(Circulation. 1995;91:2924-2932.)
© 1995 American Heart Association, Inc.
Articles |
Prolonged Kinetics of Recovery of Oxygen Consumption After Maximal Graded Exercise in Patients With Chronic Heart Failure
Analysis With Gas Exchange Measurements and NMR Spectroscopy
Presented in part at the 66th Scientific Sessions of the American Heart Association, Atlanta, Ga, November 8-11, 1993.
From the Service de Cardiologie, Hôpital Beaujon, Clichy, and Service de Biophysique, Hôpital Cochin, Paris (D.M.), France.
Correspondence to A. Cohen-Solal, Service de Cardiologie, Hôpital Beaujon, 100 Blvd du General Leclerc, 92110 Clichy, France.
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Abstract |
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Background Patients with chronic heart failure (CHF) often complain of prolonged dyspnea after exercise. The determinants of oxygen consumption after exercise in these patients are unknown. We hypothesized that the kinetics of oxygen consumption recovery after graded exercise was prolonged in parallel with the recovery of muscle energy stores, was not affected by the exercise level, and could be used to assess the circulatory response to exercise.
Methods and Results Seventy-two patients with CHF in Weber's
class A (n=28), B (n=21), and C/D (n=23) and 13 healthy
subjects
performed maximal upright bicycle exercise with breath-by-breath
respiratory gas analysis. Kinetics of recovery of ventilation
(
E), oxygen consumption
(O2), and CO2
production
(CO2) after exercise were
characterized by T1/2, the time to reach 50% of the
peak value. T1/2
O2
(seconds) increased with the severity of CHF (97±17 for CHF A
[P<.05 versus CHF B, P<.05 versus CHF C/D],
119±22 for CHF B [P<.05 versus control subjects,
P<.05 versus CHF A, and P<.05 versus CHF C/D],
155±55 for CHF C/D [P<.05 versus control subjects,
P<.05 versus CHF A, and P<.05 versus CHF B]
compared with 77±17 for control subjects). T1/2
CO2 and T1/2
E also increased similarly with the
worsening of
CHF. T1/2 O2 was
correlated negatively with peak
O2
(r=.65) and was reproducible (r=.96). To study
the relation between T1/2
O2 and the duration of
exercise, 10
healthy subjects and 22 patients underwent a second graded test at 75%
and/or 50% of peak workload. T1/2
O2 was minimally shortened,
at only
50% of peak workload (P=.02). Finally, 19 patients
underwent 31P nuclear magnetic resonance spectroscopy of
the anterior compartment of the leg during exercise; the half-time of
recovery of the ratio of inorganic phosphate to creatine phosphate
(T1/2 Pi/PCr), reflecting the level of
involvement of oxidative metabolism in the restoration of energetic
metabolites after exercise, was linearly correlated with the half-time
of O2 recovery
(r=.70,
P<.01).
Conclusions Postexercise T1/2
O2 increases when CHF
worsens, perhaps
in part a result of slower kinetics of recovery of muscle energy
stores. The time course of oxygen consumption recovery may
represent a simple new criterion for measuring the impairment
of the circulatory response to exercise in CHF, even submaximal
exercise.
Key Words: oxygen consumption • exercise • heart failure • magnetic resonance spectroscopy
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Patients with chronic heart failure (CHF) are limited during exercise by dyspnea and fatigue. They generally also complain of difficulty in recovering normal breathing after an effort. In recent years, the pattern of increase in oxygen consumption during graded maximal exercise has been characterized extensively.1 2 Peak oxygen consumption is decreased, the ventilatory threshold appears earlier, and the slope of the increase in oxygen consumption versus time is reduced2 in parallel with the severity of circulatory failure. However, characterization of patients by their peak oxygen consumption is unsatisfactory because it requires maximal exercise by patients who are rarely used to strenuous activity and may lack sensitivity to detect subtle improvement in submaximal performance. Surprisingly, neither the characteristics nor the determinants of the postexercise phase in these patients are known. In healthy subjects, oxygen consumption declines rapidly after exercise.3 The kinetics of this recovery has been found to be related to the recovery of energy stores in active muscles.4 The latter has been characterized recently by the rate of recovery of inorganic phosphate (Pi) levels after exercise, which do not appear to be affected by workload.5 6 Because it has been reported that the recovery of energy stores in skeletal muscles is prolonged after exercise in patients with CHF,7 we hypothesized that repayment of the so-called "oxygen debt"8 is prolonged in these patients in parallel with the delayed recovery of energy stores in peripheral muscles and that the kinetics of recovery of oxygen consumption after exercise is a specific marker of the circulatory response during exercise, regardless of the intensity of the exercise test.
