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Original Article

Chronic Respiratory Disease


10(3) 117–126
Abnormal heart rate recovery and ª The Author(s) 2013
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chronotropic incompetence on DOI: 10.1177/1479972313493097
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exercise in chronic obstructive
pulmonary disease

Mansi Gupta1, Vishal Bansal2 and Sunil K Chhabra1

Abstract
Chronotropic incompetence (CI; failure to reach the targeted heart rate (HR) on exercise) and a delayed HR
recovery (HRR; 12 beats decline within the first minute after cessation) reflect autonomic dysfunction (AD)
and predict adverse cardiac prognosis. As chronic obstructive pulmonary disease (COPD) is known to be
associated with AD, we hypothesized that these patients may manifest these responses on exercise. The
prevalence and predictors of these responses in COPD and their association with its severity have not been
evaluated. Normoxemic, stable male patients with COPD (n ¼ 39) and 11 healthy controls underwent lung
function testing and incremental leg ergometry. HR responses were monitored during exercise and recovery
to compute the HRR and CI. Of all the patients, 33 (84.6%) had at least one of the two exercise responses as
abnormal, with the majority (23, 58.9%) having both an abnormal HRR and CI. The frequency of abnormal
responses increased with increasing Global Initiative for Chronic Obstructive Lung Disease stage and body
mass index, airflow obstruction, dyspnoea and exercise capacity index. After adjusting for smoking history and
post-bronchodilator forced expiratory volume in 1 second, only a reduced diffusion capacity for carbon monox-
ide predicted abnormal HRR, though weakly. We concluded that abnormal HRR and CI are common in patients
with COPD. These responses are observed with increasing frequency as the severity of disease increases.

Keywords
Autonomic function, BODE index, chronotropic incompetence, chronic obstructive pulmonary disease, heart
rate recovery

Introduction has been observed in studies on cardiac responses to


exercise in COPD.11,12 In a retrospective analysis,
Cardiovascular disease is a major cause of mortality
Lacasse et al.13 found abnormal HRR to be associated
in chronic obstructive pulmonary disease (COPD).1
with all-cause mortality in COPD. Chronotropic
A probable cause of mortality is autonomic dysfunc-
incompetence (CI), an attenuated HR response to
tion (AD) that may predispose to arrhythmias.2,3
exercise, is believed to represent an impaired sympa-
Though there is a lack of direct evidence, AD predicts
thetic response and is another independent predictor
fatal cardiac events in diabetes mellitus, post-
myocardial infarction state and heart failure4 and may
play a similar role in COPD. 1
Department of Cardiorespiratory Physiology, Vallabhbhai Patel
The rate of recovery of heart rate (HR) within the Chest Institute, University of Delhi, Delhi, India
first minute after cessation of exercise, termed ‘heart 2
Department of Physiology, Vallabhbhai Patel Chest Institute,
rate recovery’ (HRR), reflects parasympathetic reacti- University of Delhi, Delhi, India
vation and an abnormally delayed (12 beats) decline
Corresponding author:
implies its dysfunction.5,6 It has been shown to predict
Sunil K Chhabra, Department of Cardiorespiratory Physiology,
all-cause and cardiac mortality in population studies Vallabhbhai Patel Chest Institute, University of Delhi, Delhi
and in patients with cardiac disease.6–10 Though it has 110 007, India.
not been systematically investigated, a delayed HRR Email: skchhabra@mailcity.com
118 Chronic Respiratory Disease 10(3)

