]
.
Althoughinprinciplethesetechniqueshavebeen
shown to be powerful tools for characterization of
various complex systems, no major breakthrough has
yet been achieved by their application to bio-medical
data includingHRV analysis. I t is possiblethat integral
complexity measures are not adequate to analyse bio-
logical systemsandthus, aretoo insensitiveto detect the
non-linear perturbationsof RR interval which would be
of physiological or practical importance. Moreencour-
aging results have been obtained using dierential,
rather thanintegral complexitymeasures, e.g. thescaling
index method
[50,51]
. However, no systematic study has
been conducted to investigatelargepatient populations
using thesemethods.
At present, the non-linear methods represent
potentially promising tools for HRV assessment, but
standards arelacking and thefull scopeof thesemeth-
odscannot beassessed. Advancesin technology and the
interpretation of the results of non-linear methods are
needed beforethesemethodsareready for physiological
and clinical studies.
Stability and reproducibility of HRV
measurement
Multiple studies have demonstrated that short-term
measures of HRV rapidly return to baselineafter tran-
sient perturbations induced by such manipulations as
mild exercise, administration of short acting vasodila-
tors, transient coronary occlusion, etc. More powerful
stimuli, such as maximumexerciseor administration of
longactingdrugs may result in a much moreprolonged
interval beforereturn to control values.
There are far fewer data on the stability of
long-termmeasures of HRV obtained from24-h ambu-
latory monitoring. Nonetheless, the same amount of
data available suggest great stability of HRV measures
derived from 24-h ambulatory monitoring in both
normal subjects
[52,53]
and in the post-infarction
[54]
and
ventricular arrhythmia
[55]
populations. Therealso exists
somefragmentary datato suggest that stability of HRV
measures may persist for months and years. Because
24-h indices seem to be stable and free of placebo
eect, they may beideal variables with which to assess
intervention therapies.
Recording requirements
ECG signal
Theducial point recognised on theECG tracingwhich
identies a QRS complex may be based on the maxi-
mumor baricentrumof thecomplex, on thedetermina-
tionof themaximumof aninterpolatingcurve, or found
by matchingwith a templateor other event markers. I n
order to localizetheducial point, voluntary standards
for diagnostic ECG equipment are satisfactory in
terms of signal/noise ratio, common mode rejection,
bandwidth, etc.
[56]
An upper-band frequency cut-o
substantially lower than that established for diagnostic
equipment (200Hz) may createajitter in therecogni-
tion of the QRS complex ducial point, introducing
an error of measured RR intervals. Similarly, limited
sampling rate induces an error in the HRV spectrum
whichincreaseswithfrequency, thusaectingmorehigh
frequency components
[31]
. An interpolation of the
undersampledECG signal maydecreasethiserror. With
proper interpolation, evena100Hzsamplingratecanbe
sucient
[32]
.
When using solid-state storage recorders, data
compression techniques haveto becarefully considered
in terms of both the eective sampling rate and the
quality of reconstruction methods which may yield
amplitudeand phasedistortion
[57]
.
Duration and circumstances of ECG recording
I nstudiesresearchingHRV, thedurationof recordingis
dictated by thenatureof each investigation. Standardiz-
ation is needed, particularly in studies investigating the
physiological and clinical potential of HRV.
Frequencydomain methods should bepreferred
to the timedomain methods when investigating short-
termrecordings. Therecordingshouldlast for at least 10
times the wavelength of the lower frequency bound of
the investigated component, and, in order to ensure
the stability of the signal, should not be substantially
extended. Thus, recording of approximately 1min is
needed to assess the HF components of HRV while
approximately 2min are needed to address the LF
component. I n order to standardize dierent studies
investigating short-term HRV, 5min recordings of a
stationary systemarepreferred unless thenatureof the
study dictates another design.
Averagingof spectral componentsobtainedfrom
sequential periods of timeis ableto minimizetheerror
imposed by theanalysis of very short segments. Never-
theless, if the nature and degree of physiological heart
period modulations changes fromoneshort segment of
the recording to another, the physiological interpreta-
tion of such averaged spectral components suers from
the same intrinsic problems as that of the spectral
analysis of long-term recordings and warrants further
elucidation. A display of stacked series of sequential
power spectra (e.g. over 20min) may help conrm
steady stateconditions for a given physiological state.
Although the timedomain methods, especially
the SDNN and RMSSD methods, can be used to
investigaterecordings of short durations, thefrequency
methods are usually able to provide more easily inter-
pretableresults in terms of physiological regulations. I n
general, the timedomain methods are ideal for the
analysis of long-termrecordings (the lower stability of
heart rate modulations during long-term recordings
makes theresults of frequency methods less easily inter-
pretable). The experience shows that a substantial part
of the long-term HRV value is contributed by the
daynight dierences. Thus the long-term recording
analysedbythetimedomainmethodsshouldcontainat
least 18h of analysable ECG data that includes the
wholenight.
Littleis known about theeects of theenviron-
ment (e.g. type and nature of physical activity and
of emotional circumstances) during long-term ECG
recordings. For some experimental designs, environ-
mental variablesshouldbecontrolledandineachstudy,
the character of the environment should always be
described. The design of investigations should also
ensure that the recording environment of individual
subjects is similar. I n physiological studies comparing
HRV in dierent well-dened groups, the dierences
between underlying heart rate should also be properly
acknowledged.
Editing of theRR interval sequence
The errors imposed by the imprecision of the NN
interval sequence are known to aect substantially the
results of statistical timedomain and all frequency
domain methods. I t is known that casual editing of the
RR interval dataissucient for theapproximateassess-
ment of total HRV by thegeometric methods, but it is
not known how precisetheediting should beto ensure
correct resultsfromother methods. Thuswhenusingthe
statistical timedomain and/or frequencydomain meth-
ods, the manual editing of the RR data should be
performed to a very high standard ensuring correct
identication and classication of every QRS complex.
Automatic lters which exclude some intervals from
the original RR sequence (e.g. those diering by more
than 20%fromthepreviousinterval) should not replace
manual editingas they areknown to behaveunsatisfac-
torily and to haveundesirableeectsleadingpotentially
to errors
[58]
.
Suggestions for standardisation of commercial
equipment
Standard measurement of HRV Commercial equipment
designedto analyseshort-termHRV shouldincorporate
non-parametric and preferably also parametric spectral
analysis. I n order to minimize the possible confusion
imposed by reporting the components of the cardiac
beat-based analysis in timefrequency components, the
analysis based on regular sampling of the tachograms
should be oered in all cases. Non-parametric spectral
analysis should employ at least 512but preferably 1024
points for 5min recordings.
Equipment designed to analyse HRV in long-
term recordings should implement timedomain
methods including all four standard measures (SDNN,
SDANN, RMSSD, and HRV triangular index). I n
addition to other options, thefrequency analysis should
be performed in 5min segments (using the same preci-
sion as with the analysis of short-term ECGs). When
performing the spectral analysis of the total nominal
24-h record in order to computethewholerangeof HF,
LF, VLF and ULF components, the analysis should
be performed with a similar precision of periodogram
sampling, as suggested for the short-termanalysis, e.g.
using 2
18
points.
Thestrategy of obtaining thedata for theHRV
analysis should copy thedesign outlined in Fig. 7.
