European Heart Journal Advance Access originally published online on April 15, 2008
European Heart Journal 2008 29(15):1803-1806; doi:10.1093/eurheartj/ehn165
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org
Exercise testing in asymptomatic subjects: from diagnostic test to prognostic tool?
Paolo Palatini*
Department of Clinical and Experimental Medicine, University of Padova, 35128 Padova, Italy
* Corresponding author. Tel: +39 049 8212278, Fax: +39 049 8754179, Email: palatini{at}unipd.it
The opinions expressed in this article are not necessarily those
of the Editors of the
European Heart Journal or of the European
Society of Cardiology.
 |
Introduction
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Exercise testing historically has been considered a useful modality
for diagnosing coronary heart disease (CHD). However, false-positive
tests are common in asymptomatic adults, especially among women,
and there is no evidence at this time to recommend exercise
electrocardiography as a routine screening test. Thus, conventional
guidelines recommend against the use of exercise testing for
risk assessment in asymptomatic subjects with a <10% pre-test
likelihood of underlying CHD.
1 However, a number of recent studies
have extended our knowledge on the prognostic significance of
exercise testing and suggest that the prognostic value of this
test may have been underestimated. Measures other than those
directly related to myocardial ischaemia have proved to be strong
predictors of mortality.
1 Among these, the chronotropic response
to exercise and assessment of heart rate during recovery have
gained much credit.
1
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Chronotropic response to exercise
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In 1975, Ellestad and Wan showed that the inability of heart
rate to increase appropriately during incremental exercise was
associated with a greater risk of adverse cardiac events in
the next 5 years than was ST-segment depression.
2 Many further
studies have confirmed this finding, showing that chronotropic
incompetence is of prognostic value in asymptomatic men
3,4 or
symptomatic referral populations,
5,6 independent of traditional
risk factors, other measures derived from exercise testing,
or thallium ischaemia, and that it is also independently predictive
of death in patients taking β-blockers.
4,7 In a recent
analysis of the Paris Prospective Study I, a low heart rate
response to exercise proved to be a powerful predictor of sudden
death and all-cause mortality.
4 This finding was particularly
striking because subjects who achieved <80% of their predicted
maximum heart rate were excluded from the analysis. A major
challenge in using chronotropic response to exercise testing
is determining how best to characterize it. A number of chronotropic
indexes have been used in the literature, but there is no general
agreement on which measure provides the best prognostic information.
1 An impaired increment of heart rate from rest to an age-adjusted
predicted submaximal workload, which was based on maximal heart
rate, has been found to be associated with an increased risk
of incident CHD.
8 A more common approach is to measure peak
heart rate and the change in heart rate during exercise. However,
it is known that peak heart rate decreases with increasing age
and thus the percentage of age-based predicted maximal heart
rate should be calculated. Inability to achieve at least 85%
of age-predicted maximum heart rate has been defined as chronotropic
incompetence and predicts an increased mortality risk.
5 However,
the validity of this measure has been questioned on the grounds
that several other confounding factors may affect the chronotropic
response to exercise. Therefore, the concept of heart rate reserve,
defined as the difference between maximal predicted heart rate
and resting heart rate, was introduced, and a marker of abnormal
heart rate response during exercise was defined as a chronotropic
index. The calculation of the chronotropic index takes into
account age, physical fitness, resting heart rate, and the age-predicted
maximum heart rate.
1 Recent studies have suggested that this
measure is a better predictor of mortality than the more traditional
percentage of age-predicted heart rate,
9 and some laboratories
have identified a threshold value <80% to define chronotropic
incompetence.
5,9 However, according to Elhendy and colleagues,
6 the use of 85% of age-predicted maximum heart rate (220 bpm
minus the patient's age) was superior to the chronotropic index
as an independent predictor of all-cause mortality in 3221 patients
with known or suspected CHD, whereas the chronotropic index
was superior in predicting cardiac events. Therefore, according
to these authors, both parameters should be used, at least in
the coronary patient, because they provide complementary information.
Another measure of chronotropic incompetence recently proposed
is the calculation of the slope of heart rate increase during
exercise, an approach that uses all of the heart rate data from
rest to maximal workload.
