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(Circulation. 2000;101:1152.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Peak Oxygen Uptake Better Predicts Outcome Than Submaximal Respiratory Data in Heart Transplant Candidates
From the Hypertension and Cardiovascular Rehabilitation Unit (K.P., R.H.F.) and Cardiology Unit (J.V.C., J.V.), Department of Molecular and Cardiovascular Research, Faculty of Medicine, University of Leuven, KUL, Leuven, Belgium.
Correspondence to K. Pardaens, PhD, Functiemetingen Cardiologie, Secretariaat Hypertensie, UZ Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
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Abstract |
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Background—Many studies have focused on the prognostic power of peak oxygen uptake (
O2) in patients with chronic heart
failure, but maximal exercise testing is not without risk. The purpose
of the present study was, therefore, to assess the prognostic
significance of the steepness of changes in ventilation and
carbon dioxide output (CO2) during
submaximal exercise in comparison with
O2.
Methods and Results—The study population consisted of 284 adult
heart transplant candidates who performed a graded maximal bicycle
ergometer test with respiratory gas analysis. Using the
respiratory data up to a gas exchange ratio of 1.0, 3 submaximal slopes
were calculated in each patient. During follow-up (median, 1.33 years),
57 patients died and 149 had 
1 cardiovascular event.
When using Cox proportional hazards analysis, both peak
O2 and submaximal respiratory slopes
predicted outcome before and after accounting for age, sex, and
body mass index. However, whereas the prognostic power of peak
O2 was independent of submaximal
respiratory data, the prognostic significance of the slopes was lost
after controlling for peak O2. Stepwise
regression analysis even selected peak
O2 as an independent prognostic index
among the following factors: cause of heart failure, ejection
fraction, pulmonary vascular resistance, natremia, and the
forced expiratory volume in 1 s.
Conclusions—Respiratory data during submaximal exercise are
significant predictors of outcome in patients with chronic heart
failure, but their prognostic power is inferior to that of
peak O2. However, these data may be
useful when maximal exercise is contraindicated or not achievable.
Key Words: exercise • heart failure • prognosis • transplantation
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Impaired exercise tolerance is predictive of mortality in patients with advanced chronic heart failure (CHF).1 2 3 4 5 6 7 8 9 10 11 12 13 Therefore, current guidelines recommend using maximal exercise testing to select appropriate candidates for heart transplantation (HTx).14 Peak oxygen uptake (
O2), obtained during maximal
exercise testing, has been the gold standard of exercise performance. However, because maximal exertion
is not without risk in patients with CHF and is, in fact, not reached
by a number of patients, it is worthwhile to examine whether submaximal
data, such as the ventilatory responses to exercise, might provide
prognostic information similar to peak
O2.
Chua and colleagues1 showed that a steeper slope of minute
ventilation (VE) on carbon dioxide output
(CO2) carries a worse
prognosis for patients, over and above peak
O2, but they calculated the
VE-CO2 slope up to maximal
exercise. It is, therefore, uncertain whether the
VE-CO2 slope would predict
outcome when calculated up to a submaximal exercise level. To the best
of our knowledge, only one recent study examined the prognosis in CHF
patients from submaximal exercise data. De Vries et al6
constructed a formula to predict maximal exercise capacity on the basis
of several parameters measured during the first 6 minutes
of a maximal exercise test. The authors demonstrated that predicted
peak O2 was related to
outcome, independent of general characteristics but not of data
obtained at peak exercise. In other words, submaximal data provided
less prognostic information than maximal exercise data. However, the
VE-CO2 slope was not computed
in the latter study, so it remains uncertain whether such respiratory
slopes up to a submaximal exercise level would be better predictors of
outcome than maximal measurements.
The purpose of the present study was to assess the prognostic
significance of 3 slopes derived from relationships between respiratory
variables during submaximal exercise using data up to a respiratory
gas exchange ratio (RQ) of 1.0. An attempt was made to answer the
following 3 research questions. (1) Do both peak
O2 and submaximal data (the
slopes up to an RQ of 1.0) predict outcome? (2) Is the prognostic power
of peak O2 superior to that of
submaximal data? (3) What is the value of the exercise
parameters when compared with nonexercise data?
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Patient Selection
Between May 1991 and December 1996, 671 patients were referred to our center for assessment of their suitability for HTx. Of this cohort, we followed the 289 patients (43%) who performed an exercise test during the pre-HTx work-up. All patients were adult (aged 18 to 69 years), white individuals except 2; these 2 patients were excluded from the analyses (one was 15 years old and one was black). Two patients were not eligible because of a severe locomotor disorder. A last patient was excluded because of a fatal ventricular fibrillation in the recovery phase of the exercise test. Thus, 284 patients were considered in the present report.