Precision and testing of commercial equipment I n order
to ensure the quality of dierent equipment involved
in HRV analysis and to nd an appropriate balance
between the precision essential to research and clinical
studiesand thecost of theequipment required, indepen-
dent testingof all equipment is needed. As thepotential
errorsof theHRV assessment includeinaccuraciesinthe
identication of ducial points of QRS complexes, the
testing should include all the recording, replay, and
analysis phases. Thus, it seems ideal to test various
equipment with signals (e.g. computer simulated) of
known HRV properties rather than with existing
364 Task Force
databases of already digitized ECGs. When employing
commercial equipment in studies investigating physi-
ological and clinical aspects of HRV, independent tests
of the equipment used should always be required. A
possiblestrategy for testingof commercial equipment is
proposedinAppendixB. Voluntaryindustrial standards
should bedeveloped adopting this or similar strategy.
Summary and recommendations
I n order to minimize the errors caused by improperly
designed or incorrectly used techniques, the following
points arerecommended:
The ECG equipment used should satisfy the
current voluntaryindustrial standardsintermsof signal/
noiseratio, common moderejection, bandwidth, etc.
Solid-state recorders used should allow signal
reconstruction without amplitudeand phasedistortion;
long-term ECG recorders using analogue magnetic
media should accompany the signal with phase-locked
timetracking.
Commercial equipment used to assess HRV
should satisfy the technical requirements listed in the
Section on Standard Measurement of HRV and its
performanceshould beindependently tested.
I norder to standardizephysiological andclinical
studies, twotypesof recordingsshouldbeusedwhenever
possible: (a) short-term recordings of 5min made
under physiologically stable conditions processed by
frequencydomain methods, and/or (b) nominal 24-h
recordings processed by timedomain methods.
When using long-termECGs in clinical studies,
individual, subjects should be recorded under fairly
similar conditions and in a fairly similar environment.
When using statistical timedomain or
frequencydomain methods, thecompletesignal should
be carefully edited using visual checks and manual
correctionsof individual RR intervalsandQRScomplex
classications. Automatic lters based on hypotheses
on the logic of RR interval sequence (e.g. exclusion of
RR intervals according to a certain prematurity thresh-
old) shouldnot bereliedonwhenensuringthequalityof
theRR interval sequence.
Physiological correlates of heart rate
variability
Physiological correlates of HRV components
Autonomic inuences of heart rate
Although cardiac automaticity is intrinsic to various
pacemaker tissues, heart rate and rhythm are largely
under the control of the autonomic nervous system
[59]
.
Theparasympathetic inuenceon heart rateismediated
via release of acetylcholine by the vagus nerve.
Muscarinic acetylcholine receptors respond to this
release mostly by an increase in cell membrane K +
conductance
[6062]
. Acetylcholine also inhibits the
hyperpolarization-activated pacemaker current I f
[63,64]
.
The I k decay hypothesis
[65]
proposes that pacemaker
depolarization results from slow deactivation of the
delayed rectier current, I k, which, due to a time-
independent background inward current, causes diasto-
lic depolarization
[65,66]
. Conversely, the I f activation
hypothesis
[67]
suggest that following action potential
termination, I f provides a slowly activating inward cur-
rent predominating over decaying I k, thus initiating
slowdiastolic depolarization.
Thesympathetic inuenceon heart rateis medi-
ated by release of epinephrine and norepinephrine.
Activation of -adrenergic receptors results in cyclic
AMP mediated phosphorilation of membrane proteins
andincreasesinI CaL
[68]
andinI f
[69,70]
. Theendresult is
an acceleration of theslowdiastolic depolarization.
Under resting conditions, vagal tone prevails
[71]
and variations in heart period arelargely dependent on
vagal modulation
[72]
. Thevagal andsympatheticactivity
constantly interact. As the sinus node is rich in acetyl-
cholinesterase, the eect of any vagal impulse is brief
because the acetylcholine is rapidly hydrolysed. Para-
sympathetic inuences exceed sympathetic eects
probably via two independent mechanisms: a cholin-
ergically induced reduction of norepinephrine released
in response to sympathetic activity, and a cholinergic
attenuation of theresponseto a adrenergic stimulus.
Components of HRV
The RR interval variations present during resting con-
ditionsrepresent anetuningof thebeat-to-beat control
mechanisms
[73,74]
. Vagal aerent stimulation leads to
reex excitation of vagal eerent activity and inhibition
of sympathetic eerent activity
[75]
. The opposite reex
eects are mediated by the stimulation of sympathetic
aerent activity
[76]
. Eerent vagal activity also appears
to be under tonic restraint by cardiac aerent sympa-
thetic activity
[77]
. Eerent sympathetic and vagal activi-
ties directed to the sinus node are characterized by
discharge largely synchronous with each cardiac cycle
RR i nterval
rejecti on
RR data
edi ti ng
Artefact
i denti fi cati on
Mi crocomputer
di gi ti si ng
ECG
recordi ng
NN data
sequence
I nterpol ati on
+ sampl i ng
TI ME
DOMAI N
HRV
FREQUENCY
DOMAI N
HRV
Figure 7 Flowchart summarizingindividual steps used
whenrecordingandprocessingtheECGsignal inorder to
obtaindatafor HRV analysis.
which can bemodulated by central (e.g. vasomotor and
respiratory centres) and peripheral (e.g. oscillation in
arterial pressure and respiratory movements) oscilla-
tors
[24]
. Theseoscillators generaterhythmic uctuations
in eerent neural dischargewhich manifest as short and
long-term oscillation in the heart period. Analysis of
these rhythms may permit inferences on the state and
function of (a) the central oscillators, (b) the sympa-
thetic and vagal eerent activity, (c) humoral factors,
and (d) thesinus node.
An understanding of the modulatory eects of
neural mechanismsonthesinusnodehasbeenenhanced
by spectral analysis of HRV. Theeerent vagal activity
is a major contributor to theHF component, as seen in
clinical and experimental observations of autonomic
manoeuvres such as electrical vagal stimulation, mus-
carinic receptor blockade, and vagotomy
[13,14,24]
. More
controversial is theinterpretation of theLF component
which is considered by some
[24,7880]
as a marker of
sympatheticmodulation(especiallywhenexpressingit in
normalizedunits) andbyothers
[13,81]
asaparameter that
includes both sympathetic and vagal inuences. This
discrepancy is due to the fact that in some conditions,
associated with sympathetic excitation, adecreasein the
absolute power of the LF component is observed. I t is
important to recall that during sympathetic activation
the resulting tachycardia is usually accompanied by a
marked reduction in total power, whereas the reverse
occurs during vagal activation. When thespectral com-
ponents are expressed in absolute units (ms
2
), the
changesintotal power inuenceLF andHF inthesame
direction and prevent theappreciation of thefractional
distribution of the energy. This explains why in supine
subjects under controlled respiration atropine reduces
both LF and HF
[14]
and why during exercise LF is
markedly reduced
[24]
. This concept is exemplied in
Fig. 3showingthespectral analysisof HRV inanormal
subject during control supine conditions and 90
head-up tilt. Due to the reduction in total power,
LF appears as unchanged if considered in absolute
units. However, after normalization an increase in LF
becomes evident. Similar results apply to the LF/HF
ratio
[82]
.
Spectral analysis of 24-h recordings
[2425]
shows
that innormal subjectsLF andHF expressedinnormal-
ized units exhibit a circadian pattern and reciprocal
uctuations, withhigher valuesof LF inthedaytimeand
of HF at night. These patterns become undetectable
when a singlespectrumof theentire24-h period is used
or when spectra of subsequent shorter segments are
averaged. I n long-term recordings, the HF and LF
components account for approximately 5% of total
power. Although the ULF and VLF components
account for the remaining 95% of total power, their
physiological correlates arestill unknown.
