Download 096 Heart rate reserve in ACHD - Diller - Circ 2006

Journal of the American College of Cardiology
© 2006 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 48, No. 6, 2006
ISSN 0735-1097/06/$32.00
doi:10.1016/j.jacc.2006.05.051
Pediatric Cardiology
Heart Rate Response During Exercise Predicts
Survival in Adults With Congenital Heart Disease
Gerhard-Paul Diller, MD,*† Konstantinos Dimopoulos, MD,* Darlington Okonko, BSC, MRCP,†
Anselm Uebing, MD,* Craig S. Broberg, MD,* Sonya Babu-Narayan, MRCP,* Stephanie Bayne, BSC,*
Philip A. Poole-Wilson, MD, FRCP,† Richard Sutton, DSCMED,‡ Darrel P. Francis, MA, MRCP,§
Michael A. Gatzoulis, MD, PHD*
London, United Kingdom
To assess the prognostic value of heart rate response to exercise in adult congenital heart
disease (ACHD) patients.
BACKGROUND An abnormal heart rate response to exercise is related to autonomic dysfunction and may have
prognostic implications in ACHD.
METHODS
We identified 727 consecutive ACHD patients (mean age [⫾ SD] 33 ⫾ 13 years) with
varying diagnoses and without pacemakers. Peak oxygen consumption (peak VO2), resting
heart rate, and the increase in heart rate from resting level to peak exercise (“heart rate
reserve”) were measured. We also quantified the decrease in heart rate (“heart rate recovery”)
after cessation of exercise.
RESULTS
During a median follow-up of 28 months, 38 patients died. Lower values of heart rate reserve,
peak heart rate, heart rate recovery, and peak VO2 (p ⬍ 0.01 for each) were associated with
increased mortality in univariate analysis. Furthermore, heart rate reserve predicted mortality
independently of antiarrhythmic therapy, functional class, and peak VO2. Stratifying patients
by diagnostic groups revealed that a lower heart rate reserve was also associated with a greater
risk of death in patients with complex anatomy, Fontan circulation, and tetralogy of Fallot
(p ⬍ 0.05 for each).
CONCLUSIONS An abnormal heart rate response to exercise identifies ACHD patients with a higher risk of
mortality in the midterm, even after accounting for antiarrhythmic medication and exercise
capacity. Heart rate reserve is a simple and inexpensive way to identify ACHD patients at
higher mortality risk. (J Am Coll Cardiol 2006;48:1250 – 6) © 2006 by the American
College of Cardiology Foundation
OBJECTIVES
With advances in surgical management, an increasing number of patients with congenital heart disease reach adulthood (1,2). Such patients have a higher mortality over the
medium and long term compared with healthy individuals
with similar demographic characteristics (3–7). Development of simple risk stratification methods would permit
resources to be directed to patients with adult congenital
heart disease (ACHD) at greatest risk. Cardiopulmonary
exercise testing with measurement of peak oxygen consumption is increasingly used in ACHD patients because it
may provide similar prognostic information in ACHD as it
From the *Adult Congenital Heart Program, Department of Cardiology, Royal
Brompton Hospital, London, United Kingdom; †Department of Clinical Cardiology,
National Heart and Lung Institute, Imperial College School of Medicine, London,
United Kingdom; ‡Department of Pacing, Royal Brompton Hospital, London,
United Kingdom; and the §International Center for Circulatory Health, National
Heart and Lung Institute, Imperial College, London, United Kingdom. Dr. Dimopoulos is supported by the European Society of Cardiology, Drs. Francis, Okonko,
and Babu-Narayan by the British Heart Foundation, and Dr. Broberg by the Waring
Trust. The Royal Brompton Adult Congenital Heart Programme and the Department of Clinical Cardiology have received support from the British Heart Foundation
and the Clinical Research Committee, Royal Brompton Hospital, London. Presented
as part of the 2005 Outstanding Research Award in Pediatric Cardiology at the
American Heart Association Scientific Sessions, Dallas, Texas, November 13, 2005.