of cardiac mortality.14–16 It is also associated with excluded. All the patients had been attending the out-
atherosclerosis17 and diastolic heart failure.18 In a patient clinic and were on treatment with inhaled
recent retrospective study, it was observed that CI long-acting beta agonists (LABAs, salmeterol/formo-
improved after lung volume reduction surgery in terol), tiotropium and corticosteroids according to
patients with COPD.19 A prospective study to docu- severity.20 Eleven non-smoker healthy males in the
ment and characterize CI has not been carried out in matched age range and not known to have any chronic
COPD. disease or any medication were included as controls
Stewart et al.2 demonstrated AD in patients with from among the hospital staff and attendants of the
hypoxemic COPD, and later, we reported it even in patients.
normoxemic patients and in those with mild COPD.3
As both an abnormal HRR and CI reflect AD, we Initial assessment
hypothesized that an abnormal HRR and CI may
After blood counts, routine biochemistry panel, plain
occur in COPD. Being established as independent
chest radiograph (posteroanterior view) and a 12-lead
predictors of cardiac mortality, these markers of AD
standard electrocardiogram, the patients underwent
may find application as risk stratification tools in
lung function tests including spirometry and measure-
COPD and therefore need to be characterized. The
ment of single-breath diffusion capacity for carbon
prevalence and predictors of these markers in COPD
monoxide (DLCO) and a 6-min walk test. Dyspnoea was
and their association with severity of the disease have
graded according to the Modified Medical Research
not been evaluated. With these objectives, the present
Council scale. The severity of COPD was staged
study was carried out.
according to the GOLD criteria.20 Body mass index, air-
flow obstruction, dyspnoea and exercise capacity
Materials and methods (BODE) index was calculated.21 The BODE index
The study was conducted in an outpatient setting at the scores each of these components in an ordinal manner
Vallabhbhai Patel Chest Institute (New Delhi, India). It and a total composite score is calculated. As it is not
was approved by the Ethics Committee of Vallabhbhai scored on a ratio/interval scale, we did not use it as a
Patel Chest Institute (MD Pulmonary Medicine project continuous variable but divided the patients into two
3/2008). A total of 39 stable patients with a clinical categories, above and below the 50th percentile; these
diagnosis of COPD based on Global Initiative for were labelled as ‘low’ and ‘high’ BODE index groups,
Chronic Obstructive Lung Disease (GOLD) criteria20 respectively.
were included after a written informed consent. Inhaled bronchodilators were withdrawn 24 hours
before investigations but corticosteroids were allowed.
Subjects Spirometry was performed on a dry rolling seal spi-
rometer (Benchmark lung function equipment, P.K.
We intended to include patients with COPD due to
Morgan, Kent, UK) according to current recommenda-
their smoking habit. COPD in women in India is more
tions.22 DLCO was corrected for alveolar volume to
often due to biomass fuel exposures than due to smok-
obtain the Krogh’s constant (KCO). The 6-minute walk
ing and considering our hospital attendance patterns, it
test was performed in accordance with the American
was felt that sufficient numbers of female smokers with
Thoracic Society guidelines.23 The 6-minute walk
COPD may not be found within the study period.
distance (6MWD) was used to calculate the volume
Therefore, we selected only male patients with a his-
of oxygen consumed and the exercise workload to be
tory of smoking of 10 pack-years. Consecutive stable
applied. The maximum HR (MHR) on ergometry was
patients were screened for inclusion in the study.
calculated (MHR ¼ 220  age). The target HR (THR)
Patients with chronic respiratory failure (pulse oxime-
was set at 80% of MHR.
try saturation < 90% and partial pressure of oxygen
(PaO2) < 80 mm Hg with or without partial pressure
of carbon dioxide (PaCO2) > 45 mm Hg), recent acute Leg ergometry
exacerbation (in the previous 4 weeks), diabetes melli- After 4 hours post-prandial and a 30-minute rest, a 3-
tus, evidence of any systemic disease including hyper- minute stepwise test of increasing intensity of exer-
tension or coronary artery disease and any neurological cise was performed by leg ergometry on a manually
disorder or musculoskeletal limitation that could pre- braked cycle (Rehab Trainer 881E, Monark Exercise
vent successful performance of leg ergometry were AB, Sweden). It was supervised by the same operator
Gupta et al. 119

