Download High-Frequency Modulation of Heart Rate

High-Frequency Modulation of Heart
Rate Variability During Exercise in
Patients With COPD*
Matthew N. Bartels, MD, MPH; Sanja Jelic, MD; Pakkay Ngai, MD;
Robert C. Basner, MD; and Ronald E. DeMeersman, PhD
Study objectives: To evaluate cardiac autonomic modulation in patients with COPD during peak
exercise.
Methods: Fifty-three patients with COPD (mean FEV1, 35% predicted [SD, 11% predicted]; mean
PaO2, 68 mm Hg [SD, 11 mm Hg]; mean PaCO2, 40 mm Hg [SD, 7 mm Hg]; mean age, 61 years
[SD, 10 years]; 26 women and 27 men) and 14 healthy control subjects aged 60 years (SD, 8 years)
[seven women and seven men] were studied at rest and during ramped bicycle ergometry to their
volitional peak. Patients were not receiving autonomic medications other than inhaled ␤-agonist
agents and/or anticholinergic agents. Control subjects were not receiving any medications.
Cardiac autonomic modulation was assessed via time-frequency analysis (Wigner-Ville) of
ECG-derived heart rate variability as the power in the low-frequency (LF) band (ie, 0.04 to 0.15
Hz) and the high-frequency (HF) band (ie, > 0.15 to 0.4 Hz) averaged from > 3 min at rest and
minutes 2 through 5 of their exercise period.
Results: Patients with COPD had a significantly increased mean, ln-transformed HF band from
rest to peak exercise (9.9 ms2 [SD, 1.4 ms2] vs 10.7 ms2 [SD, 1.4 ms2], respectively; p < 0.01), while
the HF band was unchanged for the control group (10.7 ms2 [SD, 1.5 ms2] vs 10.4 ms2 [1.3 ms2],
respectively; difference not significant). The mean ln-transformed LF band was significantly
increased from rest to peak exercise in patients with COPD (10.9 ms2 [SD, 1.5 ms2] vs 11.5 ms2
[SD, 1.4 ms2], respectively; p < 0.01) and in control subjects (10.9 ms2 [SD, 1.5 ms2] vs 11.5 ms2
[SD, 1.3 ms2], respectively; p < 0.01). The mean LF/HF ratio was significantly decreased from
rest to peak exercise in patients with COPD (3.1 [SD, 1.5] vs 2.5 [SD, 1.0], respectively; p < 0.01)
and was increased in control subjects (1.9 [SD, 0.8] vs 2.4 [1.0], respectively; p < 0.01). When
expressed in normalized units ([absolute power of the components]/[total power ⴚ very low
frequency power] ⴛ 100), the HF band was again significantly greater during peak exercise than
at rest in the patients with COPD and was unchanged during peak exercise for the control group.
Autonomic changes were not significantly correlated with age, gender, body mass index,
spirometry, lung volumes, resting gas exchange, or oxygen saturation during exercise
Conclusion: These data suggest that, in contrast to control subjects, the balance of sympathetic to
parasympathetic cardiac modulation decreases in patients with COPD during maximal volitional
exercise.
(CHEST 2003; 124:863– 869)
Key words: autonomic function; COPD; exercise; heart rate variability
Abbreviations: HF ⫽ high frequency; HRV ⫽ heart rate variability; LF ⫽ low frequency; MVV ⫽ maximal voluntary
ventilation; nu ⫽ normalized units; VLF ⫽ very low frequency; V̇o2 ⫽ oxygen uptake
as well as hypoxemic patients with
N ormoxemic
COPD appear to have impaired cardiac autonomic modulation at rest, as reflected in reduced
*From the Human Performance Laboratory (Dr. Bartels), Department of Rehabilitation Medicine, Department of Medicine
(Drs. Jelic, Ngai, and Basner), College of Physicians and Surgeons and Teachers College (Dr. DeMeersman), Columbia
University, New York, NY.
This work was sponsored in part by the Rehabilitation Medicine
Scientist Development Program Fellowship (grant NIH-1-K12HD01097-01A1), the Langeloth Foundation, and the VIDDA
Foundation.
www.chestjournal.org
heart rate variability (HRV).1– 4 Autonomic dysfunction at1 rest and during exercise is also present in
patients with cardiovascular and metabolic disorders,
and has been repeatedly shown to predict poor
Manuscript received July 12, 2001; revision accepted January 9,
2003.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail:
[email protected]).