The aims of this study were (1) to determine the kinetics of recovery of oxygen consumption and other ventilatory variables after graded bicycle exercise, (2) to assess their relation with peripheral oxidative metabolism evaluated by nuclear magnetic resonance (NMR) spectroscopy, (3) to determine the reproducibility of the half-time of recovery of oxygen consumption, and (4) to assess its changes according to the degree of exercise.
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Methods |
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Subjects
This study involved 72 patients with stable CHF and 13 healthy subjects. All were men. Patients with CHF were in New York Heart Association (NYHA) functional class II (n=26) or III (n=46). Most had performed at least one preliminary exercise test before the study. They were selected because they had stopped exercising as a result of fatigue and/or dyspnea; those who stopped because of myocardial ischemia, arrhythmias, systemic hypertension, dizziness, or technical problems were excluded. The diagnosis of heart failure was based on a history of exertional dyspnea or pulmonary edema associated with one of the following: reduced left ventricular ejection fraction (<45%), increased echographic left ventricular end-diastolic diameter (>30 mm/m2), and cardiothoracic ratio >0.55 on the chest film. The causes of heart failure were ischemic or idiopathic cardiomyopathies. None of the patients had valve disease or respiratory insufficiency. Based on their peak oxygen consumption, the patients were classified into three groups according to the usual classification1 : 28 were in class A (CHF A), 21 in class B (CHF B), and 23 in class C (n=21) or D (n=2). Because of the small number of patients in class D (patients in NYHA functional class IV do not routinely exercise in our department), group D was combined with group C (CHF C/D). Age, body weight (Table 1
), height,
and body surface area were comparable in the control group and the
three patient groups. Treatments were not stopped before the exercise
test.
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The control group comprised 13 healthy untrained subjects. None had clinical signs of heart failure, echographic evidence of left ventricular dysfunction, or pulmonary disease.
All subjects gave informed consent, and the local ethics committee approved the study protocol.
Bicycle Exercise Tests
All exercise tests were performed in
the morning after the
subjects had a light breakfast. We used an upright graded bicycle
exercise with workload increments of 10 W/min for the patients and 20
W/min for the control group after a similar initial workload of 20 W.
Patients and control subjects were regularly encouraged to exercise
until exhaustion. The bicycle was an Ergoline 900 ergometer. The
calibration of the bicycle was checked regularly. Subjects pedaled at a
constant rate of 40 to 50 rpm. At maximal exercise, the load was
removed and the subjects were asked to stop pedaling.
Respiratory Gas Measurements
Respiratory gas analysis was
carried out with a Medical
Graphics Corp system. The system was calibrated with standard gas of
known concentration before each test. Subjects were asked to remain
still for 3 minutes before exercising to stabilize resting gas
measurements. A standard 12-lead ECG was recorded regularly, allowing
heart rate to be determined each minute. Blood pressure was measured by
a sphygmomanometer every 2 minutes. Oxygen consumption
(O2), CO2
production
(CO2), minute ventilation
(E), breathing rate, respiratory
exchange ratio,
ventilatory equivalents for oxygen
(E/O2)
and
CO2
(E/CO2)
production, and end-tidal pressures for oxygen
(PETO2) and for CO2
(PETCO2) were measured on a breath-by-breath
basis. The results were averaged with a moving-average filter every
seven breaths, excluding at each breath the highest and lowest value to
reduce the breath-by-breath noise. They were thereafter averaged every
15 seconds and printed. Peak oxygen consumption was defined as the
highest value of oxygen consumption obtained at the end of the test; it
was expressed both in milliliters per minute and in milliliters per
minute per kilogram. Indexed peak oxygen consumption (percent) was
calculated as peak oxygen consumption divided by maximal predicted
oxygen consumption, using the values reported by Wasserman et
al.9 The ventilatory threshold was determined by use of
the combination of multiple graphs.10 Among the classic
methods of detection of the ventilatory threshold, we generally favor
the use of a graph on which
E/O2,
E/CO2,
PETO2, and
PETCO2 are plotted simultaneously against
time. No ventilatory threshold could be determined for 1 healthy
subject and 11 patients.
