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1439
QT Intervals at Heart Rates From 50 to 120
Beats per Minute During 24-Hour
Electrocardiographic Recordings
in 100 Healthy Men
Effects of Atenolol
Matti Viitasalo, MD, and Jouko Karjalainen, MD
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Background. Conflicting reports about changes in QT intervals suggest that QT values should be
compared at similar heart rates.
Methods and Results. Relations between QT and RR intervals were determined after measurement of QT
values by Holter recording at heart rates of 50, 60, 70, 80, 90, 100, 110, and 120 beats per minute in 100
healthy young men. Fifteen men underwent a second recording during acute treatment with the
3-blocking agent atenolol. At heart rates between 80 and 120 beats per minute, the QT interval was
significantly longer (from 9 to 16 msec), and at a heart rate of 50 beats per minute significantly shorter
(26 msec), than values calculated from Bazett's formula. Sleep prolonged QT values by 18 msec at a heart
rate of 60 beats per minute and by 21 msec at a heart rate of 50 beats per minute compared with the
waking state. Atenolol lengthened QT intervals significantly (by 11-14 msec) at heart rates between 90
and 110 beats per minute and shortened them (by 12 msec) at a heart rate of 60 beats per minute. During
sleep, QT intervals were the same before and after atenolol.
Conclusions. The method of plotting QT against RR intervals after measurement of QT values at similar
stable spontaneous heart rates before and after intervention allows changes in autonomic state and heart
rate to be taken into account. By this method, QT values can be compared without distortion effects caused
by correction formulas. (Circulation 1992;86:1439-1442)
KEY WoRDs * electrocardiography * receptors, (3-adrenergic blockers * electrophysiology
P rolongation of the QT interval has been found to
correlate with the development of malignant arrhythmias in patients after acute myocardial infarction,1 in association with mitral valve prolapse syndrome,2 and in patients with congenital and acquired
long-QT syndrome.3'4 It is well known that heart rate,
autonomic tone, electrolyte levels, and many drugs influence QT intervals. QT values should be compared only
after differences in heart rate have been taken into
account. Numerous attempts have been made to allow for
the effect of heart rate on QT interval.5 Studies of the
effects of drugs on QT intervals have given conflicting
results, presumably because the changing autonomic tone
affects the relation between the QT and RR intervals.6
Previous formulas to correct QT intervals for heart
rate have been based on one QT interval value and one
RR interval value from each individual.7-10 Recently,
data from continuous ECG recordings have been used,
but the data were obtained over set intervals of time,
not at particular heart rates.1"-13 The data therefore
From the Cardiovascular Laboratory, First Department of
Medicine, University Central Hospital, Helsinki, and Central
Military Hospital, Helsinki, Finland.
Address for correspondence: Matti Viitasalo, MD, Cardiovascular Laboratory, First Department of Medicine, University Central Hospital, Haartmaninkatu 4, 00290 Helsinki, Finland.
Received October 9, 1991; revision accepted July 24, 1992.
reflect the predominant heart rates in the groups studied." One way to overcome these effects would be to
use atrial pacing in intervention studies. There would
still be major problems, however: paced cycle lengths
would be shorter than most spontaneous sinus cycle
lengths, and thus, important information would be
missed. Pacing would not control the autonomic state.
Pacing is an invasive procedure and unsuitable for use
in population studies.
The purpose of this study was to determine relations
between QT intervals and heart rates at spontaneous
stable sinus rates of 50, 60, 70, 80, 90, 100, 110, and 120
beats per minute and to determine the effects of the
,il-selective }-blocking agent atenolol on QT intervals
at similar heart rates in healthy men. The reliability of
Bazett's equation to predict QT values at different heart
rates was evaluated.