Correspondence to: Matthew N. Bartels, MD, MPH, 630
West 168th St, Box 38, New York, NY 10032; e-mail: mnb4@
columbia.edu
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863
clinical outcomes in such patients.5–7 While exercise
generally has been associated with the withdrawal of
parasympathetic tone and the concomitant increase
of sympathetic tone in healthy subjects,8 cardiac
autonomic response to exercise has not been wellcharacterized in patients with COPD. Such response
could have significant clinical importance in these
patients.
Spectral analysis of HRV is a noninvasive method
for assessing autonomic function that has been used
extensively in the clinical setting.8 The majority of
exercise studies in humans have utilized frequency
domain analyses to delineate cardiac autonomic
modulation. However, such analysis, using Fourier
transforms, is most reliably performed on stationary
data, which are not present during exercise in general, and during exercise in COPD patients in particular.
The aim of the present study was to noninvasively
evaluate cardiac autonomic modulation in patients
with COPD during their maximal volitional exercise
using time-frequency domain analysis, which does
not require stationary data for the accurate assessment of autonomic modulations. We hypothesized
that patients with COPD would demonstrate impaired cardiac autonomic regulation compared with
healthy subjects during exercise.
Materials and Methods
Subjects
Participants were prospectively recruited from a group of
patients with COPD who had been referred for cardiopulmonary
exercise testing at the New York Presbyterian Hospital (Columbia-Presbyterian campus) as a part of the routine evaluation for
possible lung volume reduction surgery or transplantation. All
patients had stopped smoking at least 6 months prior to enrollment in the study. All COPD patients who had been referred for
clinical evaluation between November 1999 and January 2001
were screened for this study. Control subjects of similar age and
gender to the study population were recruited from among
patients who had been referred to the exercise laboratory with a
diagnosis of dyspnea. Control subjects were included in the
analysis if they had normal findings on pulmonary function
testing and exercise testing, had not received a diagnosis of a
major illness during the prior 6 months, and had no history of
diagnosed pulmonary disease, cardiac disease, or malignancy. All
participants gave their informed consent to participate in the
study, which was approved by the New York Presbyterian
Hospital (Columbia-Presbyterian campus) Institutional Review
Board. No participants were financially compensated for participating in this research. All participants underwent a medical
history and physical examination by a physician investigator prior
to being accepted for the study, as well as pulmonary function
testing. Patients with COPD also underwent arterial blood gas
analysis. None of the study patients were receiving autonomically
active medications other than inhaled ␤-agonist and/or anticholinergic agents. None of the control subjects were receiving any
medications of any type. The testing was performed in the
Human Performance Laboratory of the Columbia Presbyterian
Medical Center.
Protocol and Measurements
Subjects were postprandial for at least 4 h and had refrained
from alcoholic and caffeinated beverages for at least 12 h prior to
the data collection. All patients with COPD received two puffs of
albuterol via a metered-dose inhaler 30 min prior to the resting
measurements being made, as per the clinical cardiopulmonary
exercise testing laboratory protocol. None of the control subjects
received such treatment. Resting and exercise data were collected while patients were breathing supplemental oxygen (fraction of inspired oxygen, 0.3) through a mouthpiece that was
attached to a mass flow sensor with a nose clip. Control subjects
were studied while breathing room air. During rest, subjects sat
on a bicycle ergometer maintaining their normal breathing
patterns. Resting data were collected for 5 min. Exercise stress
testing then was performed on the bicycle ergometer (Vmax 229
series workstation; SensorMedics; Yorba Linda, CA). Subjects
were familiarized with the cycling protocol prior to performing
the exercise test. The exercise testing used a ramp protocol with
5-min baseline resting data collection, followed by a 3-min warm
up at no load, and then a maximum exercise test at either 5 W per
minute (in patients with maximal voluntary ventilation [MVV] of
⬍ 40 L/min) or 10 W per minute (in patients with MVV of ⱖ 40
L/min) ramp until their maximal volitional exercise capacity was
reached. Criteria for terminating the exercise study were volitional leg fatigue (as assessed by a modified Borg scale score) or
intolerable dyspnea.9 No patient was able to achieve his/her
predicted maximal oxygen consumption (V̇o2), while all control
subjects achieved their predicted maximal V̇o2.
