Clin. Cardiol.
13, 570-576 (1990)
Electrophysiology, Pacing, and Arrhythmia
This section edited by A. John Camm, M.D . , F. R. C.P . , F. A . C,C.
Heart Rate Variability
M. MALIK.M.D., Ph.D.. A . J . CAMM. M.D..F.R.C.P., F.A.C.C.
Department of Cardiological Sciences, St. George's Hospital Medical School, London, England
Summary: Reduced heart rate variability cames an adverse
prognosis in patients who have survived an acute myocardi-
al infarction. This article reviews the physiology, techni-
cal problems of assessment, and clinical relevance of heart
rate variability. The sympathovagal influence and the clin-
ical assessment of heart rate variability are discussed.
Methods measuring heart rate variability are classified into
four groups, and the advantages and disadvantages of each
group are described. Concentration is on risk stratification
of postmyocardial infarction patients. The evidence sug-
gests that hean rate variability is the single most important
predictor of those patients who are at high risk of sudden
death or serious ventricular arrhythmias.
Key words: sympathovagal cardiac control, myocardial
infarction, long-term electrocardiograms
Introduction
Although recognized and widely known, the variations
of cardiac rhythm have been virtually ignored in practi-
cal cardiology. Cardiologists have generally believed that
irregularity of cardiac function is a pathological phenome-
non. This was probably the result of the large clinical ex-
perience with atrial fibrillation and ventricular ectopic
beats which indicate impaired intracardiac regulatory
mechanisms and are negative prognostic factors in many
Supported by the British Heart Foundation
Address for reprints:
Prof. Marek Malik. Ph.D., M.D.
Department of Cardiological Sciences
St. George's Hospital Medical School
Cranmer Terrace
London SW I7 ORE, England
Received: June 1 1 , 1990
Accepted: June 15, 1990
diseases of the heart. Clinical cardiologists were there-
fore surprised that an absolutely regular sinus rhythm is
also an indication of malfunction of cardiac regulatory
processes and that reduced variability of sinus rhythm is
a serious warning sign in patients who survive the acute
stage of myocardial infarction.
The first observation that reduced hean rate variability
(HRV) correlates with mortality and severe arrhythmic
complications during the postinfarction period was pub-
lished in 1978.' Since that time, several clinical studies have
been completed which fully confirm this finding (Fig. 1).
This brief review summarizes the information that has
been accumulated on the irregularity and variability of si-
nus rhythm and on its clinical usefulness, especially for
the stratification of postinfarction risk.
Physiology of Heart Rate Variability
The physiological background of HRV has been attribut-
ed to the sympathovagal system. Because of the dramatic
changes in the sympathovagal system in cold-blooded ver-
tebrates, several laboratory studies have examined changes
in hean rate and HRV provoked by different stimuli in
these animals, especially in lizards (e.g., Ref. 2). In mam-
mals, HRV has also been examined in situations which
are known to be associated with marked changes in the
tone of the autonomic nervous ~ y s t e m ,including
~,~ inves-
tigations into specific diseases which impair the autonomic
system, such as d i a b e t e ~ HRV
.~ has also been used to
demonstrate the development of tonic vagal influence on
the heart.6
HRV has been studied in humans in order to assess sym-
pathovagal balance.' HRV provoked by atropine adminis-
tration has been reported as a method of the diagnosis of
brain death. * Many neurological and psychological inves-
tigations have used HRV to evaluate the effects of stress,
emotion, and work on the autonomic nervous s y ~ t e r n , ~ - l ~
including very specialized investigations. l 4 Quantification
of HRV has also been used as the standard for evaluating
other psychological methods. I 5
Physiological studies in humans have reported an in-
crease of HRV, interpreted as an increase of cardiac va-