Methods
Characteristics of Subjects
The subjects were 100 healthy men 18-30 years old
(mean±SD, 21.5+3.8 years). No subject exhibited any
evidence of heart disease on the basis of history, physical
examination, chest x-ray findings, or resting ECG. ECGs
had to meet the following criteria: PR interval during
normal sinus rhythm no more than 200 msec and no delta
1440
Circulation Vol 86, No 5 November 1992
TABLE 1. QT Intervals and 99% Confidence Limits for Measured QT Values* and Corresponding QT
Values Calculated From Bazett's Equation
Calculated QT
99% Confidence
No. of
Measured QT (msec)
Heart rate
(msec)
interval
(mean±SD)
subjects
(bpm)
431
394-417
29
406+23
50
389-398
393
70
393±15
60
364
363-372
82
368±16
70
348-355
340
352-+14
100
80
321
327-335
331±14
88
90
315-322
304
319+ 12
99
100
297-305
290
79
301±14
110
278
285-293
89
289+ 15
120
bpm, Beats per minute.
*At stable heart rates of 50, 60, 70, 80, 90, 100, 110, and 120 beats per minute in 100 individuals.
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wave, QRS duration <100 msec, corrected QT interval
(Bazett's equation) <440 msec, no U wave interfering
with the definition of the T wave (one subject was
excluded because of a long QTU complex), and <100
ventricular premature beats per 24 hours. No subject was
a trained athlete or was taking any medication.
All subjects gave informed consent. The study protocol was approved by the local ethical committee.
ECG Recording Protocol
All 100 participants were subjected to 24-hour ECG
recording (Model 445, Avionics). The next day, 15 of the
participants, 19-27 years old (mean, 20.3±2.1 years),
were subjected to a second 24-hour recording after
treatment with the p1-selective 8-blocking agent
atenolol, 100 mg of which was taken by mouth at 8 AM.
Recording started at 10 AM. A second dose of 100 mg
was taken at 8 PM. The sleeping period was considered
to be the period the subjects recorded themselves in
their diaries as having slept.
QTAnalyzing System
The recordings were analyzed with an Avionics Electrocardioscanner model 660A. The frequency response
of the entire recording and playback system is 0.09-27
Hz.14 Heart rates of 50, 60, 70, 80, 90, 100, 110, and 120
beats per minute were sought by observing a display of
RR intervals indicating heart rate. Heart rate had to be
stable for at least 60 seconds. A variation of ±5 beats
per minute was allowed (e.g., heart rate could have been
between 45 and 55 beats per minute to be accepted as a
heart rate of 50 beats per minute). The samples were
printed on chart paper at a speed of 25 mm/sec, and the
final desired heart rates were sought on these strips,
taking 10 successive RR intervals. A variation of ±2
beats per minute was allowed (e.g., heart rates between
48 and 52 beats per minute were accepted as rates of 50
beats per minute). The duration of the QT interval was
then measured from these samples with a digitizing
board (Microgrid MGRX 12, Summagraphics Corp.)
interfaced with a PDP 11/34 DEC computer. Ten
complexes were measured from each trace, and arithmetic means were determined. The duration of each QT
interval was measured from the beginning of the Q or R
wave to the termination of the T wave at the point of its
merger with the TP segment. In those few measurements in which a separate U wave interrupted the T
wave before return to the TP segment, the QT interval
was measured to the nadir of the curve between T and
U waves in the lead corresponding to V5.5 Measured
QT values were compared with values calculated from
Bazett's equation (QT=k x ViRR). The constant k is the
QT interval at a heart rate of 60 beats per minute. It was
0.393 seconds in this study.
To determine speed errors of the recording and analyzing systems, pulses were fed to the recorder tape from
a pulse generator (Interstate P 24), and their frequencies
were checked with a Universal Counter Timer (Racal
9903). The tape was analyzed with the Electrocardioscanner, and errors were calculated. The mean speed
error in relation to the whole system was 1%. The SD of
the speed jitter was 2% of the pulse interval.
Statistical Analysis
To test significances of intraindividual changes
caused by ,B-blockade or sleep, the paired t test was
used. To evaluate the reliability of Bazett's equation in
predicting QT values at different heart rates, 99%
confidence limits were calculated for measured QT
intervals for the whole group.
Results
QT Versus Heart Rate
The measured values of QT intervals at waking heart
rates of 50, 60, 70, 80, 90, 100, 110, and 120 beats per
minute and corresponding values derived from Bazett's
equation are shown in Table 1. At heart rates of 80, 90,
100, 110, and 120 beats per minute, measured QT
intervals were longer than those predicted with Bazett's
equation, and at a heart rate of 50 beats per minute,
they were significantly shorter (Figure 1).