During rest and exercise testing, an ECG was recorded using
lead II and lead V5 with an ECG machine (Marquette Max-1;
Marquette Medical Systems; Milwaukee, WI). Oxygen saturation
was monitored noninvasively by finger pulse oximetry (Sat-Trak
Pulse Oxymeter 767589 –103; SensorMedics). The autonomic
biopotentials were obtained through an interface board (BNC
2080; National Instruments Co; Austin, TX) and were fed into a
12-bit analog-to-digital converter (DAQ Card-700; National Instruments Co) and then into a Pentium computer (Vision Book
Plus; Hitachi; San Jose, CA). The data were sampled at 200 Hz.8
Postacquisition Data Analysis
Patients with technically inadequate ECG tracings or cardiac
arrhythmia were excluded from the data analysis. The current
investigation used time-frequency, or the Wigner-Ville distribution, to decompose the HRV. This analysis is preferred over the
traditional frequency spectral analysis due to the nonstationarity
of respiration in COPD patients. Specifically, the Wigner-Ville
distribution decomposes a signal expressed as a function of time
into a signal expressed as a function of both time and frequency.
The time-frequency method uses a modified Fourier transform
applied to overlapping sections of the time signal to develop a
joint density function that is dependent on both time and
frequency.10,11 In this approach, the signal is divided into a series
of short windows, and the Fourier transform then is calculated
for each section. It has been shown to provide a reliable estimate
of spectral powers without generating undesirable crossterms.10,11 The power (ie, the density of the beat-to-beat oscillation in the R-R interval) of HRV in the high-frequency (HF)
band has been shown to be influenced primarily by parasympathetic nervous system activity,12 while both parasympathetic and
sympathetic activity contribute to the low-frequency (LF)
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Clinical Investigations
band.12,13 It has been suggested that the ratio of LF to HF
reflects the sympathovagal balance.12,13 Power in the LF band (ie,
0.04 to 0.15 Hz), the HF band (ie, ⬎ 0.15 to 0.4 Hz), and the very
LF (VLF) band (ie, 0.00 to ⬍ 0.04 Hz) were averaged over the
last 3 min of resting data acquisition and during minutes 2
through 5 of exercise. Spectral components were expressed both
as absolute values in milliseconds2,14,15 and as normalized units
(nu), which were calculated as follows: (absolute power of the
components)/(total power ⫺ VLF power) ⫻ 100.16,17
Statistical Analysis
Assuming differences of 30% in baseline measurements, 48
patients with COPD provide 80% statistical power to detect a
30% difference in HRV measurements at rest and during exercise, with a type 1 error of 0.05. We recruited 64 patients,
anticipating a 30% dropout rate, to satisfy these conditions. Based
on our preliminary data in non-COPD subjects, assuming differences of 30% in baseline measurements, 12 control subjects
provide 80% power to detect a 30% difference in HRV measurements at rest and during exercise, with a type 1 error of 0.05. We
enrolled 14 control subjects to satisfy these conditions. Logarithmic transformation was used to stabilize the skewness of the raw
data.18 Five physiologic parameters (ie, lnHF, lnLF, nuHF,
nuLF, and LF/HF ratio) were compared from rest to exercise by
analysis of covariance, which was used to make comparisons
across groups, and were based on final values with baseline as the
covariate.19 Correlations between HRV changes and demographic continuous variables (ie, age and body mass index) and
physiologic continuous variables (ie, FVC, FEV1, total lung
capacity, residual volume, MVV, Pao2, Paco2, and exercise
arterial oxygen saturation), which may have influenced these
HRV changes, were performed using the Spearman-Row test.
Associations between HRV changes and gender were performed
using the Wilcoxon rank sum test.
Results
Sixty-four consecutive eligible patients with
COPD were recruited between November 1999 and
January 2001. Eleven patients were excluded after
the exercise study because of ECG artifacts or
cardiac arrhythmia that developed during the study,
thus precluding reliable spectral analysis. Thus, 53
patients of the original 64 had technically adequate
data and were included in the data analysis. We did
not use imputational methods for the analysis, as
data from patients excluded because of technically
inadequate data could not have been analyzed. The
clinical characteristics of the subjects in the COPD
and control groups are shown in Table 1. There were
no significant differences between the 53 COPD
patients included in the data analysis and the 11
patients excluded because of ECG artifacts or arrhythmia in regard to age, gender, FEV1, FVC, FVC
FEV1, Pao2, and Paco2. See Table 2 for a comparison of the included and excluded subjects.