M. Malik and A. J. Camm: Heart rate variability
“10 1 D S
-1 II 1 In studies examining very short-term HRV, such as the
6-l I1 6 1
i-I III 4 i
i
21 I/ A as the difference (max RR)-(min RR).21 Similar simple
FIG.I Typical differences in HRV between high- and low-risk pa-
tients who have survived acute myocardial infarction. The plots show
sample density distributions of RR intervals from a continuous 24-h
Holter recording made on Day 7 after myocardial infarction in two
patients (labeled D and S in the figure). Both patients were male
of similar age (D=73and S=71 years), suffering from anterior in-
farction with pathological Q waves on the electrogram. Their LVEF
was similar (D=35% and S=30%);neither was treated with beta
blockers. Patient S had an uncomplicated postinfarction course during
a 2-year follow-up, Patient D died suddenly on Day 27 after the
infarction. Note that the duration of RR intervals (i.e., the rate of
the sinus rhythm) was virtually constant in Patient D while it was
very variable in Patient S. The horizontal axes RR show duration
of normal-to-normal intervals in seconds, the veltical axes NN show
the number of normal-to-normal intervals in thousands.
gal tone at rest, following intensive exercise for several
days. l 6 A similar study performed in dogs” showed that
the postexercise increase of vagal tone was lower in
animals who were at higher risk of ventricular fibrillation
induced by artificial coronary occlusion performed the fol-
lowing day.
These and other similar studies create a continuous spec-
trum between purely physiological and mainly clinical in-
vestigations. There appears to be a “prima facie” case
that HRV, sympathovagal tone, and cardiac arrhythmias
are linked and that a mechanical relationship is probable.
Measurement of Heart Rate Variability
Both research and clinical studies have reported a vari-
ety of recording techniques and different methods for ac-
tual measurement and numerical quantification of HRV.
For example, special Computerized systems were deve-
loped for the assessment of fetal heart rate (FHR) varia-
bility,I8 including automatic recognition and differentia-
tion of fetal and maternal cardiac depolarizations.l9
Unfortunately, many of these methods were designed for
very specific purposes and cannot be used or easily adapted
for the measurement of HRV in other situations, such as
those for stratification of patients who are at high risk af-
ter acute myocardial infarction.
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57 1
From a purely technical point of view, the methods used
for HRV assessment can be approximately divided into
four groups.
Simple Methods
sudden changes in heart rate provoked by instantaneous
stimuli, a very simple measurement of HRV can be used.
Instantaneous change in heart rate can be expressed as the
ratio (min RR)/(max RR)20(e.g.. the Valsalva ratio), or
methods have been used for the assessment of FHR varia-
bility. For instance, simple counts of marked accelera-
tions of FHR occurring during 30 min intervals have been
used to express FHR variability.22
These methods are unsuitable for the assessment of
HRV in studies oriented to postinfarction risk stratifica-
tion. Most of these studies are based on elaborating the
signals obtained by computerized recognition of long-term
electrocardiograms. The first observation that post-
myocardial infarction risk was associated with reduced
HRV was based on short-term and manually measured
electrocardiograms.I However, more recent studies have
shown that the most significant and powerful distinction
between patients at low and high risk following acute my-
ocardial infarction must be based on HRV assessed from
Holter records. In the majority of these studies, 24-h elec-
trocardiograms were used, and both commercial and
research algorithms were employed to analyze the tapes
and identify the sinus rhythm beats.
Spectral Analysis and Autocorrelation
Spectral analysis of electrocardiograms is an important
field of both theoretical and practical biomedical engineer-
ing. Often, spectral analysis is performed on signal-
averaged electrocardiograms where it can reveal late
potentials and serve as one of the methods for the assess-
ment of the homogeneity and synchrony of cardiac exci-
tation. Analogous methods can also be used to analyze
the sequence of RR interval^.^^-^^
Broadly speaking, spectral analysis evaluates and quan-
tifies periodicities which can be found in the analyzed data.
For each length of time, the results of spectral analysis
express the range of changes in the variable data cor-
responding to the given period. In this way, spectral anal-
ysis allows superimposed periodicities to be unravelled.
A similar spectrum of periodical components is provided
by the so-called autocorrelation and autoregression
methodsz6which are based on comparisons of individual
and variable segments of the analyzed data.
The major advantage of spectral methods lies in their
accuracy. These methods can be used to evaluate physio-
logical variations of sympathovagal tone in individualsand
are also able to distinguish cases in which only one of the
mechanisms of a known periodicity is impaired. For in-
stance, a selective depression of vagal tone with preser-