Baseline Data: The pre-HTx Work-Up
All patients performed a maximal bicycle ergometer test after
having provided oral informed consent. The test always took place
before noon, without interruption of medical treatment. After 2
minutes of sitting rest on the bicycle, patients started cycling at a
workload of 10 W, which was increased by 10 W after each minute.
Patients were encouraged to exercise until they felt unable to
continue. At rest and during exercise,
O2,
CO2 (L/min), and VE (L/min)
were measured continuously using a mixing chamber (Sensormedics 2900).
Peak O2 was defined as the
highest O2 during any stage
that could be sustained for 1 minute; in most instances, this
corresponded to the highest workload that was sustained for 1 minute
(ie, peak workload). Peak O2
is reported in absolute units (L/min), after correction for body weight
(mL · min-1 ·
kg-1), and as a percentage of predicted normal
values accounting for age, weight, and sex.15
Peak RQ (ie,
CO2/O2)
was defined as the highest 20-s value at the end of exercise. In each
individual patient, respiratory data from rest to an RQ of 1.0 were
used to calculate the slope (ie, the regression coefficient) between
the square root of CO2
(
CO2) on
O2,16 the slope of the
logarithmically transformed VE on
O2,17 and the slope of
VE on CO2.16 18 19 20 21
Previous studies16 17 18 19 20 21 have shown a linear relationship
between these pairs of variables. In patients who did not achieve a
peak RQ of 1.0 (n=61; 22%), the slopes were calculated using all data
from rest to the end of exercise. Slopes could not be determined in 11
patients because of technical problems during exercise testing. Heart
rate was derived from the ECG at the end of the sitting rest period and
throughout the exercise test.
Nonexercise parameters were considered to assess whether exercise-derived variables would have independent prognostic value. To prevent "overfitting" by considering too many predictor variables in the regression models,22 we decided to use the following 4 biologically unrelated variables, which have a proven relationship with severity of CHF3 4 5 9 10 13 23 24 25 : radionuclide left ventricular ejection fraction (%; determined in 259 patients), pulmonary vascular resistance (mm Hg · L-1 · min-1; n=268), serum sodium concentration (mmol/L; n=283), and the forced expiratory volume in 1 s (FEV1; n=274; expressed in absolute values [liters] and as a percentage of predicted normal values according to age, height, and sex).26 All data were available in 243 patients.
Outcome Data: Follow-Up
Data collection on follow-up was started in January 1997 and
finished by the end of the year. The aim was to obtain information on
the patients’ vital and health status starting at the date of the
exercise test. In the first phase, local hospital files were checked.
If patients had not been followed in our hospital until 1997 or if data
were considered incomplete, a questionnaire concerning vital and health
status was sent to the patient’s physician(s). If deemed necessary,
doctors and—exceptionally—patients were contacted by telephone.
Objective evidence was required for acceptance of an event, and
2 investigators (K.P. and R.F.) had to agree on the interpretation of
the available information.
Statistical Analyses
The SAS software (SAS Institute) was used for all
statistical analyses. Variables were coded as 1 when the
condition was present and as 0 when absent. Single regression
analysis was used to calculate slopes (ie, regression
coefficients). Characteristics of survivors and nonsurvivors and of
patients who had versus those who did not have events were compared
using unpaired Student’s t tests and
2 analysis. The Cox proportional
hazards regression model was used for survival
analysis.27 We examined whether the data
obtained during the pre-HTx work-up were predictive for either the time
to death (all-cause mortality) or the time to the first-occurring fatal
or nonfatal cardiovascular event. Patients who
underwent transplantation were censored at the time of HTx in all
analyses. The prognostic value of a parameter is
given by its relative hazard rate, which estimates how much the
incidence of an event changes when the independent variable
increases by 1 unit. P<0.05 was considered significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Patient Characteristics at Baseline and Follow-Up Data
Tables 1
and 2 present the characteristics
of the patient population at baseline, including data obtained during
exercise testing. Exercise was limited by general fatigue, leg fatigue,
or dyspnea in most patients (n=245; 86%); other tests were terminated
because of ST depression, angina pectoris, or an arrhythmia
(n=18; 6%) or for other reasons, such as anxiety (n=21; 7%). Table 3 summarizes the correlation coefficients
associated with the various slopes and the relationships between these
slopes and peak O2.
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Vital status and health status could be ascertained in all but 2
patients. One of these patients moved abroad, and only the cause and
date of death could be identified in the other. Of all patients, 36%
(n=102) underwent HTx at a median age of 53 years (range, 21 to 68
years). Median time of follow-up (ie, time until death, HTx, or the
date of the last available information on vital status) was 1.33 years;
time ranged from 9 days to 6.01 years. During the total follow-up time
of 523 patient-years, 57 patients died (Table 4) at a median age of 60 years (range, 25
to 72 years); 48% of the deaths occurred during the first year after
the pre-HTx evaluation. At least one fatal or nonfatal
cardiovascular event was experienced by 149 patients.