Table 3 displays the change in subjects’ physiologic parameters from rest to exercise. Patients with
COPD achieved a mean peak V̇o2 of 18 mL/kg/min
(SD, 4 mL/kg/min). The control group achieved a
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Table 1—Demographic Characteristics and Pulmonary
Function*
Characteristics
Age, yr
Gender, No.
Male
Female
FEV1,† % predicted
FVC,† % predicted
FEV1/FVC
Pao2, mm Hg
Paco2, mm Hg
COPD Patients
(n ⫽ 53)
Control Subjects
(n ⫽ 14)
63 (10)
60 (8)
27
26
35 (11)
64 (18)
0.43 (0.13)
68 (11)
40 (7)
7
7
77 (6)
82 (12)
0.79 (0.08)
p Value
0.41
0.99
0.99
⬍ 0.01
⬍ 0.01
⬍ 0.01
*Values given as mean (SD), unless otherwise indicated.
†Values based on norms adjusted for age, height, and gender.
mean V̇o2 max of 31 mL/kg/min (SD, 5 mL/kg/min).
The mean ln-transformed HF band was significantly
increased in patients with COPD from rest to exercise (9.9 ms2 [SD, 1.4 ms2] vs 10.7 ms2 [SD, 1.4 ms2],
respectively; p ⬍ 0.01) as was the mean ln-transformed LF (10.9 ms2 [SD, 1.5 ms2] vs 11.5 ms2 [1.4
ms2], respectively; p ⬍ 0.01). The mean LF/HF ratio
was significantly decreased from rest to exercise (3.1
[SD, 1.5] vs 2.5 [SD, 1.0], respectively; p ⬍ 0.02). In
contrast, for the control group, the ln-transformed
HF was unchanged from rest to exercise (10.7 ms2
[SD, 1.5 ms2] vs 10.4 ms2 [SD, 1.3 ms2], respectively;
difference not significant), while the ln-transformed
LF was increased from rest to exercise (10.9 ms2
[SD, 1.5 ms2] vs 11.5 ms2 [SD, 1.3 ms2], respectively;
p ⬍ 0.01). The LF/HF ratio increased in the control
subjects (1.9 [SD, 0.8] vs 2.4 [SD, 1.0], respectively;
p ⬍ 0.01).
When expressed in nu, the HF band was again
significantly increased from rest to exercise (0.08 nu
[SD, 0.03 nu] vs 0.09 nu [SD, 0.03 nu], respectively;
Table 2—Demographic Characteristics and Pulmonary
Function of COPD Patients Who Were Included and
Excluded From the Study*
Characteristics
Age, yr
Gender, No.
Male
Female
FEV1,† % predicted
FVC,† % predicted
FEV1/FVC
Pao2, mm Hg
Paco2, mm Hg
Included
COPD Patients
(n ⫽ 53)
Excluded
COPD Patients
(n ⫽ 11)
p Value
63 (10)
62 (7)
0.91
27 (51%)
26 (49%)
35 (11)
64 (18)
0.43 (0.13)
68 (11)
40 (7)
6 (54%)
5 (45%)
37 (9)
62 (15)
0.45 (0.17)
66 (9)
42 (5)
0.99
0.99
0.89
0.87
0.76
0.43
0.60
*Values given as mean (SD), unless otherwise indicated.
†Values based on norms adjusted for age, height, and gender.
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Table 3—Heart Rate Variability and Physiologic Parameters at Rest and During Peak Exercise*
COPD Patients (n ⫽ 53)
Control Subjects (n ⫽ 14)
Variables
Rest
Exercise
p Value†
Rest
Exercise
p Value†
lnHF
lnLF
nuHF
nuLF
LF/HF
Respiratory rate, breaths/min
Heart rate, beats/min
Sao2, %
Peak V̇o2, mL/kg/min
9.9 (1.4)
10.9 (1.5)
0.08 (0.03)
0.24 (0.06)
3.1 (1.5)
17 (5)
87 (14)
96 (1.1)
10.7 (1.4)
11.5 (1.4)
0.09 (0.03)
0.23 (0.06)
2.5 (1.0)
27 (5)
110 (16)
94 (1.6)
18 (4)
⬍ 0.01
⬍ 0.01
⬍ 0.01
0.14
⬍ 0.02
⬍ 0.01
⬍ 0.01
⬍ 0.01
10.7 (1.5)
10.9 (1.5)
0.07 (0.02)
0.16 (0.04)
1.9 (0.8)
16 (4)
77 (12)
98 (1.2)
10.4 (1.3)
11.5 (1.3)
0.06 (0.01)
0.22 (0.07)
2.4 (1.0)
35 (6)
156 (15)
99 (1.4)
31 (5)
0.57
⬍ 0.01
0.45
⬍ 0.01
⬍ 0.01
⬍ 0.01
⬍ 0.01
0.72
*Values given as mean (SD), unless otherwise indicated. Sao2 ⫽ arterial oxygen saturation.
