Download Heart rate variability depression in patients with unstable angina

Heart rate variability depression in patients with unstable
angina
J ian Huang, MD, S. Mark Sopher, MRCP, Edward Leatham, MRCP, Simon Redwood, MRCP,
A. J o h n Camm, MD, and J u a n Carlos Kaski, MD London, United Kingdom
The degree of reduction in heart rate variability (HRV) after
myocardial infarction has been shown to have prognostic
significance, but HRV has not been studied extensively in
patients with unstable angina. We assessed spectral and
nonspectral measurements of HRV in 52 patients with
unstable angina, 52 patients with acute myocardial infarction, and 41 normal subjects. The spectral bands of 0.04 to
0.15 Hz (low frequency), 0.15 to 0.4 (high frequency), and
nonspectral parameters SDNN, SDANN, SDNN index, rMSSD,
and pNN50 were calculated from continuous 24-hour ECGs.
All measures of HRV were reduced in patients with acute
coronary syndromes compared to normal controls
(p < 0.001), and there was no significant difference in measure of HRV between unstable angina and myocardial
infarction patients. In patients with unstable angina who
stabilized after admission, HRV had increased by the second
24 hours of monitoring. In contrast, HRV was further depressed in patients who had episodes of chest pain or transient ST-segment depression during the second 24 hours.
rMSSD, pNN50, and SDNN index were lower in patients with
unstable angina who had transient silent ischemia compared to those without silent ischemia. Of the patients with
unstable angina, 4 died and I had nonfatal acute myocardial
infarction within 11 months. HRV was lower in these patients
than in patients without further cardiac events. (AM HEART J
1995;130:772-79.)
Analysis of h e a r t rate variability (HRV) is a noninvasive method of assessing the integrity of neural
input to the cardiovascular system. TM Kleiger et al. 5
and Bigger et al. 6 have extended the use of HRV
analysis into the clinical domain by demonstrating
its value in risk stratification of patients after myocardial infarction. This finding has been confirmed
by o t h e r investigators 7 and has also been found in
patients with stable coronary ar t e r y disease, s
From the Department of Cardiological Sciences, St. George's Hospital
Medical School.
Drs. Sopher, Leatham, and Redwood were supported by research fellowships from the British Heart Foundation.
Received for publication Feb. 7, 1995; accepted March 30, 1995.
Reprint requests: Juan Carlos Kaski, MD, Department of Cardiological
Sciences, St. George's Hospital Medical School, London, SW 17 ORE,
United Kingdom.
Copyright © 1995 by Mosby-Year Book, Inc.
0002-8703/95/$5.00 + 0 4/1165301
772
Unstable angina and acute myocardial infarction
are thought to share a similar pathogenesis. 9 Unstable angina is associated with a high incidence of
acute myocardial infarction and sudden death within
6 months1°,11; however, little information about
HRV in patients with unstable angina is available at
present. Preliminary studies suggest t h a t HRV m a y
be depressed 12, la and t h a t this finding m a y be of
prognostic significance. 14We performed spectral and
nonspectral analyses of HRV in patients within 24
hours of onset of unstable angina, patients with myocardial infarction, and normal controls. In patients
with unstable angina we also investigated the relations between silent myocardial ischemia and HRV
and between clinical outcome and HRV.
METHODS
Patients. Seventy-two consecutive patients with acute
unstable angina admitted to the coronary care unit between March and December 1993 were selected for the
study. In addition, 52 patients with acute myocardial
infarction and 41 normal control subjects were studied for
comparison. Patients and control subjects with diabetes
mellitus were excluded because diabetes mellitus is an established cause of reduced HRV. 15
Unstable angina was defined by standard World Health
Organization criteria. 16 This definition includes only patients with symptoms of myocardial ischemia at rest and
does not include deteriorating exertional angina. Patients
with unstable angina were studied only if chest pain lasting >10 minutes had occurred within 24 hours in association with transient ECG (ST segment or T wave) changes.
Of the 72 patients in whom we recorded the continuous
ECGs, 20 were excluded for the following reasons: 3 had
atrial fibrillation or atrial flutter; 5 had second-degree
atrial ventricular block; 5 had a recording time of <4 hours
at nighttime (midnight to 5 AM)or <8 hours during the day;
4 had acute myocardial infarction diagnosed by elevated
cardiac enzymes and new Q waves on the electrocardiogram; and 3 required emergency angioplasty or coronary
artery surgery during the recording. The remaining 52 patients entered the study. All patients were treated with
combinations of nitrates, [3-adrenergic blockers, calcium
channel antagonists, heparin, and aspirin.
