Download Respiratory Muscles Performance Is Related to Oxygen Kinetics

Respiratory Muscles Performance Is Related to Oxygen
Kinetics During Maximal Exercise and Early Recovery in
Patients With Congestive Heart Failure
Serafim Nanas, MD; John Nanas, MD, PhD; Christos Kassiotis, MD; George Alexopoulos, MD;
Anastasia Samakovli, MD; John Kanakakis, MD;
Elias Tsolakis, MD; Charis Roussos, MD, MSc, PhD, MRS, FRCP(C)
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Background—Dyspnea and fatigue are the main causes of exercise limitation in chronic heart failure (CHF) patients,
whose peak inspiratory (Pimax) and expiratory pressures (Pemax) are often reduced. The aim of this study was to examine
the relationship between respiratory muscle performance and oxygen kinetics.
Methods and Results—A total of 55 patients (NYHA class I to III) and 11 healthy subjects underwent cardiopulmonary
exercise tests (CPET) on a treadmill. In 45 of the 55 patients (group I) and in healthy subjects (group II), pulmonary
function tests, Pimax, and Pemax were measured before and 10 minutes after exercise, and oxygen kinetics were monitored
throughout and during early recovery from CPET. The first degree slope of oxygen consumption (V̇O2) decline during
early recovery (V̇O2/t-slope) and V̇O2 half-time (T1/2) were calculated. In 10 of the 55 CHF patients (group III), the
measurements of Pimax were repeated 2, 5, and 10 minutes after CPET. A .10% reduction in Pimax after CPET (subgroup
IA) was measured in 11 of 45 patients. In contrast, 34 of 45 CHF patients (subgroup IB) and all control subjects (group
II) had Pimax.90% of baseline value after CPET. Subgroup IA patients had significantly lower peak V̇O2 (13.562.1
versus 17.865.6 mL z kg21 z min21; P,0.001), lower anaerobic thresholds (10.162.4 versus 13.664.6 mL z kg21 z min21;
P50.003) and lower V̇O2/t-slopes (0.36560.126 versus 0.51960.227 L z min21 z min21; P50.008) than subgroup IB
patients.
Conclusions—The reduction of Pimax after exercise is associated with prolonged early recovery of oxygen kinetics, which
may explain, in part, the role played by respiratory muscles in exercise intolerance in CHF patients. (Circulation.
1999;100:503-508.)
Key Words: respiratory muscles n heart failure n oxygen n exercise test
I
Recent data support the view that the rate of decline in
oxygen consumption (V̇O2) during early recovery from exercise correlates well with exercise tolerance in patients with
CHF.21,22 The half-time of V̇O2 decline in early recovery from
exercise is prolonged in these patients compared with normal
volunteers, and nuclear magnetic resonance spectroscopy
shows that a slower recovery of limb-muscle energy stores
partly accounts for this phenomenon.22 These findings agree
with the results of experiments in isolated perfused canine
muscles, which showed that the recovery of V̇O2 follows the
same time course as the recovery of high-energy
phosphates.23
Because the time course of energy-store resynthesis resembles the recovery of maximum strength after exhaustive
exercise in humans,24,25 we hypothesized that the recovery of
muscle energy stores, as expressed by early exercise recovery
in oxygen kinetics, is associated with respiratory muscle
t has been suggested that respiratory muscle fatigue may
limit the exercise capacity of even normal subjects.1– 4
Dyspnea and fatigue are the main causes of exercise limitation, which negatively affects the quality of life of patients
with chronic heart failure (CHF).5–7 Respiratory muscle
dysfunction may play a role, although this has not been
investigated in depth. It has been proposed that dyspnea is
influenced by the central nervous system’s perception of
inspiratory motor output, a signal that increases with a
reduction in respiratory muscle strength.8 Respiratory muscle
strength depends, among others, on age, sex, nutritional
status, smoking, and fitness level.9 –14 Clinical studies have
shown that peak inspiratory (Pimax) and expiratory pressures
(Pemax),15–18 as well as respiratory muscle endurance,19 are
reduced in patients suffering from CHF compared with
age-matched normal subjects. This reduction correlates with
the degree of dyspnea.20 The cause of this respiratory muscle
dysfunction remains speculative.