Manuscript received January 23, 2006; revised manuscript received May 17, 2006,
accepted May 22, 2006.
does in patients with acquired heart disease. Measuring peak
oxygen consumption, however, requires expensive equipment and specific expertise and is therefore not widely
available.
Chronotropic incompetence—a blunted increase in heart
rate during exercise—is an established predictor of mortality
in patients with coronary artery disease and in healthy
populations (8 –10). Little is known about its prevalence and
prognostic implications across the spectrum of ACHD.
Attenuation of heart rate recovery—the rate of decrease in
heart rate after cessation of exercise—also is associated with
increased mortality in patients being assessed for coronary
artery disease (11). Because cardiac autonomic dysfunction
is common in ACHD patients (12,13), we hypothesized
that abnormal heart rate response to exercise may also be
common in ACHD and could be a simple means of risk
stratification.
The aims of this study were: 1) to evaluate the prevalence
of an abnormal heart rate response to exercise (chronotropic
incompetence) in ACHD patients; 2) to assess the relationship between heart rate response and exercise capacity; and
3) to evaluate whether chronotropic incompetence is a
prognostic marker in ACHD patients after accounting for
exercise capacity and use of antiarrhythmic medication.
Diller et al.
Heart Rate Response and Survival in ACHD
JACC Vol. 48, No. 6, 2006
September 19, 2006:1250–6
Abbreviations and Acronyms
ACHD ⫽ adult congenital heart disease
AUC ⫽ area under curve
NYHA ⫽ New York Heart Association
ROC ⫽ receiver-operating characteristic
METHODS
Study population. This was a retrospective study. We
analyzed data from all cardiopulmonary exercise tests performed in ACHD patients at our institution between
February 1999 and April 2005. Patients were referred for
exercise testing as part of a protocolized clinical follow-up
for ACHD patients. This study was approved by the local
ethics committee. Almost all patients underwent only 1 test
during the study period. Any repeat test was not included in
the analysis. A main diagnosis was determined for every
patient from the hospital records. If more than 1 cardiac
lesion was present, the lesion considered hemodynamically
most important was recorded as the main diagnosis. Patients with multiple complex cardiac lesions substantially
affecting hemodynamics were classified as complex anatomy. The New York Heart Association (NYHA) functional
class was determined by physician assessment of patients’
self-reported symptoms before the date of the exercise test.
Antiarrhythmic drug use was recorded at the time of
exercise testing.
Cardiopulmonary exercise testing. Cardiopulmonary exercise testing was performed on a treadmill according to a
modified Bruce protocol (14,15) with the addition of a
“stage 0” in which the patient walks at a velocity of 1 mile/h
and a gradient of 5% for 3 min. All subjects were encouraged to exercise to exhaustion regardless of the maximal
heart rate achieved. Ventilation, oxygen uptake, and carbon
dioxide production were measured continuously using a respiratory mass spectrometer (Amis 2000; Innovision, Odense,
Denmark) as described previously (16). Heart rate was
assessed by continuous electrocardiography, and arterial
blood pressure was recorded manually by sphygmomanometry. Resting heart rate was measured after at least 30 s in a
seated position, and peak heart rate was defined as the
maximal heart rate achieved during exercise. Predicted
maximum heart rate was estimated according to the Astrand
formula (220-age) (17), and percentage of maximum agepredicted heart rate was calculated as the ratio between peak
heart rate and age-predicted maximum heart rate (220-age).
Calculation of heart rate reserve. Heart rate reserve was
calculated as the difference between peak and resting heart
rates. The chronotropic index, (peak heart rate ⫺ resting
heart rate)/(220-age ⫺ resting heart rate) (9), is derived by
applying the chronotropic metabolic relationship concept
introduced by Wilkoff et al. (18) to a symptom-limited
exercise test as described previously (10). This allows definition of the normal chronotropic response independently
of age, resting heart rate, and functional state (18). In a
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group of 410 healthy adults,Wilkoff et al. (18) reported 95%
limits of normality of chronotropic index to be 0.8 to 1.3.
