(Circulation. 1996;93:940-952.)
© 1996 American Heart Association, Inc.
Articles |
Contribution of Muscle Afferents to the Hemodynamic, Autonomic, and Ventilatory Responses to Exercise in Patients With Chronic Heart Failure
Effects of Physical Training
From the Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London (M.P., A.L.C., M.V., S.A., A.J.S.C.), and the Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford (M.P., P.S.), UK.
Correspondence to Massimo Piepoli, MD, Department of Cardiac Medicine, National Heart and Lung Institute, Dovehouse St, London SW3 6LY, UK.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background A neural linkage between peripheral abnormalities and the exaggerated exercise responses in chronic heart failure (CHF) was postulated. We studied the ergoreceptors (afferents sensitive to skeletal muscle work) in CHF and whether training can affect their activity.
Methods and Results In 12 stable CHF patients (ejection fraction [EF]=26.4%) and 10 control subjects (EF=55.3%), we compared the responses to dynamic handgrip and during a 3-minute period of posthandgrip regional circulatory occlusion (PH-RCO). The ergoreflex contribution was quantified as the percentage responses to exercise maintained by PH-RCO compared with recovery without PH-RCO. Patients showed ergoreflex overactivation compared with control subjects in terms of ventilation (86.5% versus 54.5%), diastolic pressure (97.8% versus 53.5%), and leg vascular resistance (108.1% versus 48.9%) (all P<.05). The contribution of the ergoreflex to vagal withdrawal (high frequency of RR variability) and sympathetic activation (low frequency of RR, pressure variability) was evident in both groups. Nine control subjects and nine CHF patients participated in 6 weeks of forearm training. Training reduced the ergoreflex contributions more in CHF than in control subjects: diastolic pressure (-33.2% versus -4.6%), ventilation (-57.6% versus -24.6%), and leg vascular resistance (-59.9% versus -8.0%) (all P<.05).
Conclusions (1) The ergoreflex role has a larger effect on the responses to exercise in CHF than in control subjects. (2) Training may reduce this exaggerated ergoreflex activity, thereby improving the responses to exercise.
Key Words: heart failure • exercise • muscles
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Reduced exercise capacity with increased breathlessness and muscle fatigue is a major cause of morbidity in patients with stable CHF who limit activity to avoid these symptoms. This results in deconditioning and hence possibly leads to a vicious circle of progressively worsening exercise tolerance.
Ventilatory responses to exercise are increased in CHF.1 2 Peripheral abnormalities have been demonstrated in skeletal muscle histology,3 mitochondria,4 oxidative enzyme activities,5 and high-energy phosphate handling6 together with early muscle fatigue,7 sympathetic overactivity, and parasympathetic withdrawal.8 9 The exact mechanisms causing these modifications after the development of left ventricular dysfunction have not been fully characterized.10
Several observations suggest that changes in the periphery are important determinants of exercise performance in CHF. First, left ventricular function and systemic hemodynamics correlate poorly with exercise capacity.11 Second, central hemodynamic improvements with drug therapy, including angiotensin-converting enzyme inhibitors, are rapid, but increases in exercise capacity are delayed for weeks or months.12 Neither pulmonary capillary wedge pressure13 nor blood lactate14 correlates well with exertional breathlessness, suggesting a crucial missing link in the mechanisms of exercise limitation in CHF.
Physical training in CHF has been shown to partially reverse the muscle
metabolic abnormalities15 in addition to those
of the autonomic tone (a reduction of sympathetic and an increase in
vagal activity9 16 ) and the ventilation (reductions
in
ventilatory equivalents for CO2
[
/CO2],
tidal volume, and
respiratory rate during submaximal exercise) but without any detectable
effect on central hemodynamics.13 16 Thus,
the major adaptations to training may be peripheral. This
may clarify the link between the abnormal skeletal muscle
metabolism and the heightened respiratory, circulatory, and
autonomic responses seen in CHF.17
Unmyelinated and small myelinated afferents in muscle exist that are sensitive to metabolic changes related to work (ergoreceptors).18 They have been shown to be responsible for the early circulatory response to exercise, including activation of the sympathetic vasoconstrictor drive.19 20 This reflex might be sensitized by the muscle acidosis seen in CHF during exercise. Therefore, we investigated this reflex in patients with CHF before and after physical conditioning.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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The study was approved by the local ethics committees. All subjects gave written informed consent.