Received December 31, 1998; revision received May 5, 1999; accepted May 5, 1999.
From the Departments of Pulmonary and Critical Care Medicine (S.N., C.K., A.S., C.R.) and Clinical Therapeutics (J.N., G.A., J.K., E.T.), National
and Kapodestrian University, Athens, Hellas, Greece.
Correspondence to Serafim Nanas, MD, Pulmonary and Critical Care Department, Evgenidio Hospital, Papadiamantopoulou 20, Athens 11528, Hellas,
Greece.
© 1999 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
503
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August 3, 1999
TABLE 1.
Baseline Characteristics of Study Participants
Male/female
Age, y, mean6SD (range)
CHF Patients
(Group I, n545)
Healthy Volunteers
(Group II, n511)
CHF Patients
(Group III, n510)
41/4
5/6
8/2
48615 (20–74)
42613 (19–63)
54611 (29–64)
P*
NS
NYHA functional class (n)
I
19
II
17
III
Body mass index, kg/m2
1
NA
4
27.163.7
24.963.8
9
25.463.4
5
NS
Cause of CHF (n)
Ischemic
16
Dilated cardiomyopathy
25
3
NA
7
Valvular disease
2
zzz
Other
2
zzz
*Group I vs. Group II.
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performance. The objective of this study was to examine the
relationship between maximal respiratory mouth pressures,
before and after exercise, and early recovery oxygen kinetics.
Patients and Methods
A total of 55 patients (49 men and 6 women) with CHF and
11 healthy volunteers were studied. The study was reviewed
and approved by the Human Study Committee of our Institution, and informed consent was formally obtained from
each participant. All subjects performed tests of maximal
respiratory pressures before and after cardiopulmonary exercise tests (CPET). In 45 of the 55 patients (41 men and 4
women) with CHF (group I) and in the 11 healthy volunteers
(group II), the measurements of maximal respiratory pressures were performed before and 10 minutes after the end of
CPET. In the remaining 10 of the 55 patients with CHF
(group III), the measurements of maximal respiratory pressures were performed before the beginning of CPET and were
repeated 2, 5, and 10 minutes after the end of CPET. Table 1
lists selected characteristics pertaining to each group. All
patients were clinically stable and optimally treated at the
time of study. Those with recent myocardial infarction,
respiratory insufficiency, or other conditions affecting exercise capacity were excluded from the study.
Pulmonary Function Tests
Each study participant had forced vital capacity (FVC) and
forced expiratory volume in 1 second (FEV-1) measured in
the sitting position before exercise.
Maximal Respiratory Pressures
The measurements of maximal respiratory pressures were
performed using the Vmax 229 system of pulmonary and
metabolic tests (Sensormedics). The method used was similar
to that described by Black and Hyatt.10 Patients were seated
and breathed through a scuba-type mouthpiece attached to a
3-way valve with a small leak incorporated in the airway.26
For the measurement of Pimax, each patient was instructed to
exhale to the residual volume followed by a maximal inspiratory effort through the mouthpiece. The maneuver was
repeated until 3 reproducible measurements with a ,5%
variability had been obtained; the highest pressure measured
was used for analysis. For the measurement of Pemax, each
patient was instructed to inhale to total lung capacity followed by a maximal expiratory effort through the mouthpiece. During expiratory maneuvers, light pressure was applied to the cheeks to minimize the contribution of facial
muscles.26
Pulmonary function tests and respiratory pressure measurements were repeated 10 minutes after the end of CPET for all
study participants. However, in group III, additional respiratory
pressure measurements were obtained 2 and 5 minutes after the
end of CPET. Differences in maximal respiratory pressures
measured before and after the exercise test were considered an
index of respiratory-muscle endurance. A reduction of 10% in
maximal pressures after CPET was chosen to separate 2 subgroups of patients included in group I. This arbitrary percentage
was chosen because it represents twice the generally accepted
intraindividual variation in measured maximal respiratory pressures. Subgroup IA includes the patients who had a reduction in
Pimax.10% between baseline value and exercise, and subgroup
IB included the patients who had a Pimax.90% of baseline value
after exercise.