Effect of Sleep
In 23 subjects, QT intervals could be measured when
subjects were awake and asleep at stable heart rates of
50 and 60 beats per minute. At a heart rate of 50 beats
per minute, the QT interval was 405 ± 17 msec
(mean+ SD) while awake and 426± 15 msec while asleep
(p<0.01). At a heart rate of 60 beats per minute, the
corresponding values were 388±16 and 406+f17 msec,
respectively (p<0.01) (Figure 1).
Effects of Atenolol
The mean waking heart rate before atenolol administration was 77+6 beats per minute. After atenolol
administration, it was 66±+-4 beats per minute
Viitasalo and Karjalainen QT Intervals and Effects of Atenolol
1441
TABLE 2. QT Intervals* in 15 Men Before and After Atenolol
Administration
QT (msec)
aT msoc
Heart rate
600
400
800
1000
1200
RR-interval msec
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FIGURE 1. Graph showing relation between QT and RR
interval in 100 healthy young men at stable waking heart rates of
50, 60, 70, 80, 90, 100, 110, and 120 beats per minute (A)
compared with values derived with Bazett's equation (m).Asterisks indicate where the values derived with Bazett's equation
remain out of the 99% confidence intervals of the measured
values. Dotted line indicates QT values durng sleep in 23 men.
(p<0.001). During sleep, the corresponding values of
mean heart rates were 56±6 and 51+3 beats per
minute, respectively (p<0.001) (Figure 2). Values of
QT intervals before and after atenolol treatment are
shown in Table 2. After ,-blockade, QT intervals were
significantly longer at heart rates of 90, 100, and 110
beats per minute and significantly shorter at a heart rate
of 60 beats per minute than before p-blockade (Figure
3). At heart rates of 50 and 120 beats per minute, the
effects of atenolol on QT intervals were not analyzed
because too few observations were available. While the
subjects were asleep, at a heart rate of 60 beats per
minute, the QT interval was 408±13 msec before
,3-blockade and 408±18 msec after p-blockade.
Discussion
Measured Versus Calculated QT Interval
The results show the relations between QT and RR
intervals during normal daily activities in healthy men
when momentary changes are excluded. As Figure 1
shows, the slope of the line relating QT and RR
intervals is less than would be expected on the basis of
Bazett's equation. Bazett's formula seems to work best
at sinus cycle lengths from 1,000 to 860 msec (from 60 to
No. of
subjects
13
15
15
15
15
12
(mean+SD)
After
Baseline
atenolol
395+12
383+19
367+17
366±15
347±15
350±16
326±14
339±13
311±12
325±13
304±16
315±17
(bpm)
p
60
<0.05
70
NS
80
NS
90
<0.05
100
<0.05
110
<0.05
bpm, Beats per minute.
*At stable heart rates of 60, 70, 80, 90, 100, and 110 beats per
minute.
70 beats per minute). At a sinus cycle length of 1,200
msec as well as at sinus cycle lengths from 750 to 500
msec, skewing is significant.
Sleep and QT Interval
Sleep prolongs the QT interval, as Browne et al,"
using a complex calculation method, and Bexton et al,16
after studies in pacemaker patients, have noted. Our data
confirmed this. The magnitudes of the prolongation were
almost identical: the difference in QT interval between
the waking and sleeping states at a heart rate of 60 beats
per minute was 19 msec in the study of Browne et al and
18 msec in the study reported here. At a heart rate of 50
beats per minute, the prolongation was 21 msec in the
present study. With a ventricular pacing rate of 70 beats
per minute, the difference was 23 msec.16 Allowing the
heart rate to vary by no more than ±5 beats per minute
during sampling seems to exclude errors caused by
short-term reflex changes in QT intervals, and thus, the
present method gives reliable results. It has been suggested that prolongation of the QT interval during sleep
may be a result of heightened parasympathetic tone and
decrease in levels of circulating catecholamines.16
Effects of p-Blockade
Increases in steady-state pacing frequencies cause QT
intervals to decrease.17 On the other hand, autonomic
tone has direct effects on QT intervals, independent of
OT msec
450
HEART RATE
85,1
-
425.
400
375
.1...