Study Population
We studied 12 patients with stable CHF due
to ischemic
heart disease and 10 control subjects with normal left
ventricular function (Table 1
). All subjects
were clinically stable, physically inactive, in sinus rhythm, and on
unchanged medication for at least 3 months before the study. None were
participating in any exercise training program or had any significant
chronic lung or valvular heart disease, diabetes, or
neuromuscular disorder.
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The CHF patients were all symptomatic (mean
duration of
heart failure, 18±3 months; range, 8 to 38 months). They were selected
only if they were limited by breathlessness or muscle fatigue, without
evidence of exercise-induced myocardial ischemia,
arrhythmias, or claudication; patients with diabetes,
peripheral vascular disease, myopathy, or thyroid
dysfunction or those taking ß-blockers, ß-stimulants, or
digoxin were excluded because these interfere with the autonomic
indexes and potassium homeostasis. Left ventricular
ejection fraction was <30% at cardiac catheterization
(9 cases) or radionuclide ventriculography (3 cases) in patients and
>50% in the control subjects who had previously undergone cardiac
catheterization for ischemic heart disease
assessment. Exercise capacity and peak O2 consumption
(O2max) were tested on a
Tunturi
upright bicycle ergometer in 5-minute, 25-W incremental stages to
exhaustion; the tests were repeated at least twice in the laboratory
until reproducible exercise performances were determined.
Protocol
After clinical screening, the subjects performed the
bicycle
exercise tests to determine their exercise capacity and to become
familiar with the laboratory environment.
A first assessment test was
performed to evaluate the muscle ergoreflex
activity (assessment 1); thereafter, the subjects were enrolled for the
training program (Fig 1). The study was designed as a
random-order, crossover, controlled comparison21 of 6
weeks of localized training and 6 weeks of restricted activity
(detraining). The physician supervising the patient during the exercise
test was unaware of the clinical conditions and the training status of
the subject.
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The subjects were asked to avoid strenuous physical activity for at least 24 hours before each assessment test and to refrain from eating and smoking for 3 hours before. All exercise tests were performed at the same time of day on constant medication with the patient supine with the arm extended. First, a maximal voluntary handgrip contraction was measured as the greatest of the peak forces produced by three brief maximal handgrip contractions.
The evaluation of the ergoreflex
activity before and after training or
detraining (Fig 1
) included two exercises, performed in random
order:
(1) a control handgrip exercise using repetitive finger flexion by
pulling a lever of a dynamometer at 50% of the predetermined maximal
contraction (this was done with the nondominant arm at the rate of 40
pulls per minute until exhaustion); (2) the same protocol followed by,
from 10 seconds before the end of exercise, 3 minutes of circulatory
(venous and arterial) occlusion by forearm tourniquet
inflation to +30 mm Hg above systolic pressure (PH-RCO). After
the cuff was inflated, the subject was instructed to relax. Thus, the
contribution of the muscle ergoreceptors was evaluated by trapping of
the metabolites in the exercising muscle after exercise. This protocol
has been shown to fix the metabolic state of the muscle and
to prolong the activation of the ergoreceptors.20 22
Thirty minutes separated each bout of handgrip exercise. A control RCO by tourniquet inflation at 200 mm Hg at rest without previous exercise was also performed to exclude the possibility that occlusion alone was producing any reflex response.
Handgrip tests were performed on a conventional handgrip dynamometer (Jamar) modified and connected to a display positioned in front of the subject to show him or her the amount of effort of each contraction (in watts) to help the subjects maintain the same level of exercise.