†Values derived from analysis of covariance.
p ⬍ 0.01) in patients with COPD, while the LF band
showed no significant change from rest to exercise
(0.24 nu [SD, 0.06 nu] vs 0.23 nu [SD, 0.06 nu,
respectively; difference not significant). The normalized HF band was again unchanged for the control
group from rest to exercise (0.07 nu [SD, 0.02 nu] vs
0.06 nu [SD, 0.01 nu], respectively; difference not
significant), and the normalized LF band was significantly increased (0.16 nu [SD, 0.04 nu] vs 0.22 nu
[SD, 0.07 nu], respectively; p ⬍ 0.01). Autonomic
changes were not significantly correlated with age,
gender, body mass index, baseline spirometry, and
lung volumes, resting gas exchange, or oxygen saturation during exercise.
A comparison of the control group and the COPD
group at both stages was performed and is presented
in Table 4 for completeness. There is a difference in
subjects with COPD compared to the healthy control subjects at rest in terms of resting heart rate (87
beats/min [SD, 14 beats/min] vs 77 beats/min [SD,
12 beats/min], respectively; p ⬍ 0.05), and in the
autonomic indexes of the normalized LF band (0.24
[SD, 0.06] vs 0.16 [SD, 0.04], respectively; p ⬍ 0.01)
and the LF/HF ratio (3.1 [SD, 1.5] vs 1.9 [SD, 0.8],
respectively; p ⬍ 0.01). At maximum exercise, the
differences seen are predominantly in the areas of
peak V̇o2 (18 mL/kg/min [SD, 4 mL/kg/min] vs 31
mL/kg/min [SD, 5 mL/kg/min], respectively;
p ⬍ 0.01) oxygenation (94% [SD, 1.6%] vs 99%
[1.4%], respectively; p ⬍ 0.05), lower maximum
heart rate (110 beats/min [SD, 16 beats/min] vs 156
beats/min [SD, 15 beats/min], respectively;
p ⬍ 0.01), and lower respiratory rate (27 breaths/min
[SD, 5 breaths/min] vs 35 breaths/min [SD, 6
breaths/min], respectively; p ⬍ 0.05) at maximum
exercise. The autonomic indexes are more comparable at peak exercise in the COPD group and the
healthy control group, with no significant difference
in any of the indexes, including the LF/HF ratio and
the overall normalized LF values.
Discussion
The major and novel finding of this investigation is
that patients with COPD display an increased HF
Table 4 —Heart Rate Variability at Rest and During Peak Exercise Between COPD and Control Groups*
Variables
lnHF
lnLF
nuHF
nuLF
LF/HF
Respiratory rate, breaths/min
Heart rate, beats/min
Sao2, %
Peak V̇o2, mL/kg/min
COPD Patients
at Rest
(n ⫽ 53)
Control Subjects
at Rest
(n ⫽ 14)
p Value†
9.9 (1.4)
10.9 (1.5)
0.08 (0.03)
0.24 (0.06)
3.1 (1.5)
17 (5)
87 (14)
96 (1.1)
10.7 (1.5)
10.9 (1.5)
0.07 (0.02)
0.16 (0.04)
1.9 (0.8)
16 (4)
77 (12)
98 (1.2)
0.10
0.62
0.27
⬍ 0.01
⬍ 0.01
0.48
⬍ 0.05
0.17
COPD Patients
at Exercise
(n ⫽ 53)
Control Subjects
at Exercise
(n ⫽ 14)
p Value†
10.7 (1.4)
11.5 (1.4)
0.09 (0.03)
0.23 (0.06)
2.5 (1.0)
27 (5)
110 (16)
94 (1.6)
18 (4)
10.4 (1.3)
11.5 (1.3)
0.06 (0.01)
0.22 (0.07)
2.4 (1.0)
35 (6)
156 (15)
99 (1.4)
31 (5)
0.48
0.39
0.30
0.74
0.76
⬍ 0.05
⬍ 0.01
⬍ 0.05
⬍ 0.01
*Values given as mean (SD), unless otherwise indicated. See Table 3 for abbreviations not used in the text.