We selected 52 age- and sex-matched patients at a median of 7 days (range 5 to 10 days) after myocardial infarc-
Volume 130, Number 4
American Heart Journal
tion for comparison. Myocardial infarction was defined
with established criteria. 16 We attempted to control for
medication at the time of continuous ECG recording
between the two patient groups. The normal control subjects had no history of cardiovascular disease, no current
cardiovascular symptoms, normal cardiovascular examination results, and a normal 12-lead ECG. They included
hospital employees and patients admitted for noncardiac
procedures.
Twenty-four hour continuous ECG. Recordings were
performed on two channels (leads II and CM5, Marquette
series 8500). Patients were instructed to press the event
button during any episodes of chest pain and to record
these episodes in a diary. At the end of the recording period, patients were interviewed to check whether symptoms had occurred. Two consecutive, continuous 24-hour
electrocardiograms were recorded in patients with unstable angina. These patients were confined to bed. Patients
with myocardial infarction were studied for 24 hours while
they were hemodynamically stable and mobilizing on a
medical ward. An ischemic episode was defined as a 1 m m
ST-segment depression occurring 80 msec after the J-point
and lasting at least I minute. An interval of>l minute was
required between two successive episodes of ST-segment
depression to constitute two separate episodes. Normal
control subjects refrained from sport activities but were
studied during routine daily activities for 24 hours.
Heart rate variability analysis. Calculation of HRV
required recording of >12 hours of sinus rhythm with -<4
hours acquired during the night (midnight to 5 AM). The
Marquette 8000 system was used to digitize the data from
the tapes and apply algorithms for QRS labeling and editing, enabling automated calculation of both spectral and
nonspectral measures of HRV. To eliminate errors in QRS
labeling that could interfere with the accuracy of HRV assessment, a complete manual check of QRS morphologic
features (normal, ventricular ectopic, etc.) was performed,
and those beats left unclassified by the automatic recognition procedure were labeled manually. Spectral measurements were computed for each hour and averaged for the
total recording duration. Power spectra were quantified by
the area (power) in two frequency bandwidths: 0.04 to
0.15Hz (low-frequency [LF] power) and 0.15 to 0.40 Hz
(high-frequency [HF] power). The LF/HF ratio was also
calculated because it has been proposed as an index of
sympathovagal balance. 4 The following conventional nonspectral indexes of HRV were calculated: (1) mean of all
coupling intervals between normal beats (mNN); (2) the
SD of all normal intervals in the entire 24-hour ECG
recording (SDNN); (3) SD of the means of all normal R-R
intervals during each 5-minute segment (SDANN); (4)
mean of the SDS of all normal R-R intervals during each
5-minute segment (SDNN index); (5) number of adjacent
normal R-R intervals >50 msec different (pNN50); (6)
root-mean square of difference of successive normal R-R
intervals (rMSSD).
Statistics. Data is presented as mean _+ SD. Spectral
and nonspectral measurements of HRV were compared
between the three groups by an unpaired Student's t test.
H u a n g et al.
773
Table I. Clinical characteristics
Clinical d a t a
Age (yr)
Female/male
P r e v i o u s MI
Hypertension
Cigarette smokers
Cardiac m e d i c a t i o n
Nitrates
Calcium antagonists
[~-blockers
Aspirin
Heparin
A C E inhibitors
Unstable
angina
(n = 52)
Myocardial
infarction
(n = 52)
Normal
controls
(n ---41)
56 -_ 9
8/44
16 (31%)
20 (38%)
29 (56%)
56 --- 9
4/48
14 (27%)
20 (38%)
30 (58%)
50 -+ 12
6/35
--16 (24%)
39
20
23
47
31
9
43
22
20
48
35
10
(75%)
(38%)
(44%)
(90%)
(60%)
(17%)
(83%)
(43%)
(38%)
(93%)
(68%)
(20%)
-------
MI, Myocardial infarction; ACE, angiot ensin-converting enzyme inhibitors.