The first event, which was fatal in 28 patients (Table 4),
occurred at a median age of 55 years (range, 20 to 69 years) and a
median of 279 days after the HTx work-up.
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Among the patients who were considered too good for HTx (n=149), actuarial survival was 95% after 1 year, 91% at 2 years, 83% at 3 years, and 71% at 4 and 5 years. In patients presenting with contraindications to HTx (n=50), actuarial survival rates were 72%, 55%, 50%, 43%, and 21%, respectively (patients were re-evaluated during follow-up, so that some crossed over from one category to another).
Prognostic Value of Patient Characteristics
Nonsurvivors were older (P<0.05) and had a higher
prevalence of ischemic heart disease (P<0.01) and a
lower FEV1 (in absolute and in normalized values; P<0.01)
than survivors; the other characteristics were similar in both groups.
Characteristics did not differ between patients who did and did not
experience cardiovascular events, except for normalized
FEV1, which was significantly lower (P<0.05) in patients
who had an event. Single Cox regression analysis identified age
as a significant predictor of all-cause mortality (P=0.01)
but not of the first-occurring fatal or nonfatal
cardiovascular event. The same was true for
ischemic heart disease, but a diagnosis of idiopathic
cardiomyopathy was associated with better
(P<0.01) survival and a lower incidence of all
cardiovascular events (P<0.05). A higher
pulmonary vascular resistance (P<0.05), a lower
serum sodium concentration (P<0.05), and a lower FEV1
(P<0.05) consistently carried a worse prognosis
(ie, both time to death and time to the first-occurring
cardiovascular event were significantly lower). The
other characteristics, including medication and left
ventricular ejection fraction, did not have prognostic
significance.
Prognostic Value of Exercise Data
Nonsurvivors had a steeper
CO2-O2
slope (P<0.05) and a lower exercise tolerance (peak
O2 [L/min],
P<0.05; peak
O2 [mL ·
min-1 · kg-1],
P<0.001; peak
O2 [% predicted],
P<0.05; peak workload, P<0.01) than survivors;
the other data collected during exercise testing (including the
VE-CO2 slope and
logVE-O2 slope) were
similar among the 2 groups. None of the parameters differed
between the patients who had versus those who did not have
cardiovascular events. In single Cox regression
analysis, data measured at rest before exercise (Table 5) were not related to outcome, except
that the presence of sinus rhythm predicted a lower incidence of
cardiovascular events (P<0.05). Of the data
obtained during exercise, steeper slopes, a lower peak
O2, a lower peak
workload, and a lower peak heart rate univariately
predicted higher mortality.
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Peak heart rate did not predict mortality independently of peak
O2. The relative hazard rate
of 0.89 for weight-adjusted peak
O2 indicates that a 1 mL
· min-1 · kg-1
higher peak O2 is associated
with an 11% lower mortality throughout the observation period. The
results obtained by using single regression analysis remained
similar (eg, peak O2) or
became somewhat weaker (eg, submaximal slopes) after adjustment for
age, sex, and body mass index (Table 5
). The predictive power of
exercise data were, in general, lower when the first-occurring
cardiovascular event was considered as the end point of
interest (Table 5). Results were not substantially altered when
only cardiovascular deaths (n=54) instead of all-cause
mortality (n=57 deaths) were considered.
Comparison of the Prognostic Value of Maximal and Submaximal
Exercise Data
In the next step, we compared the prognostic value of submaximal
exercise data with peak O2.
The results are given for the
CO2-O2
slope, which is representative of the other slopes.
Figure 1A presents the prognostic
value of peak O2 when
accounting for the submaximal
CO2-O2
slope, whereas Figure 1B depicts the prognostic value of the
CO2-O2
slope when accounting for the prognostic value of peak
O2. The prognostic
significance of peak O2 was
independent of the slope, but that of the slope was lost by controlling
for peak O2. Stepwise
regression models containing the 3 slopes but not peak
O2 showed that the prognostic
value of the slopes was not additive.
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Prognostic Value of Exercise Data Compared With Nonexercise
Data
A stepwise regression model with general characteristics
(age, sex, body mass index, and cause of heart failure) and
established, nonexercise prognostic indices (FEV1, natremia,
pulmonary vascular resistance, and left ventricular
ejection fraction) selected peak
O2 as an independent predictor
of mortality (P<0.01), together with sex
(P<0.05) as the only significant covariate.