LF and HF can increase under dierent condi-
tions. AnincreasedLF (expressedinnormalizedunits) is
observed during 90 tilt, standing, mental stress and
moderateexercisein healthy subjects, and during mod-
erate hypotension, physical activity and occlusion of a
coronaryarteryor commoncarotidarteriesinconscious
dogs
[24,79]
. Conversely, an increasein HF is induced by
controlled respiration, cold stimulation of the face and
rotational stimuli
[24,78]
.
Summary and recommendations for interpretation of
HRV components
Vagal activity is the major contributor to the HF
component.
Disagreement exists in respect of theLF compo-
nent. Some studies suggest that LF, when expressed in
normalized units, is a quantitative marker for sympa-
thetic modulations, other studies view LF as reecting
both sympathetic and vagal activity. Consequently, the
LF/HF ratio is considered by some investigators to
mirror sympatho/vagal balanceor to reect sympathetic
modulations.
Physiological interpretation of lower frequency
components of HRV (that is of the VLF and ULF
components) warrants further elucidation.
I t is important to note that HRV measures
uctuationsinautonomicinputsto theheart rather than
the mean level of autonomic inputs. Thus both auto-
nomic withdrawal and a saturatingly high level of
sympathetic input leads to diminished HRV
[28]
.
Changes of HRV related to specic
pathologies
A reduction of HRV has been reported in several
cardiological and non-cardiological diseases
[24,78,81,83]
.
Myocardial infarction
DepressedHRV after MI mayreect adecreaseinvagal
activity directed to the heart which leads to prevalence
of sympathetic mechanisms and to cardiac electrical
instability. I n the acute phase of MI , the reduction in
24-h SDNN is signicantly related to left ventricular
dysfunction, peak creatinekinase, and Killip class
[84]
.
The mechanism by which HRV is transiently
reduced after MI and by which a depressed HRV is
predictiveof theneural responseto acuteMI is not yet
dened, but it is likely to involve derangements in the
neural activity of cardiac origin. One hypothesis
[85]
involves cardio-cardiac sympatho-sympathetic
[86,87]
and
sympatho-vagal reexes
[75]
andsuggeststhat thechanges
in the geometry of a beating heart due to necrotic and
non-contracting segments may abnormally increase the
ring of sympathetic aerent bres by mechanical dis-
tortion of the sensory ending
[76,87,88]
. This sympathetic
excitation attenuates theactivity of vagal bres directed
to the sinus node. Another explanation, especially
applicable to marked reduction of HRV, is the
reduced responsiveness of sinus nodal cells to neural
modulations
[82,85]
.
Spectral analysisof HRV inpatientssurvivingan
acute MI revealed a reduction in total and in the
individual power of spectral components
[89]
. However,
366 Task Force
when the power of LF and HF was calculated in
normalized units, an increased LF and adiminished HF
wereobserved duringboth restingcontrolled conditions
and 24-h recordings analysed over multiple 5min
periods
[90,91]
. These changes may indicate a shift of
sympatho-vagal balance towards sympathetic predomi-
nanceand reduced vagal tone. Similar conclusions were
obtainedbyconsideringthechangesintheLF/HF ratio.
The presence of an alteration in neural control mecha-
nismswasalso reectedbythebluntingof thedaynight
variationsof theRR interval
[91]
andLF andHF spectral
components
[91,92]
present in aperiod rangingfromdays
to afewweeksafter theacuteevent. I n post MI patients
with avery depressed HRV, most of theresidual energy
isdistributedintheVLF frequencyrangebelow003Hz,
with only asmall respiration-related HF
[93]
. Thesechar-
acteristics of the spectral prole are similar to those
observed in advanced cardiac failure or after cardiac
transplant, and are likely to reect either diminished
responsivenessof thetarget organ to neural modulatory
inputs
[82]
or asaturatinginuenceonthesinusnodeof a
persistently high sympathetic tone
[28]
.
Diabetic neuropathy
I n neuropathy associated with diabetesmellitus, charac-
terized by alteration of small nervebres, areduction in
timedomain parameters of HRV seems not only to
carry negative prognostic value but also to precede the
clinical expression of autonomic neuropathy
[9497]
. I n
diabetic patients without evidenceof autonomic neuro-
pathy, reduction of the absolute power of LF and HF
duringcontrolledconditionswasalso reported
[96]
. How-
ever, when theLF/HF ratio wasconsidered or when LF
and HF were analysed in normalized units, no signi-
cant dierence in comparison to normals was present.
Thus, the initial manifestation of this neuropathy is
likely to involve both eerent limbs of the autonomic
nervous system
[96,98]
.
Cardiac transplantation
A very reduced HRV with no denite spectral compo-
nents was reported in patients with a recent heart
transplant
[97,99,100]
. The appearance of discrete spectral
components in a few patients is considered to reect
cardiac re-innervation
[101]
. This re-innervation may
occur as early as 1 to 2 years post transplantation
and is usually of sympathetic origin. I ndeed, thecorre-
lation between therespiratory rateand theHF compo-
nent of HRV observed in some transplanted patients
indicatesthat anon-neural mechanismmayalsocontrib-
ute to generate respiration-related rhythmic oscilla-
tion
[100]
. The initial observation of identifying patients
developinganallograft rejectionaccordingto changesin
HRV could be of clinical interest but needs further
conrmation.
Myocardial dysfunction
A reduced HRV has been consistently observed in
patientswith cardiac failure
[24,78,81,102106]
. I n thiscondi-
tion characterized by signs of sympathetic activation,
such as faster heart rates and high levels of circulating
cathecolamines, arelationship between changesin HRV
and the extent of left ventricular dysfunction was con-
troversially reported
[102,104]
. I n fact, whereas the reduc-
tionintimedomainmeasuresof HRV seemedtoparallel
the severity of the disease, the relationship between
spectral components and indices of ventricular dysfunc-
tion appears to bemorecomplex. I n particular, in most
patients with a very advanced phaseof thediseaseand
withadrasticreductioninHRV, aLF component could
not be detected despite clinical signs of sympathetic
activation. Thus, in conditions characterized by marked
and unopposed persistent sympathetic excitation, the
sinus node seems to drastically diminish its responsive-
ness to neural inputs
[104]
.
Tetraplegia
Patients with chronic completehigh cervical spinal cord
lesionshaveintact eerent vagal andsympatheticneural
pathways directed to the sinus node. However, spinal
sympatheticneuronsaredeprivedof modulatorycontrol
and in particular of baroreex supraspinal inhibitory
inputs. For thisreason, thesepatientsrepresent aunique
clinical model withwhichto evaluatethecontributionof
supraspinal mechanisms in determiningthesympathetic
activity responsible for low frequency oscillations of
HRV. I t has been reported
[107]
that no LF could be
detected in tetraplegic patients, thussuggestingthecriti-
cal role of supraspinal mechanisms in determining the
01Hz rhythm. Two recent studies, however, haveindi-
cated that an LF component can also be detected in
HRV and arterial pressure variabilities of some tetra-
plegicpatients
[108,109]
. WhileKohet al.
[108]
attributedthe
LF component of HRV to vagal modulations, Guzzetti
et al.
[109]
attributed thesamecomponent to sympathetic
activity because of the delay with which the LF com-
ponent appeared after spinal section, suggesting an
emerging spinal rhythmicity capable of modulating
sympathetic discharge.
Modications of HRV by specic
interventions
Therationalefor tryingto modify HRV after MI stems
from multiple observations indicating that cardiac
mortality is higher amongpost-MI patients who havea
moredepressed HRV
[93,110]
. Theinferenceis that inter-
ventions that augment HRV may be protective against
cardiac mortality and sudden cardiac death. Although
the rationale for changing HRV is sound, it contains
also theinherent danger of leading to theunwarranted
assumptionthat modicationof HRV translatesdirectly
into cardiac protection, which may not be the case
[111]
.