Based on this finding, we defined chronotropic incompetence as failure to achieve a chronotropic index of 0.8 (i.e.,
falling below 97.5% of healthy adults).
Calculation of heart rate recovery. Heart rate was also
recorded 1, 2, 3, and 5 min after the cessation of exercise,
and heart rate recovery was calculated as the difference
between peak heart rate and the heart rate at these recovery
time points. In addition, the relative decrement in heart rate
was calculated as heart rate recovery divided by the heart
rate at peak exercise.
Follow-up. Follow-up was complete for all patients. Survival status and time to death was assessed through the
health service computer system, which is linked to a national
database held by the Office of National Statistics. We
planned the study to use all-cause mortality as the end point
to eliminate any possibility of bias arising from incorrect
classification of cause of death.
Statistical analysis. All values are presented as mean ⫾
standard deviation. Comparisons between groups were
made using the Student t test, Mann-Whitney U test, or
chi-square test as appropriate. Variables were assessed
on univariate analysis. Significant parameters were subsequently included into a multivariate regression model in a
stepwise forward procedure. Univariate Cox proportional
hazards analysis was used to assess the association between
variables and the end point of all-cause mortality. Parameters significantly predicting prognosis in univariate analysis
were subsequently tested in a multivariate Cox proportional
hazards analysis by the stepwise forward method to assess
the independent effect of these variables. Areas under curve
(AUC) for sensitivity and specificity were calculated using
receiver-operating characteristic (ROC) analysis to compare
prognostic accuracy of different parameters. Statistical analyses were performed using the StatView 5.0 (Abacus Concepts, Berkeley, California) and MedCalc 8.2.1 (MedCalc
Software, Mariakerke, Belgium) software packages.
RESULTS
Patient characteristics. Characteristics of the 727 consecutive ACHD patients (mean age 33 ⫾ 13 years, 52% male)
included in this analysis are presented in Tables 1 and 2.
Patients with chronotropic incompetence were more likely
to be cyanotic, female, or treated with antiarrhythmic drugs.
In addition, by definition, such patients had lower values of
peak heart rate and heart rate reserve, as shown in Table 1.
Prevalence of chronotropic incompetence. Chronotropic
incompetence was present in 62% of the patients. The
prevalence was highest in patients after Fontan palliation
(84%) and in patients with Eisenmenger physiology (90%),
and it was lowest in patients with repaired tetralogy of Fallot
(52%), repaired ventricular septal defect (52%), and isolated
valvar disease (47%), as shown in Table 2. On considering
only those patients who reached anaerobic threshold (i.e.,
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Diller et al.
Heart Rate Response and Survival in ACHD
JACC Vol. 48, No. 6, 2006
September 19, 2006:1250–6
Table 1. Selected Baseline Characteristics According to the Ability to Reach a Chronotropic
Index of at Least 80%
Characteristic
All Patients
(n ⴝ 727)
Failed
(n ⴝ 453)
Reached
(n ⴝ 274)
p Value*
Age (yrs)
Gender (% male)
Deaths
NYHA functional class I/II/III (%)
Cyanosis (%)
Sinus rhythm (%)
Class I–IV† anti-arrhythmic drugs (%)
Antiarrhythmic drugs incl. digoxin (%)
Digoxin (%)
Amiodarone (%)
Sotalol (%)
ACE inhibitors (%)
Heart rate reserve (beats/min)
Chronotropic index
Peak VO2 (ml/kg/min)
Percentage age-predicted heart rate
Peak pulse (beats/min)
Resting pulse (beats/min)
33 ⫾ 13
52
38
45/40/15
17
96
28
26
5
13
4
19
71 ⫾ 29
0.70 ⫾ 0.28
23.3 ⫾ 9.6
83 ⫾ 16
154 ⫾ 30
83 ⫾ 14
33 ⫾ 13
47
34
34/47/19
24
96
39
37
6
19
5
21
57 ⫾ 24
0.54 ⫾ 0.20
20.4 ⫾ 8.2
74 ⫾ 13
138 ⫾ 26
82 ⫾ 16
33 ⫾ 13
61
4
64/30/6
5
97
10
7
4
3
2
16
95 ⫾ 18
0.96 ⫾ 0.20
28.0 ⫾ 9.9
97 ⫾ 8
181 ⫾ 14
85 ⫾ 15
0.87
0.001
0.0004
⬍0.0001
⬍0.0001
0.34
⬍0.0001
⬍0.0001
0.18
⬍0.0001
0.02
0.14
⬍0.0001
⬍0.0001
⬍0.0001
⬍0.0001
⬍0.0001
0.004
Plus-minus values are mean ⫾ standard deviation. *p values (t test or Mann-Whitney U test) for comparison between patients
achieving and patients failing to reach a chronotropic index of at least 80%. †Classification of antiarrhythmic drugs according
to Vaughan Williams.