Recovery was defined as the period beginning
when the workload was
removed. During this period, ventilatory variables gradually fall. In
healthy subjects, the kinetics of recovery of oxygen consumption
generally is considered to fit a single exponential
curve,11 12 13 14 but in most
cases, a multiexponential fitting
seems more suitable.14 15 Thus, we plotted oxygen
consumption versus time, assessed the slope of the single exponential
regression between the two during the first 3 minutes of recovery
(because it is recognized that a multiexponential fitting is more
accurate after this period, even in healthy subjects14 ),
and calculated the slope, k, of the exponential relation as
O2(t)=Ae-kt+C,
where k, the rate constant, is the slope of the curve, A is a
parameter, and C is the asymptotic baseline value, and the derived 
is the constant of time defined as 1/k and
T1/2(exp), the half-time, is defined as 0.693.
r varied from .99 to .88 (mean, .96±.02), indicating that
in some patients the kinetics of oxygen consumption recovery was
complex and incorrectly described by such a single exponential curve
fitting,13 in opposition to a previous
report.16
We thus characterized recovery kinetics by
simply measuring the
half-time of recovery, T1/2, ie, the time required
for a 50% fall in the peak value. When this occurred in the middle of
two sampling points, we set T1/2 at the second of these
points. This method has the advantage of being independent of the
regression model chosen (Fig 1). T1/2(exp)
O2 and T1/2
O2 were closely correlated
(r=.86, P<.0001). We also verified that
averaging the measures did not alter the results by comparing in 5
patients the slope obtained when breath-by-breath values instead of
averaged values were used.
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Continuous heart rate monitoring was evaluable in 57 subjects (11 healthy subjects, 12 patients in CHF A, 12 patients in CHF B, and 22 patients in CHF C/D). All were in sinus rhythm, and the mean age was the same in the four groups. Heart rate was averaged every 15 seconds during the first 3 minutes after exercise. Because T1/2 heart rate often exceeded this time, its determination was not possible. Thus, to analyze the kinetics of recovery of heart rate, each value was divided by the heart rate attained at peak exercise, and the slope of heart rate versus time was determined for each group. The decrease in heart rate during this period was well fitted to a second-order polynomial regression (r>.995 for each group), in accordance with previous studies.17 18
31P NMR Measurements
To study the relation between
the kinetics of recovery of oxygen
consumption and that of energetic metabolites in skeletal muscle after
exercise, 19 patients underwent a 31P NMR spectroscopy
exercise protocol during the same week as the bicycle exercise test.
Their mean age was 47±12 years; 10 were in NYHA class II and 9 in
class III; and their mean peak oxygen consumption was 19.5±6.2
mL · min-1 · kg-1.
Measurements were obtained with a Gyrex system operating at 2 T (Elscint). The patient lay prone in the magnet and exercised with the anterior compartment of the leg. The lower limb was positioned in mild hyperextension. The subject's foot was placed on a pedal attached to a load by a pulley system. A system of multiple Velcro straps was used to immobilize the limb to allow only the foot to move.