In unstable angina patients the HRV measures recorded in
the first 24 hours were compared to measures recorded in
the second 24 hours by paired Student's t test. Discrete
variables between the groups were compared with the chisquared test or Fisher's exact test as appropriate. A difference was considered significant at p < 0.05.
RESULTS
Clinical data. T h e clinical characteristics of the
t h r e e s t u d y groups a r e s u m m a r i z e d in T a b l e I. T h e r e
w e r e no significant differences in age or g e n d e r or the
proportion of cigarette s m o k e r s b e t w e e n the t h r e e
groups. Clinical characteristics, including a n t i a n g i nal medication, w e r e well m a t c h e d b e t w e e n t h e unstable a n g i n a a n d m y o c a r d i a l infarction p a t i e n t s (all
p > 0.05).
T w e n t y - o n e of t h e 52 u n s t a b l e a n g i n a p a t i e n t s
showed a t l e a s t one ischemic episode in t h e first 24
h o u r s of monitoring. T h i r t y - f o u r p a t i e n t s w e r e stabilized w i t h i n 24 h o u r s of medical t r e a t m e n t , a n d 18
p a t i e n t s h a d f u r t h e r a t t a c k s of chest p a i n or showed
episodes of S T - s e g m e n t d e p r e s s i o n d u r i n g t h e second 24-hour m o n i t o r i n g period. D u r i n g a m e a n
follow-up period of 11 m o n t h s (range 6 to 15 months),
4 d e a t h s occurred (at 3, 6, 7, a n d 11 m o n t h s ) a n d 1
p a t i e n t h a d a n o n f a t a l m y o c a r d i a l infarction at 5
m o n t h s . T h r e e d e a t h s w e r e sudden, a n d one p a t i e n t
died f r o m cardiogenic shock a f t e r a c u t e m y o c a r d i a l
infarction.
Heart rate variability analysis. Table I I and Figs. 1
a n d 2 show t h e r e s u l t s of spectral a n d n o n s p e c t r a l
m e a s u r e m e n t s of H R V in t h e t h r e e groups (with the
first 24-hour r e c o r d i n g i n the u n s t a b l e a n g i n a group).
T h e m e a n h e a r t r a t e w a s s i m i l a r in all groups; no
significant differences in m N N w e r e observed. B o t h
s p e c t r a l a n d n o n s p e c t r a l m e a s u r e m e n t s of H R V
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American Heart Journal
--]-]UGTI~" et al.
Fig. 1. Spectral HF measurements of HRV in the three groups; the first 24-hour recording was used in
the unstable angina group. Square, subsequent death or myocardial infarction.
Table ]]. Heart rate variability analyzed by spectral and nonspectral methods
Unstable angina
(n = 52)
Mean
LF (msec 2)
H F (msec 2)
LF/HF
m N N (msec)
S D N N (msec)
SDANN (msec)
S D N N index (msec)
r M S S D (msec)
pNN50
5.17
4.13
1.28
849
90
79
41
24
5.13
_+ 0.99
_+ 0.95
-+ 0.22
_+ 163
_+ 26
+- 27
+ 14
_+ 10
_+ 5
p Value
<0.001
<0.001
NS
NS
<0.001
<0.001
<0.001
<0.001
<0.001
Myocardial infarction
(n = 52)
Mean
5.13
4.14
1.25
836
86
77
42
24
5.9
+_ 1.42
_+ 1.12
_+ 0.24
-+ 151
+- 29
_+ 34
+ 19
_+ 10
-+ 6
p Value
<0.001
<0.001
NS
NS
<0.001
<0.001
<0.001
<0.001
<0.001
Normal controls
(n = 41)
Mean
6.40
5.36
1.21
843
130
109
62
37
15
-+ 1.05
-+ 1.09
+_ 0.17
-+ 159
-+ 37
_+ 39
-+ 24
+ 18
_+ 14
All p values reflect comparison of patient group (unstable angina or myocardial infarction) vs normal controls, p > 0.05 was considered not significant (NS).
Volume 130, Number 4
American Heart Journal
Huang et aL. 775
Fig. 2, NonspectralSDNNmeasurementsofHRVinthethreegr•ups;thefirst24-hourrecordingwasused
in the unstable angina group. Square, subsequent death or myocardial infarction.
were significantly lower in patients with unstable
angina and acute myocardial infarction compared
with normal controls (all p < 0.001). There were no
significant differences in these parameters between
the patients with unstable angina and acute myocardial infarction (allp > 0.05). The LF/HF was similar in patient groups and in normal controls.