Vishal Bansal. The patients were instructed to pedal at of variance. Chi-square test was used to compare the
frequencies of 50–55 cycles/min. In this range, the association between abnormal HRR and CI. Correlation
cycle delivered a constant workload. This frequency analysis was carried out to determine Pearson’s correla-
was maintained throughout the exercise and in the tion coefficient. Multiple logistic regression was carried
cooling phase. The predicted maximal oxygen con- out to identify significant predictors of HRR/CI after
sumption (VO2) was calculated from the 6MWD and adjusting for other variables. Abnormal/normal HRR
the workload to be applied was obtained from equiva- and presence/absence of CI were the dependent binary
lent charts (Monark) available for cycle ergometer variables and age, pack-years of smoking, post-
workload estimation. After a 3-minute warm-up period bronchodilator forced expiratory volume in 1 second
of unloaded pedalling (0 watts), the workload was (FEV1) percentage predicted, percentage predicted
increased to the calculated level and maintained for DLCO and percentage predicted KCO were the predictor
3 minutes. If the THR was not achieved, the load was variables. A two-tailed p value of <0.05 was considered
further increased in steps of 10 watts every 3 minutes statistically significant.
until it was achieved or patient reported fatigue, chest
pain or dyspnoea. At this point, the subject continued
to pedal for 20 seconds to ensure maintenance of a con- Results
stant HR (17: + 5 beats per minute) in a steady state. The clinical characteristics and baseline laboratory
This was followed by the recovery phase, where the parameters are shown in Table 1. Patients with severe
load was removed and the patient continued unloaded COPD had a lower body mass index as compared to
pedalling to cool down for another 3 minutes. HR was those with mild COPD (p < 0.01), while age, smoking
recorded at baseline, throughout the exercise and dur- intensity and duration of disease were similar across
ing the cooling-down period on a Nellcor pulse oxi- categories by GOLD severity. There was a significant
meter (Model N 560, Nellcor Puritan Bennett, progressive deterioration of lung function parameters
Pleasanton, California, USA). The HR recorded repre- and BODE index with increasing severity.
sented an average of last six beats. The HR was read off The duration of exercise (in seconds) was
from the display at specific time points as required. 444.7 + 173.7 in patients and 637.7 + 229.3 in controls.
HRR was calculated as the difference between the The HR response during exercise in patients and controls
HR at peak exercise and at first minute into the cool- is shown in Table 2. The resting HR was not different
ing period. A cut-off point of 12 beats was taken as (p > 0.05), but the latter achieved a higher peak HR
an abnormal HRR.6 The utilization of HR reserve at (p < 0.001). The CRI and HRR were significantly
peak exercise was expressed as the chronotropic reduced in patients (p < 0.01 and p < 0.0001, respec-
response index (CRI)15 and was calculated as follows: tively). Only 13 patients could achieve the THR, 6 of the
CRI ¼ ððpeak HR  resting HRÞ  100Þ=ðð220  ageÞ 10 mild and only 2 of the 12 severe COPD patients
ðresting HRÞÞ. CRI is independent of age and exercise (p ¼ 0.05). Majority of the patients (22, 56%) stopped
capacity, and independently predictive of mortality.15 exercise due to leg fatigue and only four stopped because
CI was diagnosed if there was a failure to reach the of dyspnoea. All the normal subjects reached the THR.
THR with a CRI below 80.16,24 Figure 1 shows the HRR and CRI across GOLD
stages. The HRR in mild COPD was 17.8 + 11.67
beats, 12.7 + 8.86 beats in moderate and 3 + 4.97 beats
Statistical analysis in severe COPD (p ¼ 0.09). The CRI in these patients
Statistical analysis was carried out using SPSS 16.0 was 49.3 + 15.89, 46.96 + 13.45 and 37.3 + 10.93
(SPSS Inc., Chicago, Illinois, USA) and Graph Pad (p ¼ 0.08), respectively. Comparison of patients with
Prism 4.01 (GraphPad Software, Inc., La Jolla, Califor- low and high BODE index scores (Figure 2) revealed
nia, USA) softwares. The data were examined for nor- that the latter had a lower HRR (15.42 + 10.15 and
mality of distribution by Shapiro–Wilk’s test and for 9.13 + 5.45 beats, respectively, p < 0.05) and a lower
homogeneity of variance by Levene’s test. Data on CRI (49.19 + 14.28 and 37.22 + 10.08, respectively,
continuous variables are presented as mean + SD. Stu- p < 0.01). The HRR was significantly correlated with
dent’s unpaired t test/Mann–Whitney’s U test was used CRI (r ¼ 0.54, p < 0.001).
for independent group comparisons. Comparison of Of them, 29 (74.4%) patients but none of the con-
data on continuous variables among multiple groups trols had an abnormal HRR (p < 0.0001). CI was found
of patients was carried out by Kruskal–Wallis analysis in 27 (69.2%) patients but in only one control subject
120 Chronic Respiratory Disease 10(3)

Table 1. Clinical characteristics and lung function across GOLD categories.