ACE ⫽ angiotensin-converting enzyme; NYHA ⫽ New York Heart Association class; peak VO2 ⫽ peak oxygen
consumption.
those with a respiratory quotient below 1.0), the frequency
of chronotropic incompetence was found to be 54% overall.
Once again it was most frequent in the Eisenmenger
patients (96%) and least frequent in patients with repaired
ventricular septal defects (35%).
Relationship to symptoms and exercise capacity. Patients
with chronotropic incompetence were more likely to be in
a higher NYHA class (34% NYHA class I, 47% NYHA
class II, 19% NYHA class III) than the remaining patients
(64% NYHA class I, 30% NYHA class II, 6% NYHA class
III) (p ⬍ 0.0001). Patients with chronotropic incompetence
also had lower peak oxygen consumption (20.4 ⫾ 8.2 ml/kg/
min vs. 28.0 ⫾ 9.9 ml/kg/min; p ⬍ 0.0001) and shorter
exercise duration (541 ⫾ 196 s vs. 732 ⫾ 196 s; p ⬍
0.0001). In addition, heart rate reserve (r ⫽ 0.53; p ⬍
0.0001) and peak heart rate (r ⫽ 0.49; p ⬍ 0.0001)
correlated with peak oxygen consumption.
Prognostic value of parameters of chronotropic incompetence. During a median follow-up of 851 days after
cardiopulmonary exercise testing (range 60 to 2,254 days),
38 patients died. The patients who died had the following
diagnoses: Fontan physiology (n ⫽ 7), complex anatomy
(n ⫽ 10), congenitally corrected transposition of the great
arteries (n ⫽ 2), atrial switch procedure for transposition of
the great arteries (n ⫽ 1), tetralogy of Fallot (n ⫽ 5),
isolated valvar disease (n ⫽ 2), single ventricle physiology
Table 2. Distribution of Parameters of Chronotropic Incompetence, Peak Oxygen Consumption, Presence of Sinus Rhythm, and Use
of Antiarrhythmic Medication by Underlying Anatomy
ASD (n ⫽ 42)
ccTGA (n ⫽ 25)
CoA (n ⫽ 23)
Complex (n ⫽ 75)
Ebstein (n ⫽ 32)
Eisenmenger (n ⫽ 53)
Fontan (n ⫽ 58)
Mustard (n ⫽ 56)
TOF (n ⫽ 228)
Valvar (n ⫽ 78)
VSD (n ⫽ 25)
Low CI
HRR
(beats/min)
Peak Pulse
(beats/min)
Peak VO2
(ml/kg/min)
Sinus
Rhythm
AAD
Treatment
Deceased
During FU
60%
68%
59%
81%
53%
90%
84%
58%
52%
47%
52%
69 ⫾ 30
70 ⫾ 33
73 ⫾ 24
56 ⫾ 28
77 ⫾ 28
51 ⫾ 23
59 ⫾ 27
77 ⫾ 26
80 ⫾ 26
76 ⫾ 31
70 ⫾ 27
154 ⫾ 34
151 ⫾ 38
156 ⫾ 27
138 ⫾ 32
158 ⫾ 31
136 ⫾ 24
140 ⫾ 33
160 ⫾ 28
162 ⫾ 26
159 ⫾ 29
157 ⫾ 26
21.6 ⫾ 7.9
21.8 ⫾ 9.6
28.9 ⫾ 7.9
20.2 ⫾ 7.7
21.5 ⫾ 5.2
12.8 ⫾ 5.7
20.9 ⫾ 6.1
25.8 ⫾ 6.9
25.7 ⫾ 8.4
26.9 ⫾ 12.8
22.2 ⫾ 7.1
89%
95%
95%
88%
90%
100%
96%
94%
98%
97%
100%
32%
43%
30%
35%
35%
40%
53%
29%
19%
17%
13%
1
2
1
10
3
1
7
1
5
2
0
Plus-minus values are mean ⫾ standard deviation.