Training Program
The subjects were randomly allocated either
to a nondominant
forearm training program (training), previously
described,23 or to avoid any exercise (detraining) (Fig
1). Training consisted of two or three sessions daily for 6
weeks.
Subjects gently stretched the forearm muscles first and then squeezed a
hand-held dynamometer device (the Gripper) as tightly as possible
for 10 seconds, followed by 20 seconds of rest, for a total of 10
repetitions per session. After a 5-minute rest period, they repeatedly
squeezed the handgrip 40 times per minute for 5 minutes. Compliance was
monitored by daily calendar; compliance exceeded 95%.
After the 6 weeks
of training or detraining periods, maximal voluntary
handgrip contraction was measured (the reported values are the means of
the three determinations), and the ergoreflex assessment tests were
repeated (assessment 2 and assessment 3) (Fig 1).
Measurements
The subject first rested for 30 minutes in a
quiet, darkened
environment. For assessment 1 only, a 20-gauge brachial artery catheter
was previously inserted into the nonexercising arm under local
anesthesia for the later withdrawal of blood samples.
Catheter patency was maintained by repeated flushing with heparinized
saline (2 IU/mL). Fig 2 is a schematic
representation of a subject with the study measurements.
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Heart
Rate, Blood Pressure, and Power Spectral
Analysis
Heart period was derived from the ECG. Blood pressure was
recorded beat to beat with the noninvasive Ohmeda 2300 Finapres
device (Ohmeda Monitoring System), which has been shown to provide a
reliable index of blood pressure changes over a short
period.24 For assessment 1 only, when a brachial artery
catheter was inserted into the nonexercising arm, the blood pressure
was also assessed with the arterial line; however, since
the line was also used for blood sampling, continuous blood pressure
monitoring was not possible for all phases of the study.
The nonquantitative respiratory signal for spectral analysis was obtained by an impedance device.25 Data were digitized on-line by a 12-bit analog-to-digital converter (NB-MIO-16 board, National Instruments) at a sampling rate of 500 samples per second and connected to a Macintosh IIcx computer (Apple Inc) equipped with 5-MB RAM memory and a 60-MB hard disk.25 Stable sections of data of 256 beats were selected by visual examination and analyzed: relatively short data records were chosen because the physiological changes that occurred during and after exercise were changing significantly on a longer time scale.
Periodic variations in the RR interval and systolic and diastolic blood pressures provide indexes to follow changes in autonomic neural activity induced by changes in physical activity, posture, or other sources of stimulation or blockade. This variability was presented as SDs and spectral power density in defining HF and LF regions. The absolute powers of the harmonic components were presented as natural logarithms (ln ms2 or ln mm Hg2) to minimize skewness. The LF range of periodicity was defined as that between 0.03 and 0.14 Hz, and the HF component was defined as lying between 0.18 and 0.4 Hz. The LF component of RR interval and blood pressure variability has been considered predominantly an index of sympathetic activity and the HF component in the RR variability an index of vagal tone.25 26 To estimate the relative predominance of each frequency component, the relative power of each component was computed as percentage of the total variability (excluding very-low-frequency fluctuations, <0.03 Hz).
Peripheral Blood Flow
Right leg
(nonexercising limb) blood flow was measured at the
same time by standard techniques27 with a
mercury-in-Silastic strain-gauge plethysmograph (Hokanson) and
expressed in mL·100 mL
tissue-1·min-1.
The corresponding leg vascular resistance (expressed in arbitrary
units) was computed from these data.