Cardiopulmonary Exercise Testing
CPET was performed on a treadmill. The protocol (modified
Bruce or modified Naughton)27 was chosen to avoid an exercise
duration longer than 15 minutes. Blood pressure measurements
were obtained every 2 minutes using a standard-cuff mercury
sphygmomanometer. ECG and peripheral blood O2 saturation
were monitored throughout the test. Patients and normal volunteers self-graded their degree of dyspnea during CPET using the
Borg scale.28 V̇O2, carbon dioxide output (V̇CO2), and air flow
were measured on a breath-by-breath basis using the Vmax 229
monitor for pulmonary and metabolic studies. The system was
calibrated with a standard gas of known concentration before
each test. These measurements were obtained with the subject in
the upright position before and during exercise and with the
subject sitting in a chair during the first 10 minutes of recovery.
Nanas et al
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Baseline V̇O2 was calculated by averaging the measurements
made for 2 minutes before the beginning of exercise.
Peak V̇O2 was calculated as the average of measurements
made for 20 s before the end of exercise. Anaerobic threshold
(AT) was determined using the V slope technique,29 and the
result was confirmed by a graph on which the respiratory
equivalent for oxygen (VE/V̇O2) and carbon dioxide (VE/
V̇CO2) were plotted simultaneously against time. To evaluate
V̇O2 kinetics during recovery in groups I and II, the firstdegree slope of V̇O2 for the first minute of the recovery period
was calculated by linear regression using an appropriate
computerized statistical program. The first minute was chosen to guarantee that the measurements would reflect the
alactic phase of the repayment of oxygen debt.23,30 The time
required for a 50% fall from peak V̇O2 (T1/2 of V̇O2) was also
calculated. When it occurred in the middle of 2 sampling
points, T1/2 of V̇O2 was set at the second of these points.22
In group III patients, the maximal respiratory pressure measurements were consecutively obtained 2, 5, and 10 minutes
after the end of CPET. Consequently, in that group, V̇O2 kinetics
could not be practically measured during recovery.
Patients and normal volunteers were instructed to exercise
until exhaustion. Endpoints of CPET were dyspnea, fatigue,
leg weakness, and chest discomfort. Subjects who terminated
CPET because of dizziness or chest pain or who developed a
serious arrhythmia were excluded from the study.
Statistical Analyses
Results are presented as mean6SD unless otherwise stated.
The significance of differences between means was examined
with Student’s t test. Correlation between Pimax, Pemax, and
peak V̇O2 were tested by Pearson’s correlation coefficient.
The Mann-Whitney test was used to compare differences
between groups classified according to Weber31 (see below).
A repeated measurement ANOVA was used to compare
changes in Pimax measurements at different times of recovery
in group III. P,0.05 was considered statistically significant.
Results
In the group I patients, the mean pulmonary capillary wedge
pressure at rest was 14.467.3 mm Hg, and the mean left
ventricular ejection fraction was 24.069.5%. Table 2 summarizes the results of CPET in CHF patients versus healthy
subjects. Both Pimax and Pemax, at rest and after exercise, were
greater in controls than in CHF patients. Conversely, T1/2 of
V̇O2 was longer in CHF patients than in healthy volunteers.
The percent change of Pimax or Pemax after exercise was not
statistically different between the two groups. No control
subject had a .10% reduction of Pimax after CPET.
In group III patients with 3 measurements of Pimax during
recovery, a repeated measurement ANOVA showed statistically significant changes (F55.6; P,0.028). A decrease was
found at 2 and 5 minutes after CPET compared with preexercise values, whereas no difference was observed 10 minutes
after CPET (Figure 1).