512 Clin. Cardiol. Vol. 13, August 1990
vation of sympathetic cardiac control has been diagnosed
using the spectral methods. 27
However, the accuracy of spectral methods also ac-
counts for their disadvantages. The accuracy of results
makes the methods largely dependent on the accuracy and
quality of the analyzed data. Unfortunately, very accurate
recording of long-term electrocardiograms is difficult to
guarantee. The exact shape of electrocardiographic sig-
nals including the QRS patterns vary during ambulatory
recording and there is much artefact in the record.
The results of spectral methods can also be affected by
‘behavioral’ noise. If the state of the patient varies dur-
ing recording, the dominant results of spectral methods
correspond to the changes in patient behavior rather than
to the changes in sympathovagal tone. Therefore, a pre-
cise validation of spectral results requires that recordings
are made during a ‘steady state.’ This is impossible to
achieve in long-term electrocardiograms.
Statistical Methods
The evaluation of spectral data in large populations of
patients leads to a comparison of selected parameters such
as the spectral components associated with one particular
form of periodicity of the cardiac cycles. This may not
necessarily be the optimum approach to the stratification
of postinfarction risk, as the general overall HRV which
comprises all spectral components may also be relevant.
The usual approach to the evaluation of the overall HRV
is the application of a standard statistical method to express
the variability within the sequence of durations of normal-
to-normal RR (NN) intervals. Different statistical methods
have been employed, including the standard deviation of
NN interval durations2*and the standard deviation of the
differences between neighboring NN intervals (expressing
the so-called beat-to-beat HRV).29 These general ap-
proaches have also been modified to include only selected
portions of the spectrum of heart rate changes. These
modifications enable both short- and long-term HRV to be
separately quantified and evaluated, but their definition and
distinction is much less accurate when compared with the
standard spectral methods. However, these combined com-
ponents of HRV may be medically important. Various
adapted methods have therefore been proposed, mainly for
the analysis of FHR variability. Several such methods were
validated on both clinical data and computer-generated ser-
ies of known predefined variability.I0
Large population studies by the North American Mul-
ticenter Post-Infarction utilized these statisti-
cal methods, but also showed their dependence on the va-
lidity of the data provided by algorithmic computer
analysis of Holter tapes. Statistical formulae expressing
standard deviation and similar parameters have a certain
preference in the values which are far from the mean of
the analyzed sequence. In practical terms this means that
the results of standard statistical formulae are seriously
affected by such misrecognition artefacts as the omission
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of QRS complexes because of their varying voltages or
the misinterpretation which classifies premature ventric-
ular depolarizations or even T waves as supraventricular
patterns. The authors of the multicenter studies employed
filtering of the computer recognized N N intervals in ord-
er to reduce the level of the artefact but also reported the
use of visual checking and manual corrections of the ana-
lyzed data. Technically oriented studies show that even
sophisticated filtering of NN sequences does not neces-
sarily lead to the desired results.’l This acknowledges the
dependence of statistical methods on the quality of the
computer recognition of N N intervals.
Similar dependence is seen with methods analyzing the
beat-to-beat HRV which are based on counting the sud-
den changes in N N interval over a given threshold.I2
Evaluation of RR Interval Distributions
From a practical clinical point of view, methods that
provide an approximation of HRV can be clinically use-
ful. Several such methods are based on the evaluations
of the statistical distribution of NN interval durations.
Even methods based on simple analysis of NN interval
di~tributions~l can offer medically relevant evaluation of
HRV (Fig. 2).I3.l4
The simplest of these methods expresses HRV as the
relative number of N N intervals with the most frequent
duration (i,e., as the fraction totlmar, where m a r is the
maximum number of computer-recognized N N intervals
with the same duration; and tor is the number of all NN
intervals recognized in a Holter record). When this sim-
ple method was applied to analysis of standard quality 24-h
recordings HRV data were provided which proved to be
of very significant value (Fig. 3).
These methods can be adapted to approximate spectral
analysis, the results of which are not affected by a low
level of noise and artefact in the analyzed data.Is At the
same time, the proof of the validity of these methods re-
quires further investigation, including theoretical mathe-
matical examinations.
For artefact-free data, the standard statistical methods
and the methods that combine several power spectrdl com-
ponents provide strongly correlating results. l6 Future
studies should investigate similar intramethod correlations
for data which include a low level of artefact.
Clinical Studies
Although postinfarction risk stratification has been the
first cardiological need for HRV assessment, it was not
the first attempt to quantify both the beat-to-beat and cir-
cadian variations in cardiac cycles.
Studies in Noncardiological Medical Fields
HRV assessment has been widely used in clinical in-
vestigations, for example in the evaluation of alcoholic
 19328737, 1990, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/clc.4960130811 by Lucian Blaga Central University Library Of Cluj-Napoca, Wiley Online Library on [17/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
M. Malik and A. J. Camm: Heart rate variability 573

HRV (ms) HRV (ms)

400 400

300 300

200 200

100 100

0 0
0 2 4 6 8 10 12 14 16 18 20 22 0 2 4 6 8 10 12 14 16 18 20 22
Time of day Time of day
FIG.2 Differences between short-term HRV in two groups of 40 postinfarction patients matched with regard to age, gender, infarct site,
ejection fraction, and beta-blocker treatment. Patients in the positive group (A) experienced serious arrhythmic events (sudden death or
sustained ventricular tachycardia) during a 6-month follow-up; patients in the negative group (B) remained free of complications for more
than 6 months after discharge. Short-term HRV (baseline width of the distribution curve of the unfiltered sequence of NN intervals) was
measured in separate 40 min intervals. For both groups, the mean values f SD are shown.