†Values derived from analysis of covariance.
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Clinical Investigations
modulation of HRV, along with a decreased LF/HF
HRV ratio, during exercise. These changes were
seen over a broad spectrum of age, gender, and
COPD severity. The findings suggest that cardiac
parasympathetic modulation increases while the balance of cardiac sympathetic to parasympathetic modulation decreases when COPD patients exercise to
their maximal volitional capacity. These changes in
HRV are in direct contrast to subjects in a control
group of similar age and gender who demonstrated
an unchanged HF cardiac modulation and an increased LF/HF HRV ratio during their peak volitional exercise. The changes in the LF/HF ratio show
a decrease in COPD, which is in part due to the
increase in the HF band. In control subjects, the
LF/HF ratio changes in response to the increase in
LF, which is not seen in the individuals with COPD.
This indicates the following two possible mechanisms of alteration of the exercise response in
COPD: (1) a loss of the ability to achieve a sympathetic response as the baseline sympathetic tone is
elevated (seen in the lack of increase in LF); and (2)
an increase in HF, which is seen in COPD patients
but not in healthy control subjects, indicating an
abnormal level of parasympathetic tone. The findings during exercise in the control subjects corroborate those of previous studies by numerous other
investigators demonstrating that parasympathetic
cardiac activity during exercise in healthy subjects
either does not change20,21 or decreases14,15,17,22
while sympathetic activity increases.
Since the known association between spectral
components of the HRV and cardiac sympathetic
and parasympathetic activity is based on studies
conducted at rest,13,23,24 an extrapolation to exercise
is more difficult to interpret.22,25 We sought to
actually evaluate sympathetic and parasympathetic
activity in exercise by direct measurement, and, in
contrast to most previous investigations of HRV in
humans during exercise, we spectrally decomposed
our data using time-frequency analysis rather than
frequency analysis since exercise data do not meet
the requirements for stationary data for frequency
domain analysis.11,26 Since HF modulation is reflective of parasympathetic cardiac modulation, we demonstrated an increase in parasympathetic activity
during exercise in COPD that was consistently
present whether analyzed as absolute power or
normalized for total power.22,25 This is in clear
contrast to the lack of change in parasympathetic
activity seen in our control group and reported in
other studies of healthy subjects.14,15,17,20 –22 Additionally, there is a lack of alteration of the sympathetic tone in the COPD group, and, in combination
with the alterations of parasympathetic tone, these
lead to the observed changes.
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The physiologic effects seen at maximum exercise
with a greater increase in heart and respiratory rates,
and a decrease in oxygen saturation are consistent
with the expected physiology of COPD. The dyspnea
at maximum exercise and the oxygen desaturation
would be expected to increase sympathetic tone and
to decrease parasympathetic tone, but the opposite
was seen. The maximum heart rate achieved was
lower, and this may have contributed in part to the
changes that were seen. However, the lower maximum heart rate could possibly be due to the increased HF band that was seen and is also related to
the lack of respiratory reserve, as evidenced by the
mild decrease in oxygen saturation and the limited
respiratory rate.
The physiologic basis by which parasympathetic
cardiac modulation may increase during exercise in
patients with COPD is unclear and was not investigated in the current study. However, several possible
mechanisms may be postulated. Large intrathoracic
pressure swings that occur in patients with obstructive airway disease can cause abnormal cardiac autonomic modulation and an increase in parasympathetic activity at rest.27,28 Such an effect could be
potentiated during dynamic hyperinflation and increased end-expiratory lung volumes, which invariably attend even minimal exercise in patients with
COPD.29 The mechanism may in part reflect a
degree of input from hypercapnia, which has been
seen to cause an increase in parasympathetic tone in
animal models.30,31
Another possible mechanism of the increased HF
component of HRV found in the COPD patients
during exercise may be an effect of increased respiratory frequency with exercise, causing a shift in
power out of the LF range and into the HF
range.22,25,32 Similarly, respiratory sinus arrhythmia
during exercise also may be influenced by nonneural
mechanisms, such as atrial stretch.16,33,34 The presence of inhaled ␤-agonist and anticholinergic agents
in the subject population could be thought to have
effects on HF modulation and LF/HF ratios. However, although inhaled ␤-agonist agents can increase
sympathetic activity as measured by HRV analysis in
healthy subjects,35,36 these agents do not change the
parasympathetic (HF) cardiac modulation.35,36 Likewise, inhaled anticholinergic agents and ipratropium
bromide do not alter HRV in human subjects.37
Therefore, it is unlikely that the inhaled medications
used by the COPD subjects influenced our findings
of increased HF modulation of HRV during exercise.