The target is the improvement of cardiac electrical
stability, and HRV is just a marker of autonomic
activity. Despitethegrowingconsensusthat increasesin
vagal activity can be benecial
[112]
, it is not yet known
howmuch vagal activity (or itsmarkers) hasto increase
in order to provideadequateprotection.
Beta-adrenergic blockadeand HRV
The data on the eect of -blockers on HRV in post-
MI patients are surprisingly scanty
[113,114]
. Despite
the observation of statistically signicant increases, the
actual changes are very modest. However, it is of note
that -blockade prevents the rise in the LF component
observedinthemorninghours
[114]
. I nconsciouspost-MI
dogs, -blockers do not modify HRV
[115]
. The un-
expected observation that, prior to MI , -blockade
increasesHRV only in theanimalsdestined to beat low
risk for lethal arrhythmias post-MI
[115]
may suggest
novel approaches to post-MI risk stratication.
Antiarrhythmic drugs and HRV
Data exist for several antiarrhythmic drugs. Flecainide
and propafenone, but not amiodarone, werereported to
decreasetimedomainmeasuresof HRV inpatientswith
chronic ventricular arrhythmia
[116]
. I n another study
[117]
propafenone reduced HRV and decreased LF much
more than HF, resulting in a signicantly smaller
LF/HF ratio. A larger study
[118]
conrmed that ecain-
ide, and also encainideand moricizine, decreased HRV
in post-MI patients but found no correlation between
the change in HRV and mortality during follow-up.
Thus, some antiarrhythmic drugs associated with
increased mortality can reduceHRV. However, it is not
known whether these changes in HRV have any direct
prognostic signicance.
Scopolamineand HRV
Lowdosemuscarinicreceptor blockers, suchasatropine
andscopolamine, mayproduceaparadoxical increasein
vagal eerent activity, as suggested by a decrease in
heart rate. Dierent studies examined the eects of
transdermal scopolamineon indices of vagal activity in
patients with a recent MI
[119122]
and with congestive
heart failure
[123]
. Scopolaminemarkedly increasesHRV,
which indicates that pharmacological modulation of
neural activitywithscopolaminemayeectivelyincrease
vagal activity. However, ecacy duringlong-termtreat-
ment has not been assessed. Furthermore, low dose
scopolaminedoesnot prevent ventricular brillationdue
to acutemyocardial ischaemia in post-MI dogs
[124]
.
Thrombolysis and HRV
The eect of thrombolysis on HRV (assessed by
pNN50), was reported in 95patients with acuteMI
[125]
.
HRV was higher 90min after thrombolysis in the
patientswith patency of theinfarct-related artery. How-
ever, this dierence was no longer evident when the
entire24h wereanalysed.
Exercisetraining and HRV
Exercisetrainingmay decreasecardiovascular mortality
and sudden cardiac death
[126]
. Regular exercisetraining
is also thought capable of modifying the autonomic
balance
[127,128]
. A recent experimental study, designed to
assesstheeectsof exercisetrainingonmarkersof vagal
activity, has simultaneously provided information on
changes in cardiac electrical stability
[129]
. Conscious
dogs, documented to be at high risk by the previous
occurrenceof ventricular brillation during acutemyo-
cardial ischaemia, wererandomlyassignedto 6weeksof
either daily exercise training or cage rest followed by
exercise training
[129]
. After training, HRV (SDNN) in-
creasedby74%andall animalssurvivedanewischaemic
test. Exercisetrainingcanalso acceleraterecoveryof the
physiological sympatho-vagal interaction, as shown in
post-MI patients
[130]
.
Clinical use of heart rate variability
Although HRV has been thesubject of numerous clini-
cal studiesinvestigatingawidespectrumof cardiological
and non-cardiological diseasesand clinical conditions, a
general consensus of thepractical useof HRV in adult
medicinehasbeenreachedonlyintwo clinical scenarios.
Depressed HRV can beused as a predictor of risk after
acute MI and as an early warning sign of diabetic
neuropathy.
Assessment of risk after acutemyocardial
infarction
Theobservation
[12]
that inpatientswithanacuteMI the
absence of respiratory sinus arrhythmias is associated
with an increasein in-hospital mortality represents the
rst of a large number of reports
[16,93,131]
which have
demonstrated theprognostic valueof assessingHRV to
identify high risk patients.
Depressed HRV is a powerful predictor of mor-
tality and of arrhythmic complications (e.g. sympto-
matic sustained ventricular tachycardia) in patients
following acute MI
[16,131]
(Fig. 8). The predictive value
of HRV is independent of other factors established for
post-infarction risk stratication, such as depressed
left ventricular ejection fraction, increased ventricular
ectopic activity, and presence of late potentials. For
prediction of all-cause mortality, the value of HRV is
similar to that of left ventricular ejection fraction, but
HRV is superior to left ventricular ejection fraction in
predictingarrhythmic events (sudden cardiac death and
ventricular tachycardia)
[131]
. This permits speculation
that HRV is a stronger predictor of arrhythmic mortal-
ity rather than non-arrhythmic mortality. However,
clear dierencesbetweenHRV inpatientssueringfrom
sudden and non-sudden cardiac death after acute MI
havenot beenobserved. Nevertheless, thismight also be
related to thenatureof thepresently used denition of
sudden cardiac death
[132]
, which is bound to includenot
only patients suering from arrhythmia-related death
but also fatal reinfarctions and other cardiovascular
events.
The value of both conventional timedomain
and frequencydomain parameters have been fully
assessed in several independent prospectivestudies, but
because of using optimized cut-o values dening nor-
mal and depressed HRV, these studies may slightly
368 Task Force
overestimatethepredictivevalueof HRV. Nevertheless,
thecondenceintervals of such cut-o values arerather
narrow because of the sizes of the investigated popula-
tions. Thus, theobservedcut-o valuesof 24-hmeasures
of HRV, e.g. SDNN <50ms and HRV triangular index
<15for highly depressed HRV, or SDNN <100ms and
HRV triangular index <20 for moderately depressed
HRV arelikely to bebroadly applicable.
I t isnot knownwhether dierent indicesof HRV
(e.g. assessments of the short- and long-term compo-
nents) can be combined in a multivariate fashion in
order to improve post-infarction risk stratication.
Thereisageneral consensus, however, that combination
of other measures with the assessment of overall 24-h
HRV is probably redundant.
Pathophysiological considerations
I t has not been established whether depressed HRV is
part of themechanismof increased post-infarction mor-
tality or ismerely amarker of poor prognosis. Thedata
suggest that depressed HRV isnot asimplereection of
thesympathetic overdriveand/or vagal withdrawal due
to poor ventricular performancebut that it also reects
depressed vagal activity which has a strong association
with the pathogenesis of ventricular arrhythmias and
sudden cardiac death
[112]
.