AAD treatment ⫽ percentage of patients treated with at least one antiarrhythmic drug (including type I–IV or digoxin); ASD ⫽ atrial septal defect; ccTGA ⫽ congenitally
corrected transposition of the great arteries; CoA ⫽ aortic coarctation; complex ⫽ complex anatomy including mostly single ventricle physiology (excluding Fontan type patients);
FU ⫽ follow-up period; HRR ⫽ heart rate reserve; low CI ⫽ percentage of patients with a low chronotropic index (⬍0.8); Mustard ⫽ patients after mustard-type atrial switch
operation for TGA; peak VO2 ⫽ peak oxygen consumption; sinus rhythm ⫽ percentage of patients in sinus rhythm at the time of the exercise testing; TOF ⫽ tetralogy of Fallot;
VSD ⫽ ventricular septal defect.
Diller et al.
Heart Rate Response and Survival in ACHD
JACC Vol. 48, No. 6, 2006
September 19, 2006:1250–6
1253
Table 3. Univariate Predictors of Mortality
Variable
Parameters of chronotropic incompetence
Heart rate reserve (10 beats/min)
Chronotropic index
Peak heart rate (10 beats/min)
Percentage predicted peak heart rate
Heart rate recovery 1 minute (beats/min)
Heart rate recovery 2 minutes (beats/min)
Heart rate recovery 3 minutes (beats/min)
Heart rate recovery 5 minutes (beats/min)
Other univariate predictors
Peak VO2 (ml/kg/min)
NYHA functional class
Antiarrhythmic therapy (excl. digoxin)
Antiarrhythmic therapy (incl. digoxin)
Amiodarone therapy
Digoxin therapy
Hazard Ratio
(95% Confidence Interval)
p Value
0.75 (0.67–0.84)
0.97 (0.96–0.98)
0.81 (0.74–0.88)
0.96 (0.95–0.98)
0.96 (0.94–0.98)
0.96 (0.94–0.98)
0.97 (0.95–0.99)
0.97 (0.96–0.99)
⬍0.0001
⬍0.0001
⬍0.0001
⬍0.0001
0.002
0.0002
0.001
0.0002
0.90 (0.86–0.94)
2.8 (1.7–4.5)
5.6 (2.8–11.3)
6.5 (3.1–13.6)
6.9 (3.5–13.5)
3.2 (1.2–8.3)
⬍0.0001
⬍0.0001
⬍0.0001
⬍0.0001
⬍0.0001
0.016
NYHA class ⫽ New York Heart Association functional class; peak VO2 ⫽ peak oxygen consumption.
(n ⫽ 1), Eisenmenger syndrome (n ⫽ 1), aortic coarctation
(n ⫽ 1), Ebstein anomaly (n ⫽ 3), repaired atrial (n ⫽ 1) and
atrioventricular (n ⫽ 2) septal defects, and others (n ⫽ 2).
On univariate analysis, heart rate reserve, chronotropic
index, peak heart rate, and percentage predicted heart rate
predicted survival (Table 3). The other univariate predictors
of survival were use of antiarrhythmic drug therapy, peak
oxygen consumption, and NYHA functional class. In addition, amiodarone or digoxin use was related to survival, as
shown in Table 3. Age, gender, cyanosis, and treatment
with sotalol, beta-blocker, calcium antagonist, class I antiarrhythmic drugs, or angiotensin-converting enzyme inhibitors were not related to survival.