The exercise consisted of active dorsiflexions of the foot against the ergometer pedal, repeated every 2 seconds for 4 minutes, against a weight of 4.5 kg. In a preliminary study, using the body coil and T2-weighted images, we checked that the muscles of the anterior compartment of the leg were specifically involved in the exercise, as shown by the specific increase in signal intensity in the tibialis anterior and extensor digitorum longus.19 We used an 11-cm, square, double-tuned 1H 31P transmitter-receiver surface coil positioned over the anterior compartment of the right leg, centered on the upper one third. A flip angle of about 90° was obtained within the anterior compartment when the radiofrequency pulse was applied. Shimming was performed on the 1H signal. 31P spectra were obtained from the free-induction decay after application of nonselective radiofrequency pulses. Acquisition parameters included a time of repetition (TR) of 1500 milliseconds and 12 transients, resulting in an 18-second acquisition time. Achieved resolution was 0.5 ppm or less (full-width half-maximum for the phosphocreatine [PCr] peak). We applied a 5-Hz line broadening to our real spectra. Manual phasing and baseline correction were performed before quantification. An integration algorithm was used to calculate the areas under peaks by use of the criterion of the trough between adjacent peaks. The phosphorus compounds of interest were Pi and PCr. Their concentrations were proportional to the area under the respective peaks. The pHi value was obtained from the chemical shift of Pi relative to that of PCr by use of an equation derived from the Henderson-Hasselbalch equation. During recovery, the Pi/PCr ratio was calculated after correction for saturation, performed by comparing, at rest, spectra with TR=1500 milliseconds and relaxed (TR=10 seconds) spectra. Spectra were acquired at rest, during exercise, and at 15, 45, 75, 105, and 300 seconds after cessation of exercise. In addition to end-exercise data, this allowed six data points to be fitted to a single exponential model20 21 according to the equation
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where ee is end of exercise and T1/2 Pi/PCr is half-time of recovery of Pi/PCr.
This allowed us to compare the kinetics of recovery
of both
Pi/PCr and whole-body oxygen consumption by relating
T1/2 Pi/PCr and T1/2(exp)
O2, both similarly
calculated
from curve fitting.
Reproducibility of the Half-time of Recovery of Oxygen
Consumption
To assess the reproducibility of T1/2
O2, 12 subjects (10 CHF
patients and 2 healthy subjects) underwent two graded bicycle exercise
tests. Peak O2 and
T1/2
O2 were compared during
these two
tests.
Influence of Exercise Level on the Half-time of Recovery of Oxygen
Consumption
Three sets of experiments were performed to study the
influence
of the degree of graded exercise on the half-time of recovery of oxygen
consumption. After a maximal graded exercise test conducted until
exhaustion, 10 healthy subjects underwent two graded bicycle exercise
tests in random order at 75% and 50% of maximal workload. Recovery
was assessed by T1/2
O2
and T1/2(exp)
O2. Other
ventilatory variables were not analyzed. Similarly, 22 patients
underwent two graded exercise tests: 17 patients underwent two tests at
peak workload and 50% of peak workload, and 5 others performed two
tests, one until exhaustion and the other until 75% of peak workload.
Kinetics of recovery was assessed in the same way as in the healthy
subjects.
Statistical Analysis
Values are reported as mean±SD.
Comparison of T1/2
values among the four groups was done with ANOVA. If a significant
difference was detected by the F test, mean values were
compared with a Newman-Keuls post hoc test.22 Probability
values <.05 were considered significant.
The reproducibility of
T1/2
O2 and its variation
between the
maximal and submaximal tests were assessed both by linear regression
analysis and the method of Bland and Altman.23 Mean
and SD of differences of values (
) measured during the first and the
second tests were calculated. A coefficient of variation was also
defined as 1/nx
n (/T1/2x100),
where n
is the number of subjects and T1/2 is the half-time of
recovery. For comparison of T1/2
O2 values calculated in the
healthy
subjects after the three levels of exercise, we also used ANOVA
(repeated measures) followed by a modified t test
(Bonferroni method).
Correlations were identified with linear, exponential, or polynomial regression analysis as appropriate.
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Results |
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Table 1
gives the baseline characteristics of the subjects.
There
were no intergroup differences in age, body weight, body surface area,
or height. Peak O2 was
36.7±7.0
mL · min-1 · kg-1 in the
healthy
subjects and 22.9±2.2, 17.7±1.4, and 13.2±1.8
mL · min-1 · kg-1 in CHF A, B,
and
C/D patients, respectively.
After peak exercise, O2,
CO2, and
E
declined toward baseline at various rates (Fig 1). The
half-times of
recovery of the ventilatory variables are reported in Table 2.
All were greater in the CHF patients than in the
healthy subjects and increased progressively as CHF worsened (Fig
2).
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There was a negative relation between T1/2
O2 and peak
O2
(r=-.65,
P<.0001) (Fig 3), T1/2
E (r=-.57,
P<.0001),
and the ventilatory threshold (r=-.43,
P=.03).