3 In 1387 men free of coronary artery
disease, Savonen and colleagues measured heart rate at rest
and during a maximal, symptom-limited bicycle exercise test
at 20, 40, 60, 80, and 100% of maximal workload.
3 The slope
of heart rate increase during the exercise test was steeper
in survivors when compared with those who died due to cardiovascular
events during follow-up, and the difference in the steepness
of heart rate slope between the groups was the strongest at
interval 40–100% (
P <0.001). In that study,
3 the 40–100%
slope of heart rate increase was a better predictor of cardiovascular
death than heart rate reserve (heart rate increase from rest
to maximum) or a variable quantifying a submaximal heart rate
increment.
8 The superiority of this index was attributed to
the fact that the 40–100% heart rate slope depends chiefly
on the response of the sympathetic nervous system activity and
does not include the early portion of the slope which reflects
mainly the withdrawal of the vagal tone. This suggests that
the main factor mediating the association between chronotropic
incompetence and mortality is a reduced ability to increase
sympathetic activity.
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Treadmill vs bicycle ergometry
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An important limitation of the studies which focused on the
prognostic value of heart rate assessment during exercise is
the lack of objective data for establishing normalcy limits
for the chronotropic index or other measures of chronotropic
incompetence. Furthermore, assessment of chronotropic response
may vary according to whether exercise is performed on a treadmill
or on a cycle ergometer. In the USA, treadmill exercise is the
preferred modality and most results were obtained with treadmill
testing using the Bruce protocol.
10 The use of bicycle ergometry
and/or different exercise protocols may lead to different results.
Several studies have demonstrated that bicycle ergometry tends
to produce a lower peak VO
2 compared with the treadmill because
untrained subjects usually terminate cycle exercise at a 10–20%
lower peak work rate due to muscle fatigue.
11 In a group of
patients with known or suspected CHD, Rahimi
et al. assessed
the chronotropic response to either bicycle (
n = 105) or treadmill
(
n = 106) exercise.
12 They found that the rate of chronotropic
incompetence (chronotropic index <0.8) was significantly
lower in treadmill than in bicycle (60 vs 76%,
P < 0.001)
tests. In addition, despite a higher peak heart rate, patients
stressed by the treadmill had a slower drop in heart rate during
the early phase of recovery with a significantly higher rate
of abnormal response (37% for treadmill vs 19% for bicycle,
P = 0.004). These ergometer-related differences make it even
more difficult to identify universal normalcy limits for the
various measures of chronotropic response to exercise.
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Heart rate recovery
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The evaluation of the heart rate changes which occur during
exercise testing includes the assessment of heart rate during
the recovery period. In normal asymptomatic subjects, there
is a rapid decline in heart rate during the first 30 s after
exercise which is more pronounced in physically trained individuals.
13 This rapid fall in heart rate has been attributed to vagal reactivation
since it can be prevented by atropine administration.
13 Because
of the strong relationship between vagal tone and cardiac risk,
the heart rate fall after exercise has been evaluated in several
cohorts of asymptomatic subjects or subjects undergoing stress
testing as part of a population-based epidemiological study
and has been found to have prognostic value in these subjects.
14,15 The association persisted after accounting for traditional risk
factors. In 3554 asymptomatic adults between the ages of 50
and 75 years an abnormal heart rate recovery, defined as a failure
of the heart rate to decrease by more than 12 bpm during the
first minute after exercise, provided prognostic information
for global mortality over and above the Framingham risk score
or the European risk score.
14 In 2428 subjects, 63% of whom
were free from disease, Cole and colleagues,
15 using the same
criteria, found that a delayed decrease in heart rate after
exercise was a powerful predictor of mortality independent of
exercise capacity, myocardial perfusion defects, or chronotropic
response during exercise. Although a potential drawback with
the measurement of heart rate recovery for prognosis is the
modality of the cool-down period, which affects the diagnostic
sensitivity of the test, the above results show that the assessment
of heart rate during the recovery period also provides important
prognostic information. However, it is not well known whether
assessments of heart rate during exercise and during the recovery
period explore the same pathophysiological mechanism or if the
two measures provide complementary information. Recently, Myers
et al. examined the heart rate changes during treadmill exercise
and recovery in 1910 male veterans referred for exercise testing
for clinical reasons.