Measures of chronotropic response correlated strongly
with each other (r value between 0.81 and 0.96; p ⬍ 0.001
for each). Therefore, for multivariate analysis we chose the
parameter with the highest predictive value on univariate
Cox proportional hazard analysis and the greatest AUC on
ROC analysis. In both analyses, heart rate reserve (chisquare ⫽ 26.1; AUC ⫽ 0.74) and chronotropic index
(chi-square ⫽ 26.9; AUC ⫽ 0.74) were superior to peak
heart rate (chi-square ⫽ 20.9; AUC ⫽ 0.72) and percentage
age-predicted peak heart rate (chi-square ⫽ 21.0; AUC ⫽
0.72) in predicting prognosis. As a consequence heart rate
reserve, representing a much simpler parameter than chronotropic index, was used in subsequent analyses.
On multivariate analysis, heart rate reserve, NYHA
functional class, and therapy with antiarrhythmic drugs
jointly predicted mortality, independently of peak oxygen
consumption, as shown in Table 4. These results remained
unchanged when patients who did not reach the anaerobic
threshold during exercise (i.e., those with a respiratory
quotient below 1.0) were excluded from the analyses. Figure
1 illustrates the relationship between heart rate reserve and
death from any cause among adult congenital heart disease
patients stratified by quartiles of heart rate reserve.
Prognostic value of heart rate reserve in individual
diagnostic groups. Heart rate reserve predicted mortality
in patients after Fontan palliation (hazard ratio [HR] ⫽
0.65 per 10 beats/min; 95% confidence interval [CI] 0.48 to
0.88; p ⬍ 0.05), complex anatomy (HR ⫽ 0.81 per 10
beats/min; 95% CI 0.65 to 0.998; p ⬍ 0.05), and repaired
tetralogy of Fallot (HR ⫽ 0.66 per 10 beats/min; 95% CI
0.48 to 0.91; p ⬍ 0.05) on univariate analysis. No significant
association between low heart rate reserve and mortality was
found in patients with simple lesions, systemic right ventricles, or Ebstein anomaly of the tricuspid valve.
Comparative prognostic value of heart rate reserve and
peak oxygen consumption. Heart rate reserve was at least
as good as peak oxygen consumption in predicting mortality, both on univariate Cox analysis (chi-square ⫽ 26.1 vs.
19.3) and on ROC analysis (AUC ⫽ 0.74 vs. 0.68) (Fig.
2A). Combining these 2 variables was also helpful: Patients
with both heart rate reserve and peak oxygen consumption
within the lowest quartile (⬍51 beats/min and ⬍16.7
ml/kg/min, respectively) had the worst prognosis, patients
with only one in the lowest quartile had an intermediate
Table 4. Multivariate Predictors of Mortality
Variable
Hazard Ratio*
(95% Confidence Interval) p Value
Heart rate reserve (10 beats/min)
Antiarrhythmic therapy
(incl. digoxin)
NYHA functional class
Peak VO2 (ml/kg/min)
0.86 (0.74–0.99)
3.7 (1.7–8.1)
0.04
0.0008
2.0 (1.2–3.4)
—
0.007
NS
Heart rate reserve (10 beats/min)
Amiodarone therapy
NYHA functional class
Peak VO2 (ml/kg/min)
0.83 (0.72–0.96)
4.7 (2.4–9.5)
2.1 (1.3–3.5)
—
0.01
⬍0.0001
0.002
NS
*Hazard ratios for heart rate reserve and peak oxygen consumption are per 10
beats/min and 1 ml/kg/min, respectively.
Abbreviations as in Table 3.
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Diller et al.
Heart Rate Response and Survival in ACHD
JACC Vol. 48, No. 6, 2006
September 19, 2006:1250–6
Figure 1. Kaplan-Meier estimates of death from any cause among adult congenital heart disease patients stratified by quartiles of heart rate reserve (HRR).
prognosis, and those with neither in the lowest quartile had
the best prognosis (p ⬍ 0.0001) (Fig. 1).