Finally, even if there had been an effect, the expected trend would have been opposite to our
findings, with a decrease in HF modulation and an
increase in the LF/HF ratio.
In summary, the novel finding in our data is that
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during exercise there is a significant increase in HF
modulation with a decrease in the LF/HF ratio in
COPD patients, while HF modulation of HRV is
stable with an increased LF/HF ratio in control
subjects. Considered together, the significant increase in the HF component of the HRV with
decreased LF/HF ratio during peak exercise in
patients with COPD suggests increased parasympathetic cardiac modulation due to this condition. This
is in direct contrast to the HRV response seen in
non-COPD control subjects during peak exercise.
While decreased HRV at rest, as represented by
decreased HF and increased LF/HF ratio, has been
associated with poorer cardiovascular prognosis in
patients with cardiovascular disease,5– 8 the physiologic and prognostic significance of increased parasympathetic cardiac modulation during exercise in
COPD patients remains to be investigated. Additionally, the increased parasympathetic tone seen with
exercise in this study may have a significant bearing
on the ability to perform exercise and on the response to a conditioning program. Further investigations into the alterations of these parameters with
training will possibly shed light on techniques to help
normalize the sympathetic to parasympathetic balance in individuals with COPD.
References
1 Stewart AG, Waterhouse JC, Howard P. Cardiovascular
autonomic nerve function in patients with hypoxaemic
chronic obstructive pulmonary disease. Eur Respir J 1991;
4:1207–1214
2 Volterrani M, Scalvini S, Mazzuero G, et al. Decreased heart
rate variability in patients with chronic obstructive pulmonary
disease. Chest 1994; 106:1432–1437
3 Stein PK, Nelson P, Rottman JN, et al. Heart rate variability
reflects severity of COPD in PiZ ␣1-antitrypsin deficiency.
Chest 1998; 113:327–333
4 Scalvini S, Porta R, Zanelli E, et al. Effects of oxygen on
autonomic nervous system dysfunction in patients with
chronic obstructive pulmonary disease. Eur Respir J 1999;
13:119 –124
5 Kleiger RE, Miller JP, Bigger JT, et al. Decreased heart rate
variability and its association with increased mortality after
acute myocardial infarction. Am J Cardiol 1987; 59:256 –262
6 Pagani M, Malfatto G, Pierini S, et al. Spectral analysis of
HRV in the assessment of autonomic diabetic neuropathy. J
Auton Nerv Syst 1988; 23:143–153
7 Kleiger RE, Miller JP, Krone RJ, et al. The independence of
cycle length variability and exercise testing on predicting
mortality of patients surviving acute myocardial infarction:
the Multicenter Postinfarction Research Group. Am J Cardiol
1990; 65:408 – 411
8 Task Force of the European Society of Cardiology and the
North American Society of Pacing and Electrophysiology.
Heart rate variability: standards of measurement, physiological interpretation, and clinical use. Circulation 1996; 93:
1043–1065
9 Borg GA. Psychophysical bases of perceived exertion. Med
Sci Sports Exerc 1982; 14:377–381
10 Novak P. Time/frequency mapping of the heart rate, blood
pressure and respiratory signals. Med Biol Eng Comput 1993;
31:103–110
11 Novak V. Slow cardiovascular rhythms at tilt and syncope.
J Clin Neurophysiol 1995; 12:64 –71
12 Pagani M, Somers V, Furlan R, et al. Changes in autonomic
regulation induced by physical training in mild hypertension.
Hypertension 1988; 12:600 – 610
13 Pagani M, Montano N, Porta A, et al. Relationship between
spectral components of cardiovascular variabilities and direct
measures of muscle sympathetic nerve activity in humans.
Circulation 1997; 95:1441–1448
14 Arai Y, Saul JP, Albrecht P, et al. Modulation of cardiac
autonomic activity during and immediately after exercise.