ne~ropathy,~' familial amyloid polyneuropathy,38diabetic
neuropathy,32.39 thyrotoxi~osis,~~ and hyperten~ion.~'
Assessment of FHR variability is an acknowledged
method for stratification of pre and intralabor risk.
Reduced variability of FHR has been observed prior to
fetal death.42 On the contrary, a physiological level of
FHR variability indicates an uncomplicated labor and nor-
mal adaptation of neonates.43
In infants, short-term HRV has also been used to exa-
mine the reaction to external stimuli, such as in tests of
hearing.44Similar studies have been performed examin-
ing FHR variability following external vibratory stimu-
lus.45
HRV n = 366
(ms)
I measurement of HRV in patients after myccardial infarc-
300 - A
n=21
Studies correlating low HRV with the risk of sudden
death are not only related to postinfarction adult patients.
Reduced HRV has also been associated with the sudden
infant death ~ y n d r o m e . ~ ~ - ~ ~
Stratification of Postinfarction Risk
Utilization of reduced HRV as a major factor for the
stratification of postinfarction risk is attractive because the
long-term electrocardiographic recording which enables
the assessment of HRV is one of the least invasive methods
of investigation.
Detailed case-matched studies as well as investigations
involving large populations of postinfarction patients have
repeatedly proved that a reduced HRV is an important nega-
tive prognostic factor correlating with both the so-called
all cause mortality and with anhythmic complications and
sudden death.28.29.3'.34.50-52 The possibility of repeated
tion has also been examined53in order to assess the state

I
n = 27
of the heart during postinfarction healing and recovery.
The findings of these studies suggest that the reduced
200 -
I c
B
vagal and increased sympathetic activity accounts for low
HRV. High sympathetic and low vagal tone decreases the
electrical threshold for ventricular fibrillati0n2~and the
probability of ventricular fibrillation during myocardial
ischemia is higher in patients with reduced HRV.
100 -
In a study of 177 consecutive patients34the relative risk
FIG.3 Risk stratification in a group of 414 consecutive myocardial of low HRV for the prediction of sudden death and /en-
infarction patients who survived until discharge. HRV (baseline tricular tachycardia was 7.0, compared with lower rela-
width of the N N intervals distribution curve) was assessed in 24-h tive risks of in-hospital complications (4.3),Killip I1 clas-
Holter records made at a median of 7 days (range 5-9 days) fol-
lowing the hospital admission. The plot shows the differences (mean
sification at admission (4.0),the presence of late potentials
f SE) of three groups of patients: (A) uncomplicated 12-month ( 3 . 3 , and left ventricular ejection fraction <40% (2.2).
follow-up; (B) serious arrhythmic events (sudden death or sustained In a multifactorial analysis, the HRV data were found to
ventricular tachycardia); ( C ) patients who died due to other reasons be the single most important prognostic factor of anhyth-
(reinfarction or cardiac failure). mic complicationsfollowing acute myocardial infarction.34