Comparison of HRV between the first and second 24hour monitoring periods. Overall, in patients with un-
stable angina HRV was greater during the second
24-hour monitoring period. Spectral measurements,
SDNN index, rMSSD, and pNN50 calculated from
the second 24-hour recordings were significantly
higher than those from the first 24-hour recordings.
It was apparent that improvement of HRV occurred
predominantly in the 34 patients who were clinically
stable, whereas measurements of HRV were further
depressed in the 18 patients who had further episodes of chest pain or ischemic ST-segment changes
during the second 24 hours (Table III). There were no
significant differences in medication between patients who were stable and those who were not.
HRV in patients with and without silent ischemic episodes, During the first 24 hours, episodes ofischemic
ST-segment change were found in 21 (40%) patients.
A total of 123 ischemic episodes were detected, 20
with ST elevation and 103 with ST depression. Forty
(33%) episodes were symptomatic and 83 (67%) were
silent. Of the 21 patients with ischemic episodes on
Holter recording, 6 (29%) had exclusively silent episodes, 2 (10%) had symptomatic episodes only, and
the remaining 13 (62%) patients had both silent and
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American Heart Journal
Huanget al.
Table III. HRV during first and second 24 hours in patients with unstable angina who were stable during second 24
hours and in patients who had further chest pain and/or transient ischemia
No chest pain or transient ischemia
Chest pain and/or transient ischemia
(n = 18)
(n = 34)
First 24
hours
LF (ln m s 2)
H F (ln m s 2)
LF/HF
m N N (msec)
S D N N (msec)
S D A N N (msec)
S D N N i n d e x (msec)
r M S S D (msec)
pNN50
5,11
4.06
1.29
819
89
77
39
22
4.34
±
+
±
±
±
±
±
±
±
Second 24
hours
1,01
0,91
0,23
167
27
27
14
10
5.14
5.63
4.60
1.25
871
100
82
48
30
8.54
± 0.80
+_ 0.88
± 0.16
± 182
± 30
± 27
± 16
± 10
+ 6.67
p Value
0.001
<0.001
NS
0.004
0.016
NS
<0.001
<0.001
<0.001
First 24
hours
5.27
4.27
1.27
893
91
83
44
27
6.62
+- 0.98
_+ 1.03
_+ 0.19
± 163
± 23
+ 27
± 12
+_ 9
_+ 5.22
Second 24
hours
5,03
4.01
1.29
906
84
74
40
23
5.66
+ 0.95
+ 1.01
± 0.23
+_ 141
+_ 20
± 25
± 11
+ 7
± 4,12
p Value
0.005
0.003
NS
NS
NS
0.036
NS
0.016
NS
p > 0.05 was considered not significant (NS).
Table IV. HRV in patients with and without silent ischemic
episodes during first 24-hour Holter monitoring
No silent ischemia
Total power
LF
HF
mNN
SDNN
SDANN
S D N N index
rMSSD
pNN50
6.33
5.22
4.13
862
95
82
43
26
5.98
+ 1.00
± 1.09
± 1.02
-+ 184
± 33
± 30
± 14
+_ 8
± 4.46
Silent ischemia
5.93
4.79
3.74
806
83
77
34
19
2.12
± 0.67
± 0.86
_+ 0.81
+_ 157
-+ 19
_+ 25
± 9
+ 5
± 1.90
p Value
NS
NS
NS
NS
NS
NS
0.008
0.001
<0.001
p > 0,05 was considered not significant.
symptomatic episodes. There were no differences in
age, sex, or medications between patients with and
without ischemic episodes. The SDNN index, rMSSD,
and pNN50 in the 19 patients with at least one silent
ischemic episode were significantly lower than in
those patients without silent ischemia (Table IV).
DISCUSSION
In this investigation we found that all measures of
HRV are low in patients with unstable angina compared to normal controls. No measure of HRV was
significantly different in unstable angina compared
to myocardial infarction patients, suggesting a similar pattern and degree of autonomic dysfunction. Of
clinical importance, patients with unstable angina
who subsequently had serious cardiac events showed
particularly low HRV. The depressed HRV in unstable angina improved after clinical stabilization with
conventional medical treatment, but patients who
continued to have episodes of chest pain or ST-seg-
ment depression during the second 24-hour monitoring period showed a further reduction in HRV.