T1/2 O2 also
correlated
with peak
E/O2
(r=.59) and peak
E/CO2
(r=.61) (P<.0001).
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Fig 4 shows the kinetics of recovery of heart rate as a
function of time during the first 3 minutes after exercise. The
regression slopes were identical in the four groups, indicating no
difference in the kinetics of recovery.
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During the NMR 31P spectroscopy exercise protocol,
cooperation was in general adequate, so the exercise could be carried
out until exhaustion, as attested to by a large decrease in
pHi at the end of exercise (from 7.04±0.05 to
6.34±0.25;
average decrease, 10±3%). The Pi/PCr ratio
increased from 0.12±0.04 to 1.41±0.66. The half-time of recovery
of
Pi/PCr and the half-time of recovery of
O2 were correlated
(r=.70,
P=.001) (Fig 5).
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The reproducibility of T1/2
O2 was quite good: the
correlation
coefficient between values measured during the two tests was
r=.96 (compared with r=.98 for peak
O2). The coefficients of
variation
were 5.9±8.0% for T1/2
O2 and 2.9±2.8% for
peak
O2 (Fig 6).
T1/2(exp) O2 was
less
reproducible (r=.86; coefficient of variation,
12.3±9.6%).
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T1/2 O2 in
the healthy
subjects after 100%, 75%, and 50% of peak exercise tests was 57±6,
57±6, and 53±8 seconds, respectively. For T1/2(exp)
O2, these values were
76±9,
72±13, and 81±8 seconds, respectively (Fig 7).
There
was no statistical difference among the three values for both
variables. Coefficients of variation between 100% and 75% and between
100% and 50% of peak workload levels were 5.7% and 8.6%,
respectively (Table 3).
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In CHF patients, the kinetics of recovery did not change significantly
when they exercised at 100% or 75% of peak workload.
T1/2(exp) O2 was
109±21
and 110±24 seconds, respectively; T1/2
O2 was 93±20 and
93±20 seconds,
respectively (NS) (Table 4). The coefficient of
variation of T1/2(exp)
O2
was only 4.4% and that of T1/2
O2 was 13.8%. However,
there was a
modest but significant difference in T1/2
O2 between 100% and 50% of
peak
workload, 103±23 and 93±19 seconds, respectively
(P=.02)
(coefficient of variation, 14%), whereas T1/2(exp)
O2 was not significantly
different
(93±19 versus 96±19 seconds) (coefficient of variation, 15%).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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This study indicates that recovery of all ventilatory variables is delayed after exercise in patients with CHF. Prolonged recovery of oxygen consumption appears to be related in part to slow recovery of energy stores in the peripheral skeletal muscles. T1/2
O2 was reproducible and
largely
unaffected by whether the test was maximal or submaximal.
The recovery kinetics of oxygen consumption following whole-body
exercise has been used as an index of oxidative capacity in healthy
subjects.12 24 The decrease in oxygen consumption
appears
to be classically related to oxygen debt8 after exercise,
which is generally considered to involve an initial fast
("alactacid") and a second slow ("lactacid")
component.3 In healthy subjects, the first component of
the recovery of oxygen consumption generally fits a single-exponential
or multiexponential fitting curve. The decrease in oxygen consumption
is immediate, and its velocity is impressive (Fig 1). The
half-time of
recovery is 25 to 45 seconds in healthy subjects, independent of the
kinetics of the oxygen consumption response during
exercise.3 11 14 25 However,
these studies were conducted
with constant-workload exercises, and it remained to be determined
whether these observations also applied to non–steady-state exercises
such as the graded maximal bicycle exercises generally used in
cardiology. For example, values of T1/2
O2 and T1/2(exp)
O2 in our control subjects
were higher
than in previous studies that used submaximal constant-workload
protocols but were similar to studies that used the same exercise
protocols.16 26 The determinants of the kinetics of
oxygen
consumption after exercise appear to be more complex in CHF patients.
We found that oxygen consumption fell much more slowly in CHF patients
in relation to the severity of circulatory dysfunction (as reflected by
peak oxygen consumption).