514 Clin. Cardiol. Vol. 13, August 1990
Studies in Clinical Cardiology
Published studies show that measurement of HRV and
the assessment of the return of HRV to normal levels can
be used as a follow-up investigation for patients after heart
transplantation. Because transplanted hearts are totally
denervated at the moment of the transplantation and there-
fore not affected by the autonomic system, the hypothe-
sis has been suggested that the increase in HRV can be
interpreted as a sign of reinnervation of the transplanted
hearts. 54
Reduced HRV has been found in groups of cardiac pa-
tients suffering from conditions other than ischemic heart
disease. A significant increase in HRV was reported in
children undergoing surgical repair of atrial septa1
defects.55Decreased HRV was found in association with
congenital prolongation of the QT interval (Romano-Ward
syndrome).56 A selective spectral analysis of heart rate
showed a large reduction in faster spectral components
of HRV in chronic congestive heart failure patient^;^^,^^
this was interpreted as diminished vagal but relatively
preserved sympathetic modulation of heart rate in these
patients. Speculations were presented that reduced HRV
following heavy ethanol consumption can contribute to
the genesis of cardiac arrhythmias in chronic a l c o h o l i ~ s . ~ ~ investigating individual differences in HRV in cardiac pa-
The clinical utility of measurement of HRV in cardiac
patients also suggests that a clinical potential might be
gained from the variability of other electrophysiological
and hemodynamic parameters of cardiac function. Several
studies have already addressed variability of various
phenomena and parameters. Variability of left ventricu-
lar ejection fraction,s9of ST-segment depression and ele-
vation in silent myocardial ischemia6" as well as in the
early phase of acute myocardial infarction,61of the nega-
tivity of T waves in hypertrophic cardiomyopathy,62and
of left ventricular end-diastolic pressure in patients with
stabilized chronic cardiac ischemic disease63 have been
examined.
Finally, there has been an attempt to treat postinfarction
patients with biofeedback training in order to increase their
vagal cardiac control and HRV.64The usefulness of this
idea is difficult to judge and it seems that it was abandoned.
Discussion
Many studies have shown that measurement of HRV
is a valuable investigation in clinical cardiology. Studies
reporting reduced HRV in association with various pathol-
ogies suggest that HRV measurement can be used as a
method which specifically addresses cardiac adaptation
to changes of sympathovagal tone. Most of the leading
manufacturers of Holter systems have already modified
their equipment with options for the assessment of HRV.
Several problems remain which need to be clarified be-
fore HRV measurement will become a routine clinical
method. These problems can be seen at two levels.
19328737, 1990, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/clc.4960130811 by Lucian Blaga Central University Library Of Cluj-Napoca, Wiley Online Library on [17/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
First, the physiological and pathophysiological back-
ground of reduced HRV has to be understood in detail.
Why do patients at high risk following acute infarction
exhibit reduced HRV? In theory, there are several diverse
explanations. It is possible that the disease of the heart
itself disables the heart from responding physiologically
to the varying background of sympathovagal tone. This
hypothesis is supported by recent observations that heavy
smoking causes long-term reduction in vagal cardiac con-
Should this be the case, the measurement of HRV
would be an extremely important method to evaluate
directly the organic state of the heart. However, it is also
possible that the disease of the heart influences the auto-
nomic nervous system. This could result in reduced vari-
ation of sympathovagal tone accounting for reduced HRV.
Even in such a situation, clinical assessment of HRV
would provide valuable information, but its interpretation
would be different. The hypothesis that any 'generally ill'
patient may exhibit reduction in HRV is supported by the
finding of significant reversible depression of HRV prior
to hemodialysis. 66
Another group of problems concerns more practical
questions. Further investigation is necessary in order to
establish standard physiological values of HRV. Studies
tients and in healthy individuals are necessary. Although
similar studies in human fetuses were performed decades
ago,67only limited populations of healthy adult individu-
als have, to date, been i n v e ~ t i g a t e d . The
~ ~ . ~results
~ of
these studies show that HRV exhibits a marked circadian
variation, and that it depends significantly on the circum-
stances of measurement. In healthy subjects, short-term
HRV has been reported to decrease with increasing age;*I
investigations of the influence of age on long-term HRV
in both high and low-risk cardiac patients must be per-
formed. Studies investigating the influence of gender are
necessary as, for instance, females at risk of sudden in-
fant death have been shown to have lower waking HRV
than do males.46 In a small population of 11 postinfarc-
tion patients, a faster mean heart rate has been observed
in patients with anterior infarction, but HRV has not been
affected by infarct site.70Future investigations involving
larger populations are necessary.
Reduced low-frequency HRV has been observed in pa-
tients following myocardial infarction treated with diltia-
zem and metoprolol, but not with nifedi~ine.'~Future
studies are required in order to investigate the effects of
other preparations frequently used after acute myocardial
infarction. 7 2
The problem of standard values of HRV will naturally
be complicated not only by the diverse scale of methods
used for its quantification but also by its natural variabili-
ty. Provisional suggest that the circadian varia-
tion of HRV must be assessed when using HRV to meas-
ure postinfarction risk stratification. The data of HRV
assessed in some sections of 24-h Holter recordings may
have a much higher prognostic value than the HRV data

M. Malik and A. J. Camm: Heart rate variability
obtained when analyzing different sections of the records.
Furthermore, the data of HRV assessed in some sections
of the record may have higher prognostic value than the
data of overall 24-h HRV. Therefore, not only the opti-
mum technique and method but also the optimum time
and environment for HRV measurement have to be es-
tablished.
Finally, values of HRV in patients surviving acute my-
ocardial infarction should be correlated with established
risk stratification factors such as left ventricular ejection
fraction or ventricular ectopic frequency, as well as with
novel risk stratification factors such as the signal-averaged
electm~ardiography~~ or baroreflex sensitivity. 36 It can be
expected that the careful combination of several stratifi-
cation criteria will provide more specific and more sensi-
tive identification of patients who are at higher risk.
In spite of these problems and difficulties, measurement
of HRV is a valuable technique and its clinical importance
will incmse in the future. When combined with other fac-
tors of known prognostic value, assessment of HRV will
substantially improve the identification of those patients
who are at high risk following acute myocardial infarction.
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