16 Chronotropic incompetence was defined
as the inability to achieve 80% of heart rate reserve during
exercise, and abnormal heart rate recovery was defined as a
decrease of <22 bpm at 2 min in recovery. Both chronotropic
incompetence and heart rate recovery predicted cardiovascular
mortality in this sample. Chronotropic incompetence was a stronger
predictor of cardiovascular mortality than heart rate recovery,
but risk was most powerfully stratified by the two parameters
together.
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Pathogenetic mechanisms
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Although several large-scale studies have established the prognostic
value of the chronotropic response during exercise, the underlying
mechanisms are not very clear. As mentioned above, the increase
in heart rate during exercise is a reflection of decreased parasympathetic
tone and increased sympathetic tone. Chronotropic incompetence
is generally believed to reflect an underlying autonomic nervous
system imbalance. An abnormal modulation of the autonomic tone
or a downregulation of β receptors are more frequent in
advanced age and can be present in several clinical settings
including dysfunction of the sinus or atrio-ventricular node,
severe coronary artery disease, increased left ventricular mass,
or left ventricular dilation and dysfunction.
1 Individuals with
abnormal autonomic heart rate responses may be more predisposed
to life-threatening ventricular arrhythmias and sudden death
regardless of the presence or extent of CHD.
17 Impaired chronotropic
response to exercise, independent of the established risk factors,
has been found also to be associated in asymptomatic individuals
with carotid atherosclerosis, which could contribute to increased
incidence of cardiovascular diseases in subjects with chronotropic
incompetence.
18 As atherosclerosis of the carotid arteries is
often associated with aortic atherosclerosis and impaired aortic
distensibility, the sensitivity of aortic baroreceptors may
also be influenced.
19 Patients with impaired chronotropic response
to graded exercise have also been found to have endothelial
dysfunction, enhanced systemic inflammation, and higher N-terminal
pro-brain natriuretic peptide (NT-proBNP) concentrations.
20 Endothelial dysfunction and markers of inflammation are closely
involved in the control of plaque stability and thrombogenicity
and are also predictors of adverse outcome.
20 The influence
of inflammation on autonomic nervous system activity is largely
unknown, but it is possible that inflammatory cytokines might
exert detrimental effects on the autonomic control. However,
it is difficult to establish whether these factors are the primary
abnormality underlying chronotropic incompetence or if there
is a common pathway that results in abnormalities of both biomarkers
and chronotropic response to exercise. A genetic link between
the heart rate response to exercise and cardiovascular risk
has recently been reported.
21
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Conclusion
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Shortcomings in exercise electrocardiography have led some to
suggest that the principal place for the exercise test is in
the assessment of prognosis. Tests capable of identifying high-risk
populations can improve the appropriate prescription of life-saving
drugs such as aspirin, statins, or β-blockers. Chronotropic
incompetence has been shown to predict adverse outcome in asymptomatic
subjects over and above the traditional risk factors and other
measures derived from exercise testing. However, there is no
evidence as yet that gaining this knowledge leads to improved
patient management. Whether the chronotropic response to exercise
can be modified in a clinically meaningful way is not known,
and it is not even known whether pursuing aggressive risk factor
changes in asymptomatic subjects with chronotropic incompetence
is beneficial. Only randomized trials can provide definite information
on whether application of clinical strategies based on non-electrocardiographic
data drawn from exercise testing can improve outcome in asymptomatic
adults or cardiac patients. Sources of variability and protocol
standardization remain contentious issues. Improvement of the
present knowledge could be achieved by standardizing the protocol
of exercise testing, including the recovery period, across laboratories.
To identify the most meaningful measure of chronotropic incompetence,
all chronotropic parameters should be calculated during and
after exercise.
Conflict of interest: none declared.
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Footnotes
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The opinions expressed in this article are not necessarily those
of the Editors of the
European Heart Journal or of the European
Society of Cardiology.
|
References
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Introduction
Chronotropic response to...