Finally, analysis of nonspectral measures of HRV
indicated a significantly lower parasympathetic tone
in patients with unstable angina who also had silent
episodes of ST-segment depression.
Heart rate variability reflects the activity of the
autonomic outflow to the heart. H F power is a measure of the modulation of parasympathetic tone by
respiratory frequency and depth, whereas LF power
is a measure of the modulation of both parasympathetic and sympathetic tone by baroreflex activity. 3, 4
The LF/HF ratio has been proposed as a measure of
sympathovagal balance# LF power averaged over a
24-hour period i n normal subjects may predominantly reflect parasympathetic activity17; however,
others is have criticized the methods leading to this
interpretation, suggesting instead that the normalized power of LF should be used as a marker of sympathetic activity. These conventional spectral measures of HRV do not include frequencies <0.04 Hz,
which account for the majority of the total power in
a 24-hour spectrum. Although the processes modulating ultra LF (ULF; <0.0033 Hz) and very LF (VLF;
0.0033 to 0.04 Hz) power remain speculative, these
measures have been shown to be better predictors of
mortality after myocardial infarction than LF or
HF. 7 However, they cannot be measured by most
commercial continuous ECG analysis systems, and
Bigger et alj9 have demonstrated that the following
variables are essentially equivalent: (1) ULF with
SDNN and SDANN index and (2) VLF with SDNN
index. Thus analysis of HRV with conventional
spectral and nonspectral measures as in the present
study includes most of the total power of HRV.
Volume 130, Numbel' 4
American Heart Journal
Heart rate variability in acute coronary syndromes.
Previous studies of HRV in acute coronary syndromes have also shown depressed measures, but
discrepancies exist. Myers et al. 2° were the first
group to show low values after MI using spectral
analysis, whereas Kleiger et al. 5 found low values of
SDNN. Bigger et al. 21 performed a comprehensive
analysis of power spectra in 68 patients 25 _+ 17 days
after myocardial infarction by using 24-hour ECG
recordings; they found a reduction in power in all
frequency bands (ULF, VLF, LF, and HF) and in total power. Lombardi et al. 22 used an autoregressive
method to estimate H F and LF from ECG recordings
lasting a few minutes only in 70 patients 2 weeks after infarction. In contrast to the findings of our study
and those of Bigger et al., Lombardi et al. found that
LF power was increased, H F power was decreased,
and total variance (equivalent to total power) was
unchanged. This group 23 also reported similar findings with this method on 24-hour ECG recordings to
assess the circadian variation of spectral indexes of
HRV in 20 patients 4 weeks after infarction. The difference between these findings is likely to be the result of method. 21 Short recordings limit the ability to
detect a difference in total power as a result of the
limited data collected and the considerably reduced
reproducibility of measurements of HRV compared
to measurements obtained with 24-hour recordings.
The autoregressive method of estimating spectral
power is complex and involves selecting portions of
data, particularly in the LF region, and "normalizing" the selected data. 4, 24 Casolo et al. 12 analyzed
24-hour SDNN in 54 patients at day 2 or 3 after myocardial infarction, in 15 patients at day 2 after unstable angina, and in 35 normal controls. SDNN was
depressed in both patient groups compared to controls but was significantly lower after infarction
compared to the unstable angina group. However, in
our study the patient groups had very similar measures of HRV, including SDNN. This apparent discrepancy m a y be explained by the differences in the
timing of the recordings. Many studies have shown
a progressive increase in measures of HRV after myocardial infarction. 12, 21, 23, 2~ Flapan et al. 25 demonstrated that the pNN50 increases between 12 hours
of admission and 7 days. Our study demonstrates
that, overall, in patients with unstable angina all
measures of HRV increase between 1 and 2 days.
Because we studied patients with myocardial infarction later and unstable angina patients sooner
after initial examination than Casolo et al., it is
predictable that our results show less difference
in HRV between the patient groups. The patients'
Huang et al.
777
level of physical activity may also influence the
comparison because activity is known to reduce
HRV. 26 Our patients with unstable angina were
prescribed bed rest, unlike those after myocardial
infarction.