Assessment of HRV for risk stratication after acute
Traditionally, HRV used for risk stratication after MI
hasbeen assessed from24-h recordings. HRV measured
from short-term electrocardiogram recordings also
provides prognostic information for risk stratication
followingMI but whether it is as powerful as that from
24-h recordings is uncertain
[133135]
. HRV measured
from short-term recordings is depressed in patients at
high risk; the predictive value of depressed HRV in-
creaseswithincreasingthelengthof recording. Thus, the
4
1.0
0.65
0
Fol l ow-up (years)
S
u
r
v
i
v
a
l

p
r
o
b
a
b
i
l
i
t
y
0.8
0.95
0.9
0.85
0.75
0.7
1 2 3
(b)
HRV i ndex > 20
HRV i ndex > 15
HRV i ndex 20
HRV i ndex 15
40
1.0
0.5
0
Ti me after MI (years)
S
u
r
v
i
v
a
l
0.8
0.9
0.7
10 20 30
(a)
Above 100
50100
Bel ow 50
0.6
Figure 8 Cumulative survival of patients after MI. (a) Shows
survival of patients stratiedaccordingto 24-hSDNN values in
threegroupswithcut-o pointsof 50and100ms. (Reprintedwith
permission
[16]
. (b) Showssimilar survival curvesof patientsstrati-
edaccordingto 24-hHRV triangular index values withcut-o
points of 15 and 20 units, respectively. (Data of St. Georges
Post-infarctionResearchSurveyProgramme.)
use of nominal 24-h recordings may be recommended
for risk stratication studies after MI . On the other
hand, the assessment of HRV fromshort-termrecord-
ings can be used for initial screening of survivors of
acuteMI
[136]
. Such an assessment has similar sensitivity
but lower specicity for predicting patients at high risk
compared to 24-h HRV.
Spectral analysis of HRV in survivors of MI
suggested that theULF and VLF components carry the
highest predictivevalue
[93]
. Asthephysiological correlate
of these components is unknown and as these compo-
nentscorrespond to up to 95%of thetotal power which
can be easily assessed in the time-domain, the use of
individual spectral components of HRV for risk strati-
cation after MI is not more powerful than the use of
thosetime-domain methods which assess overall HRV.
Development of HRV after acutemyocardial infarction
The time after acute MI at which the depressed HRV
reaches thehighest predictivevaluehas not been inves-
tigated comprehensively. Nevertheless, thegeneral con-
sensus is that HRV should be assessed shortly prior to
hospital discharge, i.e. approximately 1week after index
infarction. Sucharecommendationalso tswell into the
common practice of hospital management of survivors
of acuteMI .
Heart rate variability is decreased early after
acuteMI and begins to recover within a fewweeks; it is
maximally but not fully recovered by 6 to 12 months
after MI
[91,137]
. Assessment of heart rate variability at
boththeearlystageof MI (2to 3daysafter acuteMI )
[84]
andpre-dischargefromhospital (1to3weeksafter acute
MI ) oersimportant prognosticinformation. Heart rate
variability measured late (1 year) after acute MI also
predictsfurther mortality
[138]
. Datafromanimal models
suggest that the speed of HRV recovery after MI
correlates with subsequent risk
[115]
.
HRV used for multivariaterisk stratication
The predictive value of heart rate variability alone is
modest, but combinationwithother techniquessubstan-
tially improves its positive predictive accuracy over a
clinicallyimportant rangeof sensitivity(25%to 75%) for
cardiac mortality and arrhythmic events (Fig. 9).
I mprovementsinthepositivepredictiveaccuracy
over the range of sensitivities have been reported
for combinations of HRV with mean heart rate, left
ventricular ejection fraction, frequency of ventricular
ectopic activity, parameters of high resolution electro-
cardiograms(e.g. presenceor absenceof latepotentials),
and clinical assessment
[139]
. However, it is not known
which other stratication factors arethemost practical
and most feasible to be combined with HRV for
multifactorial risk stratication.
Systematic multivariate studies of post MI risk
stratication are needed before a consensus can be
reached and before a combination of HRV with other
variables of proven prognostic importance can be rec-
ommended. Many aspects that are not relevant for
univariate risk stratication need to be examined: it is
not obvious whether the optimum cut-o values of
individual risk factorsknownfromunivariatestudiesare
appropriate in a multivariate setting. Dierent multi-
variate combinations are probably needed for optimiz-
ingpredictiveaccuracy at dierent ranges of sensitivity.
Stepwise strategies should be examined to identify
optimumsequences of performing individual tests used
in multivariatestratication.
Summary and recommendations for interpreting
predictivevalueof depressed HRV after acute
The following facts should be noted when exploiting
HRV assessment in clinical studies and/or trials
involving survivors of acutemyocardial infarction.
Depressed HRV is a predictor of mortality and
arrhythmic complications independent of other
recognised risk factors.
Thereisageneral consensusthat HRV shouldbe
measured approximately 1 week after index infarction.
AlthoughHRV assessedfromshort-termrecord-
ingsprovidesprognosticinformation, HRV measuredin
nominal 24-h recordings is a stronger risk predictor.
HRV assessed fromshort-termrecordings may beused
for initial screening of all survivors of an acuteMI .
80
70
0
20
Sensi ti vi ty (%)
P
o
s
i
t
i
v
e

p
r
e
d
i
c
t
i
v
e

a
c
c
u
r
a
c
y

(
%
)
50
50
40
30
20
10
30 40 60 70
60
(b)
80
70
0
20 50
50
40
30
20
10
30 40 60 70
60
(a)
Figure 9 Comparisonof positivepredictivecharacteris-
ticsof HRV(solidlines)andof combinationsof HRVwith
left ventricular ejection fraction (dashed lines) and of
HRV with left ventricular ejection fraction and ectopic
countson24-hECGs(dottedlines) usedfor identication
of patients at risk of 1-year cardiac mortality (a) and
1-year arrhythmic events (sudden death and/or sympto-
matic sustained ventricular tachycardia (b) after acute
myocardial infarction. (Data of St. Georges Post-
infarctionResearchSurveyProgramme.)
370 Task Force
No currently recognised HRV measureprovides
better prognostic information than the timedomain
HRV measures assessing overall HRV (e.g. SDNN or
HRV triangular index). Other measures, e.g. ULF of
entire 24-h spectral analysis, perform equally well. A
high risk group may beselected by thedichotomy limits
of SDNN <50ms or HRV triangular index <15.
For clinically meaningful ranges of sensitivity,
thepredictivevalueof HRV aloneismodest, althoughit
is higher than that of any other so far recognised risk
factor. To improve the predictive value, HRV may be
combined with other factors. However, optimumset of
risk factors and corresponding dichotomy limits have
not yet been established.
Assessment of diabetic neuropathy
As a complication of diabetes mellitus, autonomic
neuropathy is characterized by early and widespread
neuronal degeneration of small nerve bres of both
sympathetic and parasympathetic tracts
[140]
. I ts clinical
manifestations are ubiquitous with functional impair-
ment andincludepostural hypotension, persistent tachy-
cardia, gustatory sweating, gastroparesis, bladder atony
andnocturnal diarrhoea. Onceclinical manifestationsof
diabetic autonomic neuropathy (DAN) supervene, the
estimated 5-year mortality is approximately 50%
[141]
.
Thus, early subclinical detection of autonomic dysfunc-
tion is important for risk stratication and subsequent
management. Analyses of short-term and/or long-term
HRV haveproven useful in detecting DAN
[96,142147]
.
For thepatient presentingwith a real or suspect
DAN there are three HRV methods from which to
choose: (a) simple bedside RR interval methods, (b)
long-term timedomain measures, which are more
sensitive and more reproducible than the short-term
tests, and (c) frequencydomain analysis performed
under short-termsteady stateconditions and which are
useful in separating sympathetic fromparasympathetic
abnormalities.
Long-termtimedomain measures
HRV computed from 24-h Holter records are more
sensitive than simple bedside tests (e.g. Valsava
manoeuvre, orthostatic test, and deep breathing
[11]
) for
detectingDAN. Most experiencehasbeenobtainedwith
the NN50
[144]
and SDSD (see Table 1)
[145]
methods.