A total of 11 of the 45 group I patients (subgroup IA) had
a .10% decrease in Pimax after CPET. Table 3 summarizes
the pertinent comparisons between these 11 patients and the
34 patients whose Pimax did not change significantly (sub-
Respiratory Muscles and Oxygen Kinetics
505
TABLE 2. Results of Cardiopulmonary Testing in Patients
Versus Healthy Volunteers
CHF Patients
Healthy Volunteers
(Group I, n545) (Group II, n511)
FEV-1, %
Peak V̇O2, mL z kg21 z min21
AT, mL z kg
21
z min
21
P
83615
107612
0.001
16.765.3
26.964.9
0.001
0.001
12.664.3
19.963.9
0.48160.216
0.88960.327
0.002
1.560.4
1.160.2
0.001
At rest
73624
88618
0.036
After exercise
72625
95618
0.003
20.51621
9614
0.075
At rest
53617
84618
0.001
After exercise
49620
72614
0.001
V̇O2/t-slope, L z min21 z min21
T1/2 of V̇O2, min
Pimax, % of predicted
%D in Pimax after exercise
Pemax, %
Values are mean6SD.
group IB). There was no difference in preexercise Pimax and
Pimax% between patients in subgroups IA and IB (Table 3).
Subgroup IA had lower mean peak V̇O2, mean V̇O2 at the AT,
and mean V̇O2/t-slope. There were no significant differences
between the 2 subgroups in left ventricular ejection fraction,
pulmonary capillary wedge pressure, cardiac index, FEV-1%,
FVC%, or FEV-1/FVC. Subgroup IA patients showed a trend
toward a higher degree of dyspnea (Borg scale). Subgroup IB
patients had lower mean peak V̇O2 (17.865.6 versus
26.964.9 mL z kg21 z min21; P,0.001), lower mean V̇O2 at
the AT (13.664.6 versus 19.963.9 mL z kg21 z min21;
P,0.001), lower mean V̇O2/t-slope (0.51960.227 versus
0.88960.327 L z min21 z min21; P,0.005), and greater T1/2
(1.560.4 versus 1.160.2 minutes; P,0.001) compared with
controls (group II).
The patients in group I were further subclassified using
Weber’s scale based on peak V̇O231: 12 patients were in class
A, 9 in class B, and 24 in class C/D. No patient in Weber class
A had a .10% reduction in Pimax after CPET; however, 2 of
9 patients (22.2%) in Weber class B and 9 of 24 patients
Figure 1. Mean and SEM of Pimax before CPET and 2, 5, and 10
minutes after CPET during recovery period. Statistically significant
difference compared with preexercise value: *P,0.02, **P,0.002.
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August 3, 1999
TABLE 3. Cardiopulmonary Function and Exercise Test Indices
in Patients With CHF
Group I
Subgroup IA
Subgroup IB
P*
Pimax, cmH2O
82626
80627
83627
NS
Pimax, %
73624
78631
72621
NS
Peak V̇O2, mL z kg21 z min21
16.765.3
13.562.1
17.865.6
0.001
VE peak, L/min
63.6619.9
58.7615.4
65.3621.1
NS
21
AT, mL z kg
z min
21
12.664.3
10.162.4
13.664.6
0.003
0.48160.216
0.36560.126
0.51960.227
0.008
VE/VO2 (T1/2)
55.4612.4
62.2611.1
53.2612.2
NS
PCWP, mm Hg
14.467.3
17.166.9
13.567.3
NS
LVEF, %
V̇O2/t-slope, L z min21 z min21
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24.069.5
22.468.7
24.669.9
NS
Cardiac index, L/(m2 z min)
2.460.6
2.461.1
2.460.5
NS
Borg dyspnea scale
4.362.0
5.762.9
3.961.7
NS
FEV-1, % predicted
83615
81616
84615
NS
FVC, % predicted
90614
84615
91613
NS
FEV-1/FVC, % predicted
7669
7868
7569
NS
Results are mean6SD. PCWP indicates pulmonary capillary wedge pressure; LVEF, left ventricular
ejection fraction; and NS, not significant. VE/V̇O2 (T1/2)5ventilation per liter of oxygen uptake during
the measurement of T1/2 V̇O2.
*Subgroup IA vs IB.
(37.5%) in Weber class C/D did (Figure 2). The differences
between these groups were statistically significant
(P50.028). In group III, 4 patients were in class A, 2 in class
B, and 4 in class C. Two of these patients failed to return to
within 10% of the preexercise Pimax within 10 minutes.
A weak correlation was measured between peak V̇O2 and
Pimax before CPET (r50.33; P50.027) in group I patients.