Am J Physiol 1989; 256:H132–H141
15 Yamamoto Y, Hughson RL, Peterson JC. Autonomic control
of heart rate during exercise studied by heart rate variability
spectral analysis. J Appl Physiol 1991; 71:1136 –1142
16 Bernardi L, Salvucci F, Suardi R, et al. Evidence for an
intrinsic mechanism regulating heart rate variability in the
transplanted and the intact heart during submaximal dynamic
exercise? Cardiovasc Res 1990; 24:969 –981
17 Rimoldi O, Furlan R, Pagani M, et al. Analysis of neural
mechanisms accompanying different intensities of dynamic
exercise. Chest 1992; 101(suppl):226S–230S
18 Goldberger JJ. Sympathovagal balance: how should we measure it? Am J Physiol 1999; 4:H1273–H1280
19 Zar JH. Biostatistical analysis. Englewood Cliffs, N J: Prentice
Hall, 1974
20 Perini R, Orizio C, Baselli G, et al. The influence of exercise
intensity on the power spectrum of heart rate variability. Eur
J Appl Physiol 1990; 61:143–148
21 Casadei B, Cochrane S, Johnston J, et al. Pitfalls in the
interpretation of spectral analysis of the heart rate variability
during exercise in humans. Acta Physiol Scand 1995; 153:
125–131
22 Nakamura Y, Yamamoto Y, Muraoka I. Autonomic control of
heart rate during physical exercise and fractal dimension of
heart rate variability. J Appl Physiol 1993; 74:875– 881
23 Pomeranz B, Macaulay RJB, Caudill MA, et al. Assessment of
autonomic function in humans by heart rate spectral analysis.
Am J Physiol 1985; 248:H151–H153
24 Pagani M, Lombardi F, Guzzetti S, et al. Power spectral
analysis of heart rate and blood pressure variabilities as a
marker of sympatho-vagal interaction in man and conscious
dog. Circ Res 1986; 59:178 –193
25 Casadei B, Moon J, Caiazza A. Respiratory sinus arrhythmia
does not reflect cardiac vagal tone during exercise in man
[abstract]. J Physiol 1993; 473:66P
26 Kitney RI. Techniques for studying short-term changes in
cardiorespiratory data. In: di Rienzo M, ed. Computer analysis of cardiovascular signals. Washington, DC: IOSA, 1995;
41–52
27 Buda AJ, Pinsky MR, Ingels NB, et al. The effect of
intrathoracic pressure on left ventricular performance.
N Engl J Med 1979; 301:453– 459
28 Kallenbach JM, Webster T, Dowdeswell R, et al. Reflex heart
rate control in asthma: evidence of parasympathetic overactivity. Chest 1985; 87:644 – 648
29 Marin JM, Carrizo SJ, Gascon M, et al. Inspiratory capacity,
dynamic hyperinflation, breathlessness, and exercise performance during the 6-minute walk test in chronic obstructive
pulmonary disease. Am J Respir Crit Care Med 2001; 163:
1395–1399
30 Yasuma F, Hayano J. Augmentation of respiratory sinus
arrhythmia in response to progressive hypercapnia in conscious dogs. Am J Physiol 2001; 280:H2336 –H2341
868
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21998/ on 05/14/2017
Clinical Investigations
31 Hayano J, Yasuma F, Okada A, et al. Respiratory sinus
arrhythmia: a phenomenon improving pulmonary gas exchange and circulatory efficiency. Circulation 1996; 94:842–
847
32 Brown TE, Beightol LA, Koh J, et al. Important influence of
respiration on human R-R interval power spectra is largely
ignored. J Appl Physiol 1993; 75:2310 –2317
33 Blinks JR. Positive chronotropic effect of increasing right
atrial pressure in the isolated mammalian heart. Am J Physiol
1956; 186:299 –303
34 Kohl P, Kamkin AG, Kiseleva IS, et al. Mechanosensitive cells
in the atrium of frog heart. Exp Physiol 1992; 77:213–216
www.chestjournal.org
35 Silke B, Hanratty CG, Riddell JG. Heart-rate variability
effects of beta-adrenoceptor agonists (xamoterol, prenalterol,
and salbutamol) assessed nonlinearly with scatterplots and
sequence methods. J Cardiovasc Pharmacol 1999; 33:859 –
867
36 Hanratty CG, Silke B, Riddell JG. Evaluation of the effect on
heart rate variability of a beta2-adrenoceptor agonist and
antagonist using non-linear scatterplot and sequence methods. Br J Clin Pharmacol 1999; 47:157–166
37 Dragone AJ, Parlow JL. Effects of inhaled albuterol and
ipratropium bromide on autonomic control of the cardiovascular system. Chest 1997; 111:1514 –1518
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Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21998/ on 05/14/2017
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