Pulmonary vascular resistance (P<0.001) and
natremia (P<0.05) were identified as the only predictors of
the first cardiovascular event. Figure 2 shows the risk for mortality and the
incidence of cardiovascular events after 2 years of
follow-up according to peak
O2. The prognostic value
of peak O2 was comparable
after accounting for the reason for terminating the exercise test;
stopping the exercise test for a noncardiac reason was in itself not
related to outcome.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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To select the most suitable HTx candidates, one must rely on pretransplant investigations with proven prognostic value. We focused on some established and some novel parameters obtained during exercise testing.
The Prognostic Value of Peak O2
In a relatively large number of patients and with an accurate
follow-up of a reasonable duration, the present study comes to
similar conclusions as previous reports1 2 3 4 5 6 7 8 9 10 11 12 13 regarding the
predictive power of peak O2
for transplant-free survival in patients with CHF and the fact that the
prognostic value of peak O2 is
independent of anthropometric and demographic characteristics. Similar
results were obtained when the first-occurring
cardiovascular event instead of death was the end point
of interest. Moreover, the predictive power of peak
O2 was maintained when
accounting for submaximal respiratory data, but not vice versa.
However, when maximal exercise is contraindicated or not achievable,
the submaximal slopes provide reasonable alternatives. The
analyses indicate that the slopes have significant prognostic
power, but that this power is less than peak
O2. Peak
O2 even predicts outcome
independently of nonexercise parameters. In addition, the
prognostic value of peak O2
might have been underestimated because it was at least partly taken
into account in the decision regarding HTx, and patients were censored
at the time of HTx.
The Prognostic Value of Submaximal Exercise Data
The VE-CO2 slope has
frequently been considered in the heart failure literature in
the past few years.18 19 20 21 Chua et al1
demonstrated that the VE-CO2
slope gave additional prognostic information beyond peak
O2 in patients with heart
failure, but they determined the slope using data up to maximal
exercise. Because the VE-CO2
relationship is linear, we reasoned that it should be possible to
calculate the slopes using the data up to a predefined submaximal
exercise level, such as an RQ of 1.0, and, hence, investigate the
prognostic value of these slopes. Likewise, we considered the
CO2-O2
slope and the logVE-O2 slope,
which have been described previously and were found to be
linear.16 17 These latter slopes relate to
anaerobic energy delivery during
exercise,16 17 and the
logVE-O2 slope also reflects
ventilatory efficiency,17 just like the
VE-CO2 slope. All slopes
predicted outcome, but the prognostic value was lost after adjustment
for peak O2. Similarly, de
Vries et al6 recently investigated whether peak
O2, estimated from the initial
stages of exercise testing, would predict mortality. The authors
essentially came to the same conclusion: data from the initial stages
of testing provided independent prognostic information only when making
abstractions of the data obtained at peak exercise.
It should be acknowledged that many of the alleged submaximal tests (eg, the 6-minute walk test) are, in fact, supramaximal tests. Some patients with CHF are not able to walk for 6 minutes, and in this study, 21% of the patients did not achieve an RQ of 1.0.
We also did not analyze more than half of the total cohort of patients referred between 1991 and 1996 for a pre-HTx evaluation: the patients who did not perform an exercise test were not considered. Although patients with a cardiac contraindication to exercise testing are reported to have a very poor prognosis,11 we think that we excluded patients at both ends of the heart failure spectrum because patients were not asked to exercise if their clinical status was either critical or too good. Thus, we considered a group of patients in whom prognostic precision is required to select the most suitable candidates for HTx.
Conclusions
Respiratory data during submaximal exercise are significant
predictors of outcome in patients with CHF, but their prognostic power
is inferior to that of peak
O2. However, these data may be
useful when maximal exercise is contraindicated or not achievable.
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Acknowledgments |
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R. Fagard is the holder of the Professor A. Amery Chair in Hypertension Research funded by Merck, Sharp & Dohme (Belgium).
Received July 21, 1999; revision received September 9, 1999; accepted October 6, 1999.
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A. Koike, H. Itoh, M. Kato, H. Sawada, T. Aizawa, L. T. Fu, and H. Watanabe Prognostic Power of Ventilatory Responses During Submaximal Exercise in Patients With Chronic Heart Disease* Chest, May 1, 2002; 121(5): 1581 - 1588. [Abstract] [Full Text] [PDF]
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M Guazzi, G Pontone, R Brambilla, P Agostoni, and G Reina Alveolar-capillary membrane gas conductance: a novel prognostic indicator in chronic heart failure Eur. Heart J., March 2, 2002; 23(6): 467 - 476. [Abstract] [Full Text] [PDF]
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D. Mancini, T. LeJemtel, and K. Aaronson Peak VO2 : A Simple yet Enduring Standard Circulation, March 14, 2000; 101(10): 1080 - 1082. [Full Text] [PDF]
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