There was no correlation between Pemax and peak V̇O2. In both
patients and controls, Pimax 10 minutes after the CPET
correlated significantly with V̇O2/t-slope (r50.39; P50.003)
(Figure 3). The correlation, although weaker, was still significant when controls were removed (r50.31; P50.039).
Discussion
This study showed that the pressure-generating capacity of the
respiratory muscles is not reduced 10 minutes after CPET in the
Figure 2. Frequency distribution according to Weber31 classification
of participants with and without .10% reduction of Pimax after CPET.
majority of CHF patients. However, when a fall in Pimax does
occur, it is associated with altered oxygen kinetics, ie, the
subgroup of CHF patients with Pimax,90% of baseline value
after CPET (subgroup IA) had significantly longer recovery of
basal metabolism (V̇O2/t-slope) and a significantly lower AT and
peak V̇O2 than the subgroup of CHF patients whose Pimax did not
decrease significantly after CPET (subgroup IB).
Maximal Respiratory Pressures
The maximal respiratory pressures are considered reliable
indices of respiratory muscle strength.9,10 Thorough coaching
and patient motivation allows highly reproducible measurements.13 A potential limitation of the method is that higher
maximal respiratory pressures can be reached through a
“learning effect.”13 The design of this study, which used the
Figure 3. Relationship between Pimax at the tenth minute of the
recovery period andV̇O2/t-slope in patients with congestive heart
failure and controls. Pimax is significantly correlated withV̇O2/tslope (r50.39; P50.003).
Nanas et al
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measurement of maximal respiratory pressures before exercise as baseline to evaluate the changes occurring after
exercise, aimed to circumvent this potential problem because
the learning effect, if existent, would have resulted in an
underestimation of the Pimax reduction after exercise. This
learning effect may, thus, have accounted for the borderline
(,10%) reduction in Pimax after CPET in some of our patients.
CPET is a form of endurance test for the respiratory
muscles capable of producing a decline in Pimax immediately
after exercise in healthy subjects. This is also the case for
CHF patients, as evidenced by the report of Mancini et al,20
who reported that the maximal respiratory pressures measured at peak exercise were lower than the values measured at
rest. This reduction of Pimax at peak or immediately after
exercise most likely represents high-frequency fatigue of the
respiratory muscles, because beyond 2 minutes, a gradual
return to normal occurs, at least in healthy human subjects.
To our knowledge, the pattern of recovery of Pimax in CHF
patients has not yet been studied.
Our finding that Pimax was not decreased 10 minutes after
exercise in the majority of CHF patients indicates that the pattern
of recovery of Pimax is similar to that observed in normal
subjects,32,33 where a significant decline occurs within the first 2
minutes after CPET, with a gradual return to normal thereafter.
This is further evidenced by the repeated Pimax measurements
after the end of CPET in group III patients, who showed a
decrease of Pimax at 2 and 5 minutes, but not at 10 minutes in
comparison with preexercise values. However, this was not the
case for all CHF patients. The large number of patients we
studied allowed us to identify a subgroup of CHF patients whose
Pimax was reduced 10 minutes after CPET, which probably
reflected a component of low-frequency fatigue. Was this
different respiratory muscle performance associated with oxygen
kinetics as hypothesized?
Oxygen Kinetics
Comparison of Pimax and Pemax before and after CPET in the
same individuals in relation to oxygen kinetics has not been
previously examined. Therefore, in this study, Pimax and Pemax
measurements were repeated at 10 minutes into recovery
from exercise. In agreement with previous findings, a weak
(although statistically significant) correlation, before and
after CPET, existed between Pimax and peak V̇O2.17,34
Assuming that the fall in V̇O2 during early recovery from
exercise is linear, V̇O2 recovery in patients with CHF was
examined in a linear regression model. Our measurements
applied to the fast component (alactic phase) of the repayment of
the oxygen debt.30 Investigators who studied the repayment of
oxygen debt have used single23,35,36 and double exponential
equations36 to describe the fall in V̇O2 during the recovery period.