Various factors may account for the increase in T1/2
O2 in CHF, and slowed
replenishment of
energy stores in peripheral muscles may be the most important. A close
relation exists between the time required for resynthesis of
high-energy phosphates and oxygen consumption kinetics after exercise
in isolated perfused muscle.27 28 29
Studies of PCr recovery
in the calf muscle4 30 31 or in the
forearm32
with NMR spectroscopy have shown an initial fast phase of recovery with
a half-time of 25 to 30 seconds in healthy subjects, in agreement with
the corresponding T1/2
O2
value. The half-time of recovery of PCr or Pi/PCr
after exercise, which generally fits an exponential curve such as that
of T1/2 O2, was
found to be increased in CHF
patients21 33 34 and,
conversely, decreased in athletes.30 It has also been
stated that the half-time of PCr resynthesis is independent of the
workload attained at peak
exercise6 20 35 —at least as
long as the exercise level does not result in large decreases in pH or
ATP—and is thus characteristic of the oxidative pathway capacities of
the subjects. In our study, T1/2
O2 and T1/2
Pi/PCr correlated, suggesting that the slower
kinetics of replenishment of energy stores in peripheral skeletal
muscles after exercise may partly account for the increase in
T1/2 O2. The
fact that
this correlation was not as strong as expected from experimental
studies suggests that other factors may also account for the slower
recovery of oxygen consumption.
These other factors could include the decrease in blood velocity that
causes an increased transit time between peripheral muscles and the
mouth. Venous return and thus cardiac output greatly affect oxygen
consumption kinetics at the beginning of,36 37
during,2 38 and after exercise.39 Oxygen
consumption kinetics during constant-workload tests is prolonged when
the return of deoxygenated blood is slowed by reducing heart
rate,37 with ß-blockade,39 in cyanotic
congenital heart disease,36 or in CHF.40 This
mechanism also explains why oxygen consumption at each stage is lower
during ramp-test exercises2 than during long-stage
protocols38 in CHF patients. It is likely that for the
same reasons, during the first minutes after cessation of exercise,
there is a delay between oxygen consumption measured at the peripheral
muscles and the mouth that increases as heart failure
worsens.24 41 Thus, it seems unlikely that the
reduced
muscle metabolism at the end of exercise would be reflected in the lung
as soon in CHF patients as in healthy subjects. In the former,
respiratory gases sampled at the mouth during the first seconds of
recovery probably still correspond to modifications that occurred some
seconds before, during the exercise phase at the peripheral level,
resulting in a delayed decrease in oxygen consumption despite the
removal of workload. Thus, inadequate cardiac output during exercise
probably accounts for the prolongation of T1/2
O2.
Prolonged kinetics of recovery of oxygen consumption, however, is not
specific to CHF. Oxygen consumption recovery is shortened by
training42 43 44 and prolonged by bed
rest–induced
deconditioning,45 with ß-blockade,39 and in
chronic obstructive pulmonary disease.26 Therefore,
T1/2 O2 appears
to be
increased whenever transport to or use of oxygen in the working muscles
is impaired, such as in anemia, hypoxia, peripheral artery disease,
peripheral myopathies, or simply deconditioning. It is interesting to
note that the half-time of PCr recovery has also been found to be
determined largely by the oxidative capacities of peripheral
muscles5 46 but also partly by blood
flow.7 47 Recent studies have emphasized the
potential of
this variable for assessing the effects of
training48 49
and medical interventions50 on peripheral oxygen use
during exercise in patients with CHF. Because this measurement
necessitates expensive, long, and complex NMR spectroscopy, the
demonstration that the half-times of recovery of oxygen consumption and
of PCr are closely correlated may have important clinical implications
for the evaluation of the circulatory response of these patients to
exercise and for the assessment of the effect of medical treatment or
rehabilitation programs.