Prognostic value of heart rate recovery. Data on heart
rate recovery was available in 505 patients (those patients
who underwent exercise testing after March 2001). Of
these, 16 patients died during follow-up. Heart rate recovery
at 1, 2, 3, and 5 min was significantly lower in patients who
died than in surviving patients (p ⬍ 0.05 for each), as was
heart rate recovery expressed as percentage of peak heart rate
(Fig. 2B). Heart rate recovery at 1, 2, 3, and 5 min after
exercise was significantly related to mortality on univariate
Cox proportional hazards analysis (p ⬍ 0.05 for each). After
adjustment for antiarrhythmic drug therapy heart rate recovery at 1, 2, 3, and 5 min after exercise remained
independently predictive of survival in bivariate Cox analysis
(p ⬍ 0.05 for each).
DISCUSSION
This study demonstrates that a blunted heart rate response
to exercise (chronotropic incompetence) is prevalent across
the spectrum of ACHD and predicts an enhanced mortality
risk independently of antiarrhythmic medication. Even an
attenuated rate of recovery of heart rate after exercise testing
carries important prognostic information. Moreover, a simple combination of heart rate reserve and peak oxygen
consumption identifies a subpopulation of ACHD patients
with a 3.8-fold increase in mortality.
Chronotropic incompetence was found to be prevalent
in ACHD, affecting 62% of patients. In other cohorts,
the prevalence of chronotropic incompetence ranges between 30% in patients with chronic heart failure (19) to
60% in patients with chronic atrial fibrillation (20). In the
present study, the prevalence of chronotropic incompetence was lowest in patients with simple lesions, such as
repaired ventricular septal defect, Ebstein anomaly, or
palliated transposition of the great arteries, and was
highest in patients with complex, uncorrected, and cyanotic lesions. This increase in prevalence of chronotropic
incompetence parallels the decline in peak oxygen consumption across the spectrum of ACHD. It has been
suggested that a blunted heart rate response may in part
account for the diminished exercise capacity seen in these
patients (21). The results of our study support this
notion. We found that patients with chronotropic incompetence had poorer exercise capacity compared with
patients without chronotropic incompetence. In addition,
change in heart rate correlated with peak oxygen consumption. However, in this cohort heart rate explains
only a quarter of the variation in peak oxygen consumption. Therefore, other parameters, such as age, gender,
pulmonary function, cyanosis, and level of fitness may
play an important role in determining exercise capacity in
ACHD patients. We also found a relationship between
chronotropic incompetence and symptomatic state. Patients with chronotropic incompetence were more likely
to be in a higher NYHA functional class than patients
with a normal heart rate response to exercise. Whether
this is a causal relationship remains to be determined.
JACC Vol. 48, No. 6, 2006
September 19, 2006:1250–6
Figure 2. Increase in heart rate during exercise (heart rate reserve) (A) and
decrease in heart rate at the end of exercise (heart rate recovery) (B) in
surviving and nonsurviving patients. Error bars indicate 95% confidence
intervals.
Heart rate reserve, though a simple and easily obtained
marker, turned out to be a powerful prognostic marker in
ACHD independently of antiarrhythmic medication and
exercise capacity. Stratifying patients by diagnostic groups
revealed that a lower heart rate reserve was also associated
with a greater risk of death in patients with complex
anatomy, Fontan circulation, and tetralogy of Fallot. Interestingly, despite their poor exercise capacity, Eisenmenger
patients did not have a correspondingly poor survival, and,
therefore, neither peak oxygen consumption nor heart rate
reserve failed to predict prognosis in this population. We
speculate that in the Eisenmenger patients the limitation to
exercise does not arise from the usual broad constellation of
ominous pathophysiologic abnormalities (including poor
ventricular function, vascular remodeling, autonomic dysfunction, etc.) but rather more specifically from exerciseinduced increase in right-to-left shunting. Thus there is a
“cap” on exercise capacity and therefore on heart rate
reserve. This cap may be far below that which would have
been set by the usual pathophysiologic abnormalities which
in turn are responsible for the impaired prognosis. As a
consequence, their survival is nowhere near as poor as would
Diller et al.