Stage I, mild Stage II, moderate Stage III, severe
COPD (n ¼ 10) COPD (n ¼ 17) COPD (n ¼ 12)
Age (years)a 57.4 + 9.08 60.88 + 6.24 55.33 + 5.25
BMI (kg/m2)b 24.82 + 5.46 21.05 + 3.58 18.88 + 2.46
Duration of disease (years) 4.0 + 1.63 9.35 + 6.70 9.5 + 5.6
Smoking (pack-years)a 25.70 + 11.99 33.24 + 6.73 30.96 + 10.18
Haemoglobin (g/dl)a 13.61 + 1.47 13.29 + 1.23 13.40 + 1.67
FEV1 percentage predicted (post-bronchodilator)c 94.30 + 10.91 61.41 + 8.60 39.42 + 5.50
Percentage predicted DLCOc 87.70 + 22.89 58.65 + 18.61 55.00 + 28.43
Percentage predicted KCOc 94.70 + 19.55 73.29 + 21.95 69.17 + 33.81
BODE index scorec 0.6 + 0.84 2.41 + 1.33 4.50 + 0.80
GOLD: Global Initiative for Chronic Obstructive Lung Disease; COPD: chronic obstructive pulmonary disease; BMI: body mass index;
DLCO: diffusion capacity for carbon monoxide; KCO: Krogh’s constant; BODE index: body mass index, airflow obstruction, dyspnoea
and exercise capacity index; FEV1: forced expiratory volume in 1 second.
a
p > 0.05 (not significant).
b
p < 0.001.
c
p < 0.0001.

Table 2. HR response during exercise in patients and


controls.
Patients Controls
(n ¼ 39) (n ¼ 11)
Resting HR (bpm)a 78.62 + 11.9 82.00 + 9.07
Peak HR (bpm)b 115.95 + 13.51 139.00 + 7.29
Heart rate recovery 13.0 + 9.1 23.9 + 5.85
(beats)c
Chronotropic response 44.59 + 13.99 61.15 + 5.14
indexd
HR: heart rate; bpm: beats per minute.
a
p > 0.05 (not significant).
b
p < 0.001.
c
p < 0.0001.
d
p < 0.01.
Figure 1. HRR and CRI according to GOLD categories of
severity; p values of HRR ¼ 0.09 and CRI ¼ 0.08. HRR is
expressed in beats in first minute, CRI is expressed in per-
centage. HRR: heart rate recovery; CRI: chronotropic
(p < 0.0001). Majority of the patients (33, 84.6%) had
response index; GOLD: Global Initiative for Chronic
at least one of the autonomic responses as abnormal. Of Obstructive Lung Disease.
the 39 patients, 23 (58.9%) had both abnormal HRR
and CI, 6 (15.4%) had isolated abnormal HRR, and 4
(10.3%) had isolated CI. Only six patients (15.4%) had patients with severe COPD (p < 0.05). Four of the six
no abnormality in the two exercise responses. subjects who had normal HRR and did not have CI
Figures 3 and 4 show the proportions of subjects belonged to the mild group. Abnormal HRR was
with abnormal HRR and CI across GOLD and BODE observed in 16 of 24 (66.7%) patients in the low and
categories, respectively. The frequency of patients 13 of 15 (86.7%) patients in the high BODE index
with abnormal HRR increased with increasing GOLD groups (p > 0.05). CI was significantly more frequent
severity: 5 of 10 (50%) in mild, 13 of 17 (70%) in in the high BODE index group (14 of 15 patients –
moderate and 11 of 12 (92%) in patients with severe 93.3%) compared to 13 of 24 (54%) patients in the
COPD (0.05 > p < 0.1). While 4 of 10 (40%) in mild low BODE index group (p < 0.01). All the six subjects
COPD had CI, the proportion of CI increased to 12 of who had normal HRR and no CI were in the low
17 (70.5%) in moderate and to 11 of 12 (92%) in BODE index group.
Gupta et al. 121