As for the delayed recovery of
CO2 and
E, although the repayment of the
oxygen debt may
itself explain the prolonged decrease in
E, other
mechanisms should be considered to explain the retarded recovery of
CO2. Retention of
CO2 in
exercising muscles deserves consideration.51
pHi is lower in muscles and normalizes more slowly after
exercise in CHF patients than in healthy
subjects.33 34
Lactic acid may thus be retained in muscle, decomposing bicarbonate and
raising CO2 tension in the muscle; this would stimulate
C-fiber discharges, keeping ventilation high.51 Decreased
blood flow that limits CO2 return to the lung may be
another mechanism explaining the prolongation of CO2
elimination. Because of the reduction in cardiac output, CHF patients
must increase the venoarterial CO2 content difference to
maintain CO2 during
exercise. This
difference can be widened only through a decrease in arterial
CO2 content (because of the complex relation between
CO2 content, CO2 tension,
PCO2, and pH), whereas venous
CO2 content remains unchanged, contrary to healthy
subjects.52 Thus, CHF patients must develop excess
ventilation during and after exercise beyond that needed to maintain
eucapnia to eliminate venous CO2. This probably differs
from that observed in chronic obstructive pulmonary disease, in which
the prolongation of T1/2
CO2 and
E is not
of peripheral origin but is attributed to delayed elimination of excess
CO2 by the lung.26 It seems unlikely, however,
that CO2 retention affects muscle oxidative metabolism and
prolongs oxygen consumption recovery after exercise; changes in
extracellular pH or HCO3- concentrations
decrease lactate output but do not affect PCr use, as measured by
31P NMR spectroscopy53 ; induced lactacidemia
does not affect postexercise oxygen consumption.54
A final mechanism, the increased cost of breathing, should be considered in the slow recovery of the ventilatory variables. In CHF patients, ventilatory power requirements are considered to be high.55 56 Stimulation of chemoreceptors by metabolites during recovery may stimulate ventilation, causing slowing of its return to baseline. Because respiratory muscles have high energy requirements, their elevated oxygen consumption and CO2 production will also return to baseline slowly.
Therefore, it is likely that multiple mechanisms—alterations in
oxygen
transport and/or use, CO2 retention, and increased cost of
breathing—are involved in the prolongation of recovery of
O2,
CO2, and
E
in patients with CHF.
What hemodynamic mechanisms account for the slower recovery of oxygen
consumption and CO2 after exercise? According to the Fick
equation, consumption of oxygen (or CO2 production) is the
instantaneous product of cardiac output, ie, heart rate multiplied by
stroke volume, divided by arteriovenous difference for oxygen (or for
CO2). To the best of our knowledge, the kinetics of
recovery of the arteriovenous difference for oxygen has never been
studied during the first 3 minutes after exercise in CHF patients. It
is interesting to note that an overshoot of the arteriovenous
difference for oxygen after exercise, descending beyond resting values
at minute 3, has recently been reported in patients with mild left
ventricular dysfunction.57 58 The pathophysiological
basis
of this phenomenon is unclear but may involve redistribution of blood
flow to nonexercising areas secondary to
sympathetic-induced59 60 61 or metabolic
acidosis–induced
vasoconstriction.62 This suggests that oxygen consumption
in the early recovery period is dependent on cardiac output rather than
on the arteriovenous difference for oxygen, contrary to the exercise
period, during which both participate in the increase in oxygen
consumption. This transient reduction of oxygen extraction after
exercise also suggests that blood flow during recovery is excessive for
the oxygen demand of the whole body. Sumimoto et al57
speculated that cardiac output during recovery is more responsible for
CO2 elimination than for oxygen transport. Unfortunately,
there is little information on blood flow dynamics during recovery in
healthy subjects and virtually none in CHF patients. The kinetics of
cardiac output in recovery seems to be slowed relative to the onset of
exercise in normal subjects.18 Previous studies showed
that heart rate declines more slowly in untrained than in trained
subjects,63 and our hypothesis was that CHF patients also
have a slower decrease in heart rate after exercise. Our results do not
confirm this hypothesis because the kinetics of the decrease in heart
rate during the first 3 minutes after exercise was the same as in the
control subjects and thus could not account for the marked differences
in T1/2 O2 among
the
various groups of subjects. As regards stroke volume response, a slight
rebound in stroke volume after exercise has often been reported in
healthy subjects, primarily in the supine
position,64 65 66 67
but data during the first minutes after exercise in patients with CHF
are lacking. In patients with coronary artery disease and mild left
ventricular dysfunction, Koike et al68 reported a marked
rebound of stroke volume just after cessation of upright exercise,
which may partly account for the slower decrease in oxygen
consumption.