It was observed in stable workload protocols that the time
constant and half-time (T1/2) derived from it were independent of
the work level.35 Recently, Cohen-Solal et al22 used the T1/2 of
V̇O2, calculated as the time required for a 50% fall in the peak
V̇O2, to describe the fall in V̇O2 during recovery from exercise in
patients with CHF. A close correlation was found between this
T1/2 of V̇O2 and that derived from the time constant of exponential equations.22 It was observed during graded exercise in CHF
patients that T1/2 of V̇O2 remained independent of the level of
Respiratory Muscles and Oxygen Kinetics
507
exercise as long as workload remained above 50% of maximal.
Having to choose the second point when T1/2 of V̇O2 happens to
fall between 2 sampling points is a methodological shortcoming,
which may cause considerable variability in the results, particularly when using the breath-by-breath technique. We attempted
to circumvent this problem by using the V̇O2/t-slope during the
early recovery period.
The value of V̇O2/t-slope in the early recovery period was
significantly less in subgroup IA patients than in subgroup IB
patients. The association of postexercise Pimax with oxygen
kinetics is further supported by the correlation of Pimax with
V̇O2/t-slope found in our study. This may be due to the slower
recovery of muscle energy stores,22 because the time course
of energy stores resynthesis resembles the recovery of maximum strength after exhaustive exercise in man.24,25 The
pathophysiological mechanism of the slower recovery of
muscles’ energy stores is not yet clear. Supinski et al,37 in an
animal model of heart failure, found that the maximum
phrenic arterial flow achieved during electrically induced
diaphragmatic fatigue was appreciably less and the duration
of postocclusive hyperemia in diaphragmatic muscle was
significantly longer in animals with heart failure. Furthermore, hyperemic blood volume during the first minute after
occlusion was significantly lower (ie, the time to repay the
blood volume debt of the diaphragmatic muscle in animals
with heart failure was prolonged). It is, therefore, tempting to
speculate that an analogous vascular dysfunction occurs in
the respiratory muscles of some CHF patients, which would
account for the decrease in Pimax and the slower recovery of
oxygen kinetics that was observed in this study. Recent data
suggest that oxygen delivery to working skeletal muscle, as
evaluated by nuclear magnetic resonance and near-infrared
spectroscopy, is impaired during recovery from maximal
bicycle exercise in CHF patients.38,39 Moreover, Mancini et
al20 found serratus anterior muscle deoxygenation during
maximal bicycle exercise, consistent with respiratory muscle
ischemia. At the extreme end of this dysfunction, respiratory
muscle underperfusion during cardiogenic shock caused by
tamponade in dogs led to diaphragmatic fatigue.40
These observations are concordant with a significant reduction in peak V̇O2 and AT, as well as a lower V̇O2/t-slope
during recovery among subgroup IA patients. This association of respiratory muscle function with indices of recovery
oxygen kinetics in CHF patients has not been reported before.
Patients with CHF have several histological and biochemical changes in their striated muscles, including fewer oxidative slow-twitch fibers, impaired aerobic-oxidative capacity,
and an earlier shift toward anaerobic metabolism during
exercise, causing the so-called oxygen debt.41 These changes
are not homogeneous throughout the CHF population, and
they are not attributed to changes in muscle blood flow, but
rather to intrinsic alterations in the muscle.42,43 This variability in muscle metabolism and histology38,44 may partially
explain the variability in Pimax after CPET among our patients.
In summary, respiratory muscle performance, expressed as
maximal respiratory pressure after CPET, is not reduced
(except transiently) in the majority of patients with heart
failure. However, a long-lasting .10% decrease of maximal
inspiratory pressure at late recovery was observed in CHF
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Circulation
August 3, 1999
patients, with significantly lower exercise capacity and significantly delayed recovery of resting oxygen consumption.
These observations provide new insights into the pathophysiological mechanisms of respiratory muscle performance in
patients suffering from CHF.
Acknowledgment
22.
23.
We thank Dr Theodoros Vasilakopoulos for his suggestions on the
final form of this manuscript.
24.
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25.
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Respiratory Muscles Performance Is Related to Oxygen Kinetics During Maximal
Exercise and Early Recovery in Patients With Congestive Heart Failure
Serafim Nanas, John Nanas, Christos Kassiotis, George Alexopoulos, Anastasia Samakovli,
John Kanakakis, Elias Tsolakis and Charis Roussos
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Circulation. 1999;100:503-508
doi: 10.1161/01.CIR.100.5.503
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