increasing with higher BODE index. Patients with


abnormal HRR had greater airways obstruction and
a lower diffusion capacity compared to those with a
normal HRR. After adjusting for age, smoking history
and airways obstruction, only a reduced diffusion
capacity predicted an abnormal HRR, though weakly.
No clinical or lung function parameter predictor of
abnormal CI was identified.
The first minute rapid decline in HR following
exercise-induced tachycardia is largely due to para-
sympathetic restoration and a slower decrease was first
shown to mark an increased risk of mortality by
Schwartz et al.25 This was subsequently confirmed in
other disease states independent of exercise conditions,
Figure 2. HRR and CRI in patients with low and high peak and resting HR.6–10 Though not specifically
BODE index scores (þ indicates p < 0.05, * indicates
investigated in COPD, an abnormal HRR has been
p < 0.01). HRR is expressed in beats in first minute, CRI
is expressed in percentage. HRR: heart rate recovery; noted in studies on cardiac responses to exercise in
CRI: chronotropic response index; BODE: body mass such patients. Chick et al. observed prolonged tachy-
index, airflow obstruction, dyspnoea and exercise cardia and delayed recovery after exercise that was
capacity. independent of FEV1.11 In a retrospective analysis of
data in a heterogeneous group of patients, including
Significant inverse correlations were observed COPD, Seshadri et al.12 observed that abnormal HRR
between HRR and age (r ¼ 0.41, p < 0.01) and was found with increasing frequency as FEV1
pack-years of smoking (r ¼ 0.35, <0.05), while posi- decreased. In another retrospective study, Lacasse
tive correlations were found between HRR and percent- et al.13 found an association between abnormal HRR
age predicted DLCO (r ¼ 0.37, p ¼ 0.05) and percentage and increased risk of all-cause mortality among
predicted KCO (r ¼ 0.31, p < 0.05). Correlations were patients with an FEV1 <50% predicted. Ba et al.26 fol-
not significant between HRR and post-bronchodilator lowed the HR decay after maximal cycling exercise to
FEV1 percentage predicted (p > 0.05). CRI did not show study metabolic factors affecting the recovery in
significant correlations with any of the above variables patients with COPD and identified greater lactic acid
(p > 0.05). On multiple logistic regression, KCO remai- production and/or hypoxaemia as being associated
ned a significant, though weak predictor of abnormal with slower recovery. These factors determine the
HRR, after adjusting for age, smoking intensity and recovery later on after exercise. They did not study
post-bronchodilator FEV1. It explained only 22% of the autonomic mechanisms of recovery that operate almost
variability in HRR. exclusively in the first minute. There are no previous
Comparison of clinical characteristics between reports of CI in COPD. Multiple definitions and lack
patients with abnormal/normal HRR and present/ of standardized criteria likely account for the wide
absent CI is shown in Table 3. Patients with an abnor- range in reported prevalence of CI in different disease
mal HRR were older and had poorer lung function and states.27 The most often used criteria to diagnose CI is a
lung diffusion parameters as compared to those with a failure to reach an arbitrary percentage (usually 80%)
normal HRR. On the other hand, patients with CI had of the age-predicted maximal HR or a failure to attain
higher BODE index scores (p < 0.05) as compared to 80% of the HR reserve from rest to peak exercise
those without CI. (CRI).16,24,27 We defined CI by a strict criteria requir-
ing both these conditions to be met.

Discussion
We found that nearly 85% of normoxemic patients of
Implications for clinical practice and future
COPD have either abnormal HRR or CI or both on research
exercise. These tended to occur together and were AD was first reported in advanced COPD with
observed at all levels of severity, becoming more fre- respiratory failure2 and later abnormalities of HR
quent with higher GOLD stages and significantly variability were also documented in patients without
122 Chronic Respiratory Disease 10(3)

Figure 3. Proportions of subjects with normal and abnormal HRR across GOLD severity and BODE index categories.
HRR: heart rate recovery; BODE: body mass index, airflow obstruction, dyspnoea and exercise capacity; GOLD: Global
Initiative for Chronic Obstructive Lung Disease.