UsingtheNN50count, wherethelower 95%condence
interval for total countsrangefrom500to 2000depend-
ing on the age, about half of diabetic patients will
demonstrateabnormallylowcountsper 24h. Moreover,
there is a strong correlation between the percentage
of patients with abnormal counts and the extent of
autonomic neuropathy determined from conventional
measures.
Besides their increased sensitivity, these 24-h
timedomain methodsarestrongly correlated with other
established HRV measurements and have been found
to be reproducible and stable over time. Similar to
survivors of MI , patients with DAN are also predis-
posed to poor outcomes such as sudden death but it
remains to be determined whether the HRV measures
confer prognostic information among diabetics.
Frequency domain measures
The following abnormalities in frequency HRV analy-
sis are associated with DAN: (a) reduced power in
all spectral bands which is the most common nd-
ing
[96,146148]
, (b) failure to increase LF on standing,
whichisareectionof impairedsympatheticresponseor
depressed baroreceptor sensitivity
[96,147]
; (c) abnormally
reduced total power with unchanged LF/HF ratio
[96]
,
and (d) a leftward shift in the LF central frequency,
the physiological meaning of which needs further
elucidation
[147]
.
I n advanced neuropathic states, the resting
supine power spectrum often reveals extremely low
amplitudesof all spectral componentsmakingit dicult
to separate signal from noise
[96,146,147]
. I t is therefore
recommended that an intervention such as standing or
tilt be included. Another method to overcome the low
signal to noiseratio isto introduceacoherencefunction
which utilizes thetotal power coherent with oneor the
other frequency band
[146]
.
Other clinical potential
Selected studies investigating HRV in other cardio-
logical diseases arelisted in Table4.
Future possibilities
Development of HRV measurement
Thecurrently availabletimedomain methods predomi-
nantly used to assess thelong-termproleof HRV are
probably sucient for this purpose. I mprovements are
possible, especially in terms of numerical robustness.
The contemporary non-parametric and parametric
spectral methods are probably sucient to analyse
short-term ECGs without transient changes of heart
period modulations.
Apart from the need to develop numerically
robust techniques suitablefor fully automatic measure-
ment (the geometrical methods are only one possibility
in this direction), the following three areas deserve
attention.
Dynamics and transient changes of HRV
The present possibilities of characterizing the quantify-
ing the dynamics of the RR interval sequence and
transient changes of HRV are sparse and still under
mathematical development. However, it may be
assumed that proper assessment of HRV dynamics will
lead to substantial improvements in our understanding
of both the modulations of heart period and their
physiological and pathophysiological correlates.
Table 4 Summary of selected studies investigating the clinical value of HRV in cardiological diseases other than
Diseasestate
Author
of study
Population
(no. of patients)
I nvestigation
parameter
Clinical nding Potential value
Hypertension Guzzetti 49 hypertensive Spectral AR > LF found in Hypertension is
1991
[149]
30 normals hypertensives as compared characterized by a
to normals with blunting depressed circadian
of circadian patters rhythmicity of LF
Langewitz 41 borderline Spectral FFT Reduced parasympathetic Support theuseof
1994
[150]
hypertensive in hypertensivepatients non-pathological therapy of
34 hypertensive hypertension that > vagal
54 normals tone(e.g. exercise)
Congestiveheart Saul 25 chronic CHF Spectral ? spectral power all I n CHF, thereis ? vagal, but
failure 1988
[155]
NYHA I I I , I V BlackmanTurkey frequencies, especially relatively preserved
21 normals 15min >004Hz in CHF patients sympathetic modulation of
acquisition HR
Casolo 20 CHF Timedomain RR LowHRV Reduced vagal activity in
1989
[102]
NYHA I I , I I I , I V interval histogram CHF patients
20 normals with 24h-Holter
Binkley 10 dilated Spectral FFT ? mhigh frequency power Withdrawal of
1991
[152]
cardiomyopathy 4 min supine (>01Hz) in CHF parasympathetic tone
(EF 14 to 40%) acquisition > LF/HF observed in CHF
10 normals CHF has imbalanceof
autonomic tonewith ?
parasympathetic and a
predominanceof
sympathetic tone
Kienzle 23 CHF Spectral FFT Alterations of HRV not
1992
[104]
NYHA I I , I I I , I V Time-domain tightly linked to severity of
2448h-Holter CHF
? HRV was related to
sympathetic excitation
Townend 12 CHF Timedomain HRV > during ACE
1992
[153]
NYHA I I I , I V 24 h-Holter inhibitor treatment
Binkley 13 CHF Spectral FFT 12 weeks of ACE inhibitor A signicant augmentation
1993
[154]
NYHA I I , I I I 4 min supine treatment > high of parasympathetic tone
acquisition frequency HRV was associated with ACE
inhibitor therapy
Woo 21 CHF Poincarplots Complex plots are Poincarplots may assist
1994
[155]
NYHA I I I Time-domain associated with > analysis of sympathetic
24 h-Holter norepinephrinelevels and inuences
greater sympathetic
activation
Heart Alexopoulos 19 transplant Timedomain Reduced HRV in
transplantation 1988
[156]
10 normals 24 h-Holter denervated donor hearts;
recipient innervated
hearts had moreHRV
Sands 17 transplant Spectral FFT HRV from002 to 10Hz Patients with rejection
1989
[100]
6 normals 15 min supine 90%reduced documented biopsy show
acquisition signicantly morevariability
Chronic mitral Stein 38 chronic mitral Spectral FFT HR and measures of May beprognostic indicator
regurgitation 1993
[157]
regurgitation Time-domain ultralowfrequency by of atrial brillation, mortality,
24 h-Holter SDANN correlated with and progression to valve
ventricular performance surgery
and predicted clinical events
Mitral valve Marangoni 39 femalemitral Spectral AR MVP patients had ? high MVP patients had lowvagal
prolapse 1993
[158]
valveprolapse 10 min supine frequency tone
24 female acquisition
controls
Continued
372 Task Force
Table4 Continued.