350
325
300'
275 l
400
600
800
1000
1200
RR-Interval msec
10
12
14
16
18
20
22
24
2
4
6
8
TIME OF DAY
FIGURE 2. Graph showing mean hourly heart rates in 15
men before (A) and after (o) atenolol administration.
FIGURE 3. Graph showing relation between QT and RR
intervals in 15 men before (A) and after (on) atenolol administration at stable waking heart rates of 60, 70, 80, 90, 100,
and 110 beats per minute (*p<0.05).
1442
Circulation Vol 86, No 5 November 1992
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heart rates.6 Accordingly, in the natural state, the QT
interval is modified by heart rate per se and by autonomic tone. It has been shown that ,3-blockade with
propranolol causes no significant changes in QT intervals when heart rate is held constant by pacing.18 If
3-blockade changes the normal relation between QT
and RR intervals, this could be mediated by changes in
effects of autonomic tone on QT intervals. In the study
reported here, acute treatment with the /1-selective
1-blocking agent atenolol changed the dependence of
the QT on the RR interval (Figure 3). The slope of the
curve relating QT to RR intervals was less after
13-blockade than before such blockade. The difference
was greatest at heart rates between 90 and 110 beats per
minute, when atenolol lengthened the QT interval. This
may reflect blockage of the sympathetic shortening
effect on QT intervals as heart rate increases, because it
has been shown that prolonged sympathetic stimulation
shortens QT intervals.19 At a waking heart rate of 60
beats per minute, the QT interval was shorter after
atenolol treatment than before such treatment. During
13-blockade, the heart rate slowed to 60 beats per
minute, with a relatively smaller parasympathetic influence than before atenolol; i.e., the effect of parasympathetic tone on the QT interval became weaker, and the
QT interval at a heart rate of 60 beats per minute
declined. During sleep, the QT interval was the same
before and after atenolol administration at the same
heart rates, as would be expected, because sympathetic
activity is less and secretion of circulating catecholamines decreases during sleep, and thus, the sympathetic shortening effect on QT intervals remains weak.
In this study, a high dose of atenolol was used to
produce nearly complete 13-blockade. As a result, the
induced bradycardia was marked at 2 hours after the
first dose of atenolol and did not increase during the
monitoring period (Figure 2). It is therefore unlikely
that theoretically more complete 13-blockade during the
latter portion of the 24-hour recording could have
significantly different effects on the QT interval compared with the initial portion of the monitoring period.
The results of the study reported here show that the
slope of the normal line relating QT and RR intervals is
less than would be expected on the basis of Bazett's
equation and even less after 13-blockade with atenolol.
Thus, use of Bazett's equation in studies with 13-blocking
agents gives incorrect results.
Limitations of the Study
The relation between QT and RR intervals has been
shown to depend on sex and age.8 In the study reported
here, all of the subjects were young men. Therefore, the
QT values in this study cannot be used as reference values
for women or older men. In addition, measurement of the
QT intervals was possible with only one ECG lead. In
normal 12-lead ECGs, values should be somewhat longer.
The method presented in this study is applicable to
determine the effect of a particular intervention to the QT
interval, whereas evaluating the QT interval in a particular ECG still needs the use of reference values.
Implications
In studies in ambulant subjects, use of coefficients
correcting for changes in heart rates may result in
misleading QT values, because any intervention may
change the coefficients, and the effects of possible autonomic changes may be excluded. When QT values are
compared, the curves relating QT to RR intervals give
more information than single values. The method described in this article of plotting QT against RR intervals
after measurement of QT values at similar stable spontaneous heart rates before and after intervention allows
changes in autonomic state and heart rate to be taken
into account. For patient care, this method can be used in
observing the possible effects of disease processes or
medications on the QT interval. For research purposes,
the method is applicable to evaluating the QT interval
during interventions. Previously reported changes in QT
intervals in ambulatory patients based on heart rate
correcting coefficients should be reevaluated by use of
the principle of the present method.
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QT intervals at heart rates from 50 to 120 beats per minute during 24-hour
electrocardiographic recordings in 100 healthy men. Effects of atenolol.
M Viitasalo and J Karjalainen
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Circulation. 1992;86:1439-1442
doi: 10.1161/01.CIR.86.5.1439
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1992 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
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