Figure 4. Proportions of subjects in the absence and presence of CI across GOLD severity and BODE index categories.
BODE: body mass index, airflow obstruction, dyspnoea and exercise capacity; CI: chronotropic incompetence; GOLD:
Global Initiative for Chronic Obstructive Lung Disease.

hypoxemia.28 Although Stewart et al.2 found abnorm- that AD develops early in COPD and becomes more
alities largely in the parasympathetic limb, Stein frequent as the disease advances. This is likely to be
et al.28 observed a mixed sympathetic and parasympa- a significant complication as cardiac events may be
thetic modulation of HR in COPD. From our labora- responsible for mortality even in mild COPD.1,29
tory studies, we reported that both parasympathetic CI has been shown to be associated with carotid
and sympathetic limbs of the cardiac autonomic intima–media thickness17 and diastolic dysfunction18
control were affected even in patients without hypox- in cardiac patients and may thus be a marker of cardi-
aemia and in mild COPD.3 In the present study, the ovascular involvement in COPD. An abnormal HRR
observation of an abnormal HRR suggests parasym- and CI may therefore predict a bad cardiac prognosis
pathetic dysfunction, while the findings of CI raise the in COPD as these do in other diseases.6–10,14–16 This
possibility of an impaired sympathetic response. The appears likely as both indices were associated with
present study also confirms our earlier observations increasing BODE index, a well-recognized predictor
Gupta et al. 123

Table 3. Comparison of clinical characteristics between patients with abnormal/normal HRR and present/absent CI.
HRR CI
Abnormal (n ¼ 29) Normal (n ¼ 10) Present (n ¼ 27) Absent (n ¼ 12)
Age 59.62 + 6.30a 54.40 + 8.04 57.70 + 6.35a 59.58 + 8.62
Duration of disease 8.86 + 6.12b 5.60 + 4.43 7.78 + 5.04 8.58 + 7.62
Pack-years 31.11 + 8.79b 29.13 + 12.12 30.84 + 8.68 30.06 + 11.88
Post-bronchodilator FEV1 58.93 + 21.16a 75.10 + 22.66 58.41 + 21.13 73.58 + 22.53
Percentage predicted DLCO 58.55 + 22.25c 83.60 + 29.18 61.30 + 28.64 73.25 + 18.26
Percentage predicted KCO 72.00 + 23.42a 93.50 + 31.66 73.78 + 30.21 85.92 + 16.13
BODE index score 2.90 + 1.78b 1.70 + 1.70 3.00 + 1.88a 1.67 + 1.30
HRR: heart rate recovery; CI: chronotropic incompetence; DLCO: diffusion capacity for carbon monoxide; KCO: Krogh’s constant;
BODE index: body mass index, airflow obstruction, dyspnoea, and exercise capacity index; FEV1: forced expiratory volume in 1 second
a
p < 0.05.
b
p > 0.05 (not significant).
c
p < 0.01.