Diseasestate
Author
of study
Population
(no. of patients)
I nvestigation
parameter
Clinical nding Potential value
Cardiomyopathies Counihan 104 HCM Spectral FFT Global and specic vagal HRV does not add to the
1993
[159]
Time-domain tonemeasurements of predictiveaccuracy of
24 h-Holter HRV were? in known risk factors in HCM
symptomatic patients
Sudden death or Dougherty 16 CA survivors Spectral AR HRV as measured by low HRV is clinically useful to
cardiac arrest 1992
[160]
5 CA Time-domain frequency power and risk stratify CA survivors for
nonsurvivors 24 h-Holter SDNN weresignicantly 1 year mortality
5 normals related to 1 year mortality
Huikuri 22 CA survivors Spectral AR ? High frequency power in
1992
[161]
22 control Time-domain CA survivorslow
24 h-Holter frequency power did not
discriminateCA survivors
Circadian pattern of HRV
found in all patients
Algra 193 SD cases Timedomain ? short-termvariation HRV may beused to
1993
[110]
230 24 h-Holter (005050Hz) estimatetherisk of SD
symptomatic independently increased
patients therisk of SD by a factor
26
? long-termvariation
(002005Hz) increased
therisk of SD by a factor
of 2
Myers 6 normals Timeand Both timeand frequency HF power may bea useful
1986
[162]
12 patients with frequency domain domain indices separated predictor of SD
structural heart 24 h-Holter normals fromSD patients
disease(6 with ? HF power (03505Hz)
and 6 without was thebest separator
SD) between heart disease
patients with and without SD
Martin 20 normals Time-domain SDNN index signicantly Timedomain indices may
1988
[163]
5 patients 24 h-Holter lower in SD patients I dentify increased risk of SD
experiencing SD
during Holter
monitoring
Ventricular Vybiral 24 VF Time-domain HRV indices do not
arrhythmias 1993
[164]
19 CAD 24 h-Holter changeconsistently
beforeVF
Huikuri 18 VT or CA Spectral AR all power spectra of HRV A temporal relation exists
1993
[165]
24 h-Holter weresignicantly ? before between thedecreaseof
theonset of sustained VT HRV and theonset of
than beforenonsustained VT sustained VT
Hohnloser 14 post MI with Spectral FFT HRV of post MI -CA Baroreex sensitivity, not
1994
[166]
VF or sustained Time-domain survivors do not dier HRV, distinguished post MI
14 post MI 24 h-Holter fromother post MI patients with and without VF
(matched) patients they dier strikingly and VT
in termof baroreex
sensitivity
Supraventricular Kocovic 64 SVT Spectral FFT > HR, ? HRV and ? Parasympathetic ganglia
arrhythmias 1993
[167]
Time-domain parasympathetic and bres may bemore
acquisition components after densein themid and
24 h-Holter radiofrequency ablation anterior lowseptum
AR=autoregressive; CA=cardiacarrest; CAD=coronaryarterydisease; CHF=congestiveheart failure; EF=ejectionfraction; FFT=fast
Fourier transform; HCM=hypertrophic cardiomyopathy; HF=high frequency; HRV=heart rate variability; LF=low frequency;
NYHA=NewYork Heart Associationclassication; SD=suddendeath; SVT=supraventricular tachycardia; VF=ventricular brillation;
VT=ventricular tachycardia.
I t remains to be seen whether the methods of
non-linear dynamics will be appropriate for the
measurement of transient changes in RR intervals or
whether new mathematical models and algorithmic
concepts will be needed to tailor the principles of
measurement morecloselyto thephysiological natureof
cardiac periodograms. I n any case, thetask of assessing
transient changes in HRV seems to be more important
than further renements of thecurrent technology used
to analysestablestages of heart period modulations.
PP and RR intervals
Little is known about the interplay between the PP
and PR autonomic modulations. For thesereasons, the
sequence of PP intervals should also be studied
[168]
.
Unfortunately, precise location of a P wave ducial
point is almost impossible to achieve in surface ECGs
recorded with the current technology. However,
developmentsinthetechnologyshouldallowPP interval
and PR interval variability to be investigate in future
studies.
Multisignal analysis
The modulations of heart periods are naturally not
the only manifestation of the autonomic regulatory
mechanisms. Currently, commercial or semi-commercial
equipment exists which enables simultaneous recording
of ECG, respiration, blood pressure, etc. However, in
spiteof theeasewith which thesignals can berecorded,
no widely accepted method exists for comprehensive
multisignal analysis. Each signal can beanalysed separ-
ately, e.g. with parametric spectral methods, and the
results of the analysis compared. Analysis of coupling
between physiological signalsallowthepropertiesof the
coupling to bemeasured
[169174]
.
Studies needed to improvephysiological
understanding
Eorts should be made to nd the physiological corre-
lates and the biological relevance of various HRV
measurescurrentlyemployed. I nsomecases, e.g. theHF
component, this has been achieved. I n other cases,
e.g. the VLF and ULF components, the physiological
correlates arestill largely unknown.
This uncertain knowledge limits the interpreta-
tion of associations between thesevariables and therisk
of cardiac events. The use of markers of autonomic
activity is very attractive. However, unless a tenable
mechanistic link between these variables and cardiac
events is found, there is an inherent danger of concen-
trating therapeutic eorts on the modication of these
markers
[111,112]
. This may lead to incorrect assumptions
and serious misinterpretations.
Possibilities of futureclinical utility
Normal standards
Large prospective population studies with longitudinal
follow-up are needed to establish normal HRV stan-
dards for various ageand gender subsets
[110]
. Recently,
investigators from the Framingham Heart Study
reported on thetime and frequencydomain measures
of HRV in 736 elderly subjects, and therelationship of
these HRV measures to all-cause mortality during 4
years of follow-up
[175]
. These investigators concluded
that HRV oers prognostic information independent of
and beyond that provided by traditional risk factors.
Additional population-based HRV studiesinvolvingthe
full age spectrum in males and females need to be
performed.
Physiologic phenomena
I t would be of interest to evaluate HRV in various
circadian patterns such as normal daynight cycles,
sustained reversed daynight cycles (evening-night shift
work), and transiently altered daynight cycles, such as
might occur with international travel. The autonomic
uctuations occurring during various stages of sleep
including rapid eye movement (REM) sleep have been
studied in only a few subjects. I n normal subjects, the
HF vagal component of the power spectrum is aug-
mentedonlyduringnon-REM sleep, whereasinpost-MI
patients with this increasein HF is absent
[176]
.
Theautonomic nervous systemresponseto ath-
letic training and rehabilitative exercise programmes
after various diseasestates is thought to bea condition-
ing phenomenon. HRV data should beuseful in under-
standing the chronological aspects of training and the
time to optimal conditioning as it relates to the auto-
nomic inuences on theheart. Also, HRV may provide
important information about deconditioning with pro-
longed bed rest, with weightlessness and with thezero g
that accompanies spaceight.
Pharmacological responses
Many medications act directly or indirectly on the
autonomic nervous system, and HRV can be used to
explore the inuence of various agents on sympathetic
and parasympathetic activity. I t is known that para-
sympathetic blockade with full dose atropine produces
marked diminution of HRV. Lowdosescopolaminehas
vagotonic inuences and is associated with increased
HRV, especiallyintheHR range. -adrenergicblockade
was observed into increase HRV and to reduce the
normalized unitsof theLF component
[15]
. Considerably
more research is needed to understand the eects and
clinical relevance of altered vagotonic and adrenergic
toneontotal HRV power anditsvariouscomponentsin
health and disease.
At present, few data exist on the eects of
calciumchannel blockers, sedatives, anxiolytics, analge-
sics, anaesthetics, antiarrhythmic agents, narcotics,
and chemotherapeutic agents such as vincristine and
doxorubicin on HRV.
Risk stratication
Both time and frequency measures of HRV calculated
fromlong 24-h and short 2 to 15-min ECG recordings
havebeenusedto predict timeto deathafter MI , aswell
374 Task Force
as the risk of all-cause mortality and sudden cardiac
death in patients with structural heart disease
[162,163,177]
and a number of other pathophysiological condi-
tions
[177]
. Usingdiagnosticinstrumentsthat canmeasure
HRV, together with the frequency and complexity
of ventricular arrhythmias, signal-averaged ECG, ST
segment variability, and repolarization heterogeneity, it
should be possible to markedly improve the identica-
tion of patients at risk for sudden cardiac death and
arrhythmic events. Prospective studies are needed to
evaluate the sensitivity, specicity, and predictive
accuracy of combined testing.
Fetal and neonatal heart rate variability is an
important area of investigation, and it might provide
early information about fetal and neonatal distress
and identify those at risk for the sudden infant death
syndrome. Most of thepreliminarywork inthiseldwas
carried out in theearly 1980s beforethemoresophisti-
cated power spectral techniques became available. I n-
sight into autonomic maturation in thedevelopingfetus
might also bepossiblethroughtheproper applicationof
thesetechniques.