Heart rate variability and clinical course in unstable
angina. Of clinical and pathophysiologic importance,
all measures of HRV showed a rapid improvement in
patients with unstable angina who stabilized within
a day of admission. However, patients who still had
episodes of chest pain or transient silent ischemia in
the second 24-hour monitoring period showed a further depression in HRV. The mechanisms of silent
ischemia are poorly understood. Marchant et al. 27
have shown that silent exertional angina is associated with a reduced HRV in patients with stable angina but not in patients with recent myocardial
infarction. This finding suggests that complex relations exist between ischemia, the perception of pain,
and autonomic dysfunction, and that these relations
may be affected by the nature of the underlying coronary syndrome. Although measures of HRV may
start to improve within a week of myocardial infarction, 25 it is clear that recovery continues at least up
to 3 months. 23 HRV depression is most marked in
patients whose myocardial infarction is associated
with the appearance of Q waves on the ECG or with
high peak CK-MB levels. 12 Clinically, the distinction
between non-Q-wave infarction and unstable angina is not always absolute and is often based on arbitrary rises in cardiac enzymes. These variations in
the extent of depression and the progression of HRV
after an acute coronary syndrome provide further
evidence to suggest that these syndromes form a
continuous clinical and pathophysiologic spectrum of
ischemia from unstable angina with rapid recovery
through to Q-wave infarction.
Particularly low values of HRV were present in all
five patients with unstable angina who had a further
cardiac event or died in the follow-up period (Figs. 1
and 2). Kleiger et al. 6 found a value of SDNN <50
msec to be a significant predictor of death in acute
myocardial infarction, and this finding has been
confirmed by other groups. 12 In our study only two
patients with unstable angina showed a value under
this limit, and both died. The other two patients who
died also had a relatively low SDNN (59 and 68
msec). An SDNN value of <50 msec was thus significantly associated with death in our patients with
unstable angina (p < 0.0001). Although the population in this study was not large enough to allow further risk stratification, this finding indicates a potential clinical role for monitoring of HRV in unsta-
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October 1995
American Heart Journal
1-1uanget al.
ble angina. It confirms the preliminary report of
Loricchio et al., 14 who found an SDNN index <70
msec to be predictive of major coronary events within
1 month of the appearance of unstable angina.
Limitations. There are some limitations to this
study. Although we attributed the reduction of HRV
in patients compared to HRV in controls to the
occurrence of unstable angina or recent myocardial
infarction, we cannot exclude other influences on
HRV. Mean heart rate is a major determinant of
HRV after myocardial infarction, 6 but mNN was
similar in all of our groups. Posture 2s and physical
activity 26 affect HRV. However, lack of activity could
not explain the progression of HRV and its relation
to clinical course in the patients with unstable
angina, all of whom were prescribed bed rest throughout the study, Smoking reduces behavioral variation
in HRV, 29 and there was a (nonsignificantly) higher
proportion of smokers in the patient groups. Several
groups 30-32have reported HRV to be reduced acutely
during ischemia, and we did not exclude the recordings during transient ischemic episodes from our
analysis of24-hour HRV. This finding could account
in part for our finding of greater reduction of HRV in
patients with unstable angina who continued to have
ischemic episodes. However, these episodes constitute <1% of the recording time in each patient and so
are unlikely to have markedly affected our findings.
Many patients were taking antianginal drugs at the
time of the study, which may have complex effects on
HRV. B-blockade in normal subjects has been variously reported to increase, 17 decrease, 33' 34 or not affect 35 HRV. After MI, metoprolol may increase 36 or
decrease 37 HRV. Bekheit et al. 3s have reported that
diltiazem, but not nifedipine, reduces the LF component of HRV after MI. Angiotensin-converting enzyme inhibitors m a y also affect HRV: an increase has
been noted in normal subjects, 39 whereas other
groups using different agents have not noted any effect in patients with hypertension. 4°-42 In our study,
comparison of the unstable angina patients who
were taking g-blockers with patients who were not
revealed no significant difference in any measure of
HRV. This result was also true for those taking calcium channel antagonists and angiotensin-converting enzyme inhibitors. It therefore seems unlikely
that the factors that may have influenced our results
could affect the overall conclusions regarding HRV
depression in unstable angina and its progression
and relation to clinical course.
Conclusions. Depression of heart rate variability
occurs acutely in unstable angina but starts to
resolve rapidly with clinical stabilization. The reduc-
tion is particularly marked in patients with further
cardiac events, suggesting a possible role in the risk
stratification of patients with unstable angina.
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