of mortality in COPD,21 and with increasing GOLD is unlikely to explain the delayed parasympathetic
stage, a classification based on a reduced FEV1, that restoration after exercise as these drugs were stopped
is a marker for cardiovascular mortality.30 Therefore, 24 hour earlier. Whether there is any subsensitivity
abnormal HRR and CI may be useful tools for risk stra- of cardiac muscarinic receptors in COPD that may
tification in COPD. This needs to be explored in long- explain the abnormal HRR is not known. Furthermore,
itudinal studies. as anticholinergic drugs will delay HRR by their phar-
Among the commonly measured clinical and physio- macological action, the cardiac safety of these drugs
logical parameters, only a reduced diffusion capacity may be questioned. Indeed, this has been a subject of
predicted an abnormal HRR, though weakly, and none several investigations though the results have been
predicted abnormal CI. It suggests that though AD is inconclusive.35 Recently, Kawasaki et al.24 suggested
common in COPD, it probably develops independently that a post-synaptic downregulation of b-adrenergic
of pulmonary involvement and may therefore be looked receptors in the sino-atrial node following sympathetic
upon as an extrapulmonary manifestation. activation may be responsible for CI in cardiac
patients. We speculate that similar to COPD, regular
use of LABAs may produce a downregulation of b-
Possible mechanisms for observed cardiac receptors resulting in CI.
responses
The underlying mechanisms of impaired cardiac
autonomic control during exercise are not known. Sus- Strengths and limitations
tained tachypnoea on exercise in patients with COPD11 Abnormal HRR and CI are well-known predictors of
may impair parasympathetic recovery, a response adverse cardiac prognosis. Although in recent years,
known to be enhanced by slower breathing. Reduced there has been an increasing recognition of a signifi-
baroreflex sensitivity in COPD is associated with an cant cardiovascular risk in patients with COPD, the
impaired sympathetic response.31 On the other hand, prevalence and predictors of these markers and their
increased sympathetic activity has been shown at rest association with severity have not been evaluated in
in COPD32,33 that may counter parasympathetic these patients. This is the first study to investigate these
restoration. However, we did not find any difference aspects of COPD. The study has identified markers that
in the resting HR in patients and controls, and also may be useful in risk stratification in COPD. Similar to
between patients who had and did not have abnormal their application in patients with coronary artery dis-
HRR and CI arguing against increased sympathetic ease, abnormal HRR and CI may identify patients with
activity at rest. Furthermore, Imai et al.34 have also COPD with increased risk of cardiac mortality. In view
shown that excessive sympathetic nervous system of lack of standard definitions and methods of comput-
activity does not play a dominant role in immediate ing CI,27 we used a stricter definition as pointed out
HRR. An incomplete washout of anti-cholinergic drugs above to lend greater assurance to our observations.
124 Chronic Respiratory Disease 10(3)

The study is limited by being gender-specific; the due to ventilator limitations and lung mechanics
reasons for non-inclusion of female subjects were alterations during exercise. In view of the above lim-
explained above. Smoking itself may be a factor in itations, our observations on CI may be considered as
causing AD.36 Comparison of responses in patients preliminary and require confirmation.
with non-smoking COPD is therefore required to
determine the contribution of COPD itself. This was Conclusions
not part of our study design. It may, however, be
pointed out that all the patients in the present study To conclude, abnormal HRR and CI are observed dur-
were ex-smokers. The only way autonomic balance ing exercise in a majority of patients with COPD and
can be directly evaluated is by measuring the HR tend to occur together. These occur even in early
variability. If we had also measured HR variability stages of the disease and increase in frequency with
during and after exercise, it would provide direct evi- increasing GOLD-defined severity and the BODE
dence of autonomic imbalance on exercise. Finally, index. Clinical and lung function parameters are poor
the clinical implications are only hypothetical. The predictors of these phenomena, with only a reduced
present study was cross-sectional in design and, there- diffusion capacity weakly predicting an abnormal
fore, outcome measures such as mortality or arrhyth- HRR and no factor predicting CI. Therefore, their
mias could not be built into the protocol. These need occurrence cannot be inferred and these need to be
confirmation in a longitudinal study. experimentally documented. As these indices of AD
Factors such as exercise levels, medication, cardio- are established markers of poor cardiac prognosis,
vascular fitness, neuromuscular limitations and exer- these measurements may find application as tools for
cise modality may also modulate the chronotropic risk stratification in COPD. The mechanisms underly-
response and thus the observed CI may not necessa- ing the pathogenesis of these abnormalities are not
rily represent sympathetic dysfunction. It is important known and can only be speculated. The long-term sig-
to take into account the patient’s level of effort and nificance of these abnormal responses needs to be
reasons for terminating the exercise test before con- evaluated in longitudinal studies.
cluding that a patient has CI.27 The respiratory
exchange ratio is a more definitive and objective mea- Conflicting of Interests
sure of physiological level of effort and may have pro- The authors declared no conflicts of interest.
vided a more definite confirmation of maximal
exercise. Symptom-limited exercise also, however, Funding
ensures reasonably that maximal levels are reached. This research received no specific grant from any funding
Thus, it is likely that inadequate metabolic activity agency in the public, commercial or not-for-profit sectors.
was the cause of a reduced chronotropic response.
Another important factor is the method of exercise. References
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