Heart Rate Response and Survival in ACHD
1255
be predicted from the exercise capacity. Further work will be
needed to identify the subset of patients within the Eisenmenger cohort who are at highest risk of mortality.
In acquired heart disease, both exercise capacity and
chronotropic incompetence are known to be predictors of
poor prognosis (8,9,22,23). Of these, only peak oxygen
consumption is routinely used for risk stratification, and
even this is largely limited to acquired chronic heart failure.
In ACHD patients, the prognostic value of both peak
exercise and chronotropic incompetence is far from established. The present study shows in a large cohort of ACHD
patients that both parameters of chronotropic incompetence
and peak oxygen consumption are of prognostic value and
that heart rate reserve is at least as good a predictor of
mortality in ACHD patients as peak oxygen consumption.
Combining parameters of chronotropic response with peak
oxygen consumption enables further risk stratification.
Underlying mechanisms responsible for chronotropic incompetence in ACHD patients are not fully understood. It
appears likely that chronotropic incompetence is a multifactorial phenomenon resulting from the confluence of several
factors which themselves are associated with poor prognosis.
Colluci et al. (24) reported that impaired chronotropic
response to exercise in patients with chronic heart failure is,
at least in part, due to postsynaptic desensitization of
beta-adrenergic receptors. In addition, it has been demonstrated that heart rate variability is significantly decreased in
patients with acquired heart disease who are chronotropically incompetent (25).
It remains to be elucidated whether the prognostic power
of heart rate reserve results from its dependence on mechanisms such as exercise capacity, neurohormonal activation,
autonomic dysfunction, and hemodynamic compromise.
This study identifies heart rate reserve as a physiologically
important piece of information to extract from a cardiopulmonary exercise test alongside the usual measurements.
Whether specifically targeting abnormal heart rate reserve
could improve prognosis remains unknown. There are no
data to suggest that directly intervening on heart rate (e.g.,
inserting a rate-responsive pacemaker) would improve prognosis. Rather, for now, we believe these data indicate the
potential utility of this additional information in selecting
patients for special medical or further surgical attention
because they are at greater risk of death than the clinician
might otherwise predict.
Study limitations. Cardiopulmonary exercise testing in
this study was performed as part of routine evaluation of
patients in the ACHD clinic. All patients were at a tertiary
ACHD center and, therefore, it is possible that they may
not represent the pattern of ACHD that may exist in the
community. Nevertheless, the patients were not restricted to
any particular narrow diagnostic group but rather covered
the entire spectrum of ACHD diagnoses and included all
segments of the population regardless of age, gender, history,
and nature of surgery. The number of deaths forming the basis
of this report is limited and further prospective studies with
1256
Diller et al.
Heart Rate Response and Survival in ACHD
a longer period of observation and a higher number of
clinical events are desirable to validate the results reported in
this cohort and to provide information on the potential
response to different therapies. This study cannot identify
why a blunted heart rate response to exercise in ACHD
patients predicts poor prognosis. Indeed, even the mechanisms of depressed heart rate responses in ACHD remain
unclear. Now that the prognostic value of heart rate responses are emerging, further research may be stimulated
that could elucidate the mechanisms responsible.
Conclusions. An abnormal heart rate response to exercise
is prevalent across the spectrum of adult congenital heart
disease and is associated with a greater risk of death. Even
on its own, heart rate reserve is potentially a simple means
of identifying ACHD patients at elevated risk. In combination with formal measurement of peak oxygen consumption, it identifies a subpopulation with a 3.8-fold elevated
risk of death in the mid term. Exercise testing should be
considered as part of the routine assessment of adults with
congenital heart disease.
Acknowledgment
We wish to acknowledge our exercise laboratory staff for
their ongoing support.
Reprint requests and correspondence: Prof. Michael A. Gatzoulis,
Adult Congenital Heart Program, Royal Brompton Hospital, Sydney
Street, SW3 6NP London, United Kingdom. E-mail: m.gatzoulis@
rbh.nthames.nhs.uk.
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