Diseasemechanisms
A fertile area of research is to use HRV techniques to
exploretheroleof autonomicnervoussystemalterations
in disease mechanisms, especially those conditions in
which sympathovagal factors are thought to play an
important role. Recent work suggests that alterations in
autonomic innervation to the developing heart might
be responsible for some forms of the long QT syn-
drome
[178]
. Fetal HRV studies in pregnant mothers with
this disorder is certainly feasible and might be very
informative
[179]
.
The role of the autonomic nervous system in
essential hypertension is an important area of investiga-
tion
[180]
. Thequestion regardingtheprimary or second-
ary role of enhanced sympathetic activity in essential
hypertension might beanswered by longitudinal studies
of subjects who are initially normotensive. Does essen-
tial hypertension result from augmented sympathetic
activity with altered responsiveness of neural regulatory
mechanisms?
Several primary neurological disorders including
Parkinsons disease, multiple sclerosis, Guillain-Barre
syndrome, and orthostatic hypotension of the Shy-
Drager typeareassociatedwith alteredautonomicfunc-
tion. I nsomeof thesedisorders, changesinHRV maybe
an early manifestation of the condition and may be
useful in quantitating the rate of disease progression
and/or the ecacy of therapeutic interventions. This
same approach may also be useful in the evaluation of
secondary autonomic neurologic disorders that accom-
pany diabetes mellitus, alcoholism, and spinal cord
injuries.
Conclusion
Heart rate variability has considerable potential to as-
sesstheroleof autonomicnervoussystemuctuationsin
normal healthy individuals and in patients with various
cardiovascular and non-cardiovascular disorders. HRV
studiesshouldenhanceour understandingof physiologi-
cal phenomena, theactions of medications, and disease
mechanisms. Large prospective longitudinal studies are
needed to determinethesensitivity, specicity, and pre-
dictivevalueof HRV in theidentication of individuals
at risk for subsequent morbid and mortal events.
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Appendix A
Normal values of standard measures of heart
ratevariability
As no comprehensiveinvestigations of all HRV indices
in large normal populations have yet been performed,
some of the normal values listed in the following table
were obtained from studies involving small number of
subjects. Thevalues should thereforehavebeen consid-
ered as approximateand no deniteclinical conclusions
should be based on them. The adjustment of normal
limitsfor age, sex, andenvironment whichisalso needed
has been omitted herebecauseof thelimited sources of
data.
The table lists only values of those measures of
HRV which might be suggested for standardisation of
further physiological and clinical studies.
Appendix B
Suggestion of procedures for testing of
commercial equipment designed to measure
heart ratevariability
Concept
I n order to achieve comparable accuracy of measure-
mentsreportedbydierent commercial equipment, each
device should be tested independently of the manufac-
turer (e.g. by an academic institution). Each test should
involve several short-termand, if applicable, long-term
test recordings with precisely known HRV parameters
and with dierent morphological characteristics of the
ECG signal. I f the involvement of the manufacturer is
required during the testing procedure (e.g. for manual
editing of the labels of QRS complexes), the manufac-
turer must be blinded in respect of both the true HRV
parameters of the testing recordings and the features
used to obtain thesignal. I n particular, when theresults
of thetest aredisclosed to themanufacturer for further
improvement of the device or other wise, new tests
should involvea completely newset of test recordings.
Technical requirements
Each deviceshould betested comprehensively including
all its parts. I n particular, the test should involve both
the recording and the analytical part of the device. An
appropriatetechnology should beused to record a fully
reproducible signal with precisely known HRV param-
eters, e.g. the test signal should be computer and/or
hardware generated. Both brand new recorders as well
as recorders which have been routinely used and rou-
tinely serviced for approximately a half of their lifetime
should beused in thetests if this is feasible(thetesting
should not be delayed for newly introduced systems).
I f a manufacturer claims that the device is capable
of analysing ECG records (such as Holter tapes) ob-
tained with recorders of other manufacturers, each
combination should betested independently.
As the analysis of HRV by implantable devices
may beforeseen, similar proceduresasdescribed further
should be used to generate simulated intracardiac sig-
nals. I f feasible, implantable devices with fully charged
batteries as well as devices with partly discharged
batteries should betested.
Test recordings
I t is intrinsically dicult to know precisely the HRV
parametersof anyreal ECG recordingsindependentlyof
equipment used to analyse the recording. Therefore,
simulated ECG signals are preferable. However, the
morphology of such simulated ECG signals as well as
the HRV characteristics must closely reect the mor-
phology of real recordings. Thediscretefrequency used
to generate such signals must be substantially higher
than the sampling frequency of the tested device. Fea-
tures which should be introduced into such recordings
should include dierent factors known to inuence or
potentially inuence the precision of HRV assessment,
e.g. variable noise levels, variable morphology of QRS
signals which may cause jitter of the ducial point,
randomly alternating noise in dierent channels of the
signal, gradual and abrupt changes of HRV character-
istics, and dierent frequencies of atrial and ventricular
ectopic beats with realistic morphologies of thesignal.
The quality of records on magnetic tape based
systemsmaynot beconstant duringlong-termrecording
due to spool torque control, back tension, and other
factors. Performance of all recorders can be inuenced
by changes of the outside environment. Long-term
(e.g. full 24-h test) rather than short-term tests should
thereforebeused.
Testing procedures
Each device or each conguration of the device should
betested with several dierent recordings havingdier-
ent mixtures of features and dierent HRV characteris-
tics. For eachtest recordandfor eachselectedportionof
thetest record, theHRV parameters obtained fromthe
commercial deviceshould becompared with theknown
characteristics of the initial signal. Any discrepancies
found should be itemised in respect of features intro-
duced into therecording, e.g. errorscaused by increased
noise, errors due to ducial point wander, etc. System-
atic bias introduced by the equipment as well as its
relativeerrors should beestablished.
Variable Units
Normal values
(meanSD)
Timedomain analysis of nominal 24h
[181]
SDNN ms 14139
SDANN ms 12735
RMSSD ms 2712
HRV triangular index 3715
Spectral analysis of stationary supine5-min recording
total power ms
2
34661018
LF ms
2
1170416
HF ms
2
975203
LF n.u. 544
HF n.u. 293
LF/HF ratio 1520
380 Task Force
Reporting theresults
A technical report of the testing should be prepared
solely at the testing site independent of the manufac-
turer(s) of thetested device.
Appendix C
Members of theTask Force
TheTask Forcewas composed of 17 members:
Co-chairmen:
A. J ohnCamm, London, U.K, Marek Malik, London,
U.K.
Members:
J . Thomas Bigger, J r., New York, U.S.A., Gnter
Breithardt, Mnster, Germany, Sergio Cerutti,
Milano, I taly, Richard J . Cohen, Cambridge, U.S.A.,
Philippe Coumel, Paris, France, Ernest L. Fallen,
Hamilton, Canada, Harold L. Kennedy, St. Louis,
U.S.A., Robert E. Kleiger, St. Louis, U.S.A., Federico
Lombardi, Milano, I taly, Alberto Malliani, Milano,
I taly, Arthur J . Moss, Rochester (NY), U.S.A., J erey
N. Rottman, St. Louis, U.S.A., Georg Schmidt,
Mnchen, Germany, Peter J . Schwartz, Pavia, I taly,
Donald H. Singer, Chicago, U.S.A.
Whilethetext of this report was contributed to
and approved by all members of the Task Force, the
structureof thetext was designed by theWriting Com-
mittee of the Task Force composed of the following
members:
Marek Malik (Chairman), J . ThomasBigger, A. J ohn
Camm, Robert E. Kleiger, Alberto Malliani, Arthur
J . Moss, Peter J . Schwartz.

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