T1/2 O2 was
reproducible
but slightly less so than peak oxygen consumption. This may have been
due in part to our method of measuring T1/2 every 15
seconds. Reproducibility was sufficient, however, to use
T1/2 O2
routinely as an
index of circulatory impairment during exercise and is far better than
that of the ventilatory threshold in CHF
patients.10 69 70 71 72 73
T1/2 O2 has
generally been
considered to be independent of exercise level in healthy subjects when
constant-workload protocols are
used.11 13 14 25 Hagberg
et al14 found that the half-time of the rapid component of
recovery of oxygen consumption was increased by only 5% when healthy
subjects exercised at 50% and then at 80% of
O2max. More recently,
Zanconato et
al74 reported that recovery of
O2 was independent of
work rate,
especially when the latter was above the ventilatory threshold.
However, how far this applies to graded exercises was not previously
determined. We found that during graded exercise, the exercise level
did not significantly affect T1/2
O2 when it remained greater
than 50%
of maximal workload. These characteristics may be of great value in
assessment of patients who often stop exercising before their maximum
because of symptoms or poor motivation. Thus, the kinetics of recovery
of oxygen consumption is, like that of PCr recovery, probably a
physiological feature of a given individual and can be determined with
confidence even for submaximal exercise. A T1/2
O2 >100 seconds (2 SD
above the mean
value of the control group) appears to be associated with
abnormal oxygen transport and/or use (Fig 3), even for
submaximal
exercise. Further studies are required to determine whether
T1/2 O2 is a
better
criterion of exercise tolerance than peak oxygen consumption for these
reasons.
Limitations
Our number of NMR spectroscopy measurements
during recovery for
fitting was limited compared with the acquisition conditions that can
be obtained with dedicated spectrometers. However, our values of
T1/2 Pi/PCr are in very good agreement
with those in the literature. The fact that we compared exercise
responses obtained with protocols that were quantitatively and
qualitatively different (the bicycle graded exercise protocol involving
about 40% of whole-body muscle mass and the NMR spectroscopy
constant-workload protocol being performed with a limited muscle
compartment of the leg, although both exercises were conducted until
exhaustion) may have yielded an underestimation of the correlation
between muscle T1/2 Pi/PCr and whole-body T1/2
O2.
Assessment of
oxygen consumption recovery by T1/2(exp)
O2 may not be very reliable
in case of
irregular breathing or when the sampling interval exceeds 15 seconds.
We found that T1/2
O2 was
simpler to determine than and yielded similar information to
T1/2(exp) O2,
and its
reliability might be increased by use of shorter sampling intervals.
Further studies are necessary to compare the sensitivity of these two
parameters for longitudinal changes in circulatory function.
T1/2 O2 must be
interpreted with care in the most severely affected patients (when peak
O2 is lower than three
times the
resting value) or when exercise is markedly submaximal (50% of peak
workload or less). However, our results indicate that the severity of
circulatory failure can be established with confidence for healthy
subjects and for most patients by the duration of recovery of oxygen
consumption when the exercise level is between 50% and 100% of peak
workload.
Conclusions
The recovery phase of exercise provides new
insight into the
impairment of the overall circulatory response during exercise in CHF
patients. Recovery of all ventilatory parameters is delayed in parallel
with the severity of the disease. This is likely to be related in part
to the slowed replenishment of energy stores in peripheral skeletal
muscles and to CO2 retention. This has implications for
understanding the symptoms reported by these patients after repeated
submaximal efforts during their daily activities because delayed
recovery of ventilation and oxygen consumption confer an added
metabolic cost to performance of repeated tasks. We also found that
T1/2 O2 was
largely
unaffected by exercise level. Therefore, the kinetics of recovery of
oxygen consumption, as determined by T1/2
O2, appears to be a
promising
criterion for evaluating the efficiency of oxygen transport and use
during maximal or submaximal exercise in CHF patients in addition to
classic measures of maximal exercise capacity.
|
Acknowledgments |
|---|
This work was supported by an INSERM grant 9110405. We thank Richard Hughson and Christian Prefaut for their helpful comments.
Received October 18, 1994; revision received December 15, 1994; accepted December 27, 1994.
|
References |
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