Ventilatory Data
Subjects breathed air through a mouthpiece with a nose clip in
place, and continuous on-line ventilation and expiratory gas data
were collected. The analysis was performed with two different
systems but with the same equipment throughout the different stages of
the study for a given subject. One method evaluated ventilation
(, inspiratory flow, by Harvard Instruments Dry
Gas Meter) and
expiratory CO2 and O2 concentrations (Servomex
570 and PA404 meters) to derive O2 consumption
(O2) and CO2
production (CO2) from
standard
formulas. The gas meters were calibrated against gases of known
concentrations before each test.16 The other
equipment calculated ,
CO2, and
O2 on line every 10 seconds
by an inert
gas dilution technique using a respiratory mass spectrometer
(Innovision).28 29
Arterial
Potassium and Gases
Arterial blood was sampled before each exercise,
at
peak effort, and at 3 and 8 minutes of recovery. The plasma was
centrifuged within 15 minutes for potassium (K+)
and analyzed by flame photometry using a dedicated machine
(CIBA-Corning) calibrated before each run. Arterial blood
samples were immediately analyzed for partial pressure of
carbon dioxide (PaCO2), oxygen
(PaO2), and pH with a Ciba-Corning Blood Gas
System (after a two-point calibration before each run).
Statistical Analysis
Assessment 1
Within each
group, we assessed (1) whether there was any
difference between exercise runs with or without PH-RCO, (2) the effect
of these two exercises in comparison with respective resting values,
and (3) the ergoreflex contribution by comparing 3-minute PH-RCO with
the 3-minute recovery run without RCO, evaluated as absolute values.
For the ventilatory and hemodynamic data, we also
compared the percentage values of the peak exercise responses still
persisting at 3 minutes.
Between the two groups (CHF and control subjects), we compared (1) the difference in the resting values and in the exercise responses (at peak exercise and at matched work duration, ie, 3-minute handgrip); (2) the ergoreflex contribution to the exercise changes, estimated as the difference between the 3-minute PH-RCO and the 3-minute recovery run without RCO; and (3) (autonomic data excepted) the percentage values of the peak exercise responses still persisting at 3 minutes.
Assessments 2 and 3 (After Detraining Phase or Training
Phase)
Within each group, the physical conditioning effect was
assessed
by comparison of the detraining with the training data for the resting
values, the exercise responses, and the ergoreflex contribution to
exercise changes.
Between the two groups, we compared the exercise responses (at peak exercise and at matched work duration) and the ergoreflex contribution to the exercise changes.
To compare the resting and exercise data after detraining and after training, we considered the means of the two runs (with and without PH-RCO), since preliminary analysis had shown no significant difference between the two runs. To compare the ergoreflex contribution, we considered the absolute differences and (autonomic data excepted) the percentage differences between the two recovery runs with and without PH-RCO (at 3 minutes of recovery).
ANOVA for repeated measures was used. Post hoc assessment of individual point comparisons was assessed by paired t test when the same group of subjects was evaluated, with a two-tailed level of significance less than the 5% level.
Unpaired t test or nonparametric tests, depending on the normality of the distributions, corrected when appropriate by Scheffé's procedure for multiple comparisons, were used in the post hoc comparison between different groups. Results are quoted as mean±SEM.
At rest there was no significant change in any of the measured variables with RCO compared with no RCO.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Assessment 1
All 12 CHF patients and the 10 normal subjects completed the three phases of the exercise protocol. Compared with control subjects, the CHF patients were sex- and age-matched but showed lower ejection fraction and
O2max (Table
1).
Rest
Within each group, the resting
values of all considered
variables were not significantly different before the two exercise
runs (ie, with and without PH-RCO).
Compared with control subjects, the
CHF patients had significantly
higher diastolic pressure and heart rate but reduced
CO2 and
O2 values. When power
spectral
analysis data were used, the CHF patients showed depressed RR
variability with reduced values of both LF and HF components and
depressed systolic and diastolic blood pressure
variability with reduced LF components. When normalized for the total
variability, the LF component of RR interval variability (%) was more
elevated in CHF patients than in control subjects (Table 2).
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Handgrip
Within each group of subjects, no
differences in the exercise
duration or for any variable at peak exercise were seen between the
two handgrip exercises (ie, with and without PH-RCO). The CHF patients
exercised less than control subjects (Table 2) and had lower
maximal
strength (67.5±3.7 versus 75.4±5.5 kg, P<.01).
Increases of heart rate, systolic and diastolic
pressures, , respiratory rate,
CO2,
O2, leg vascular
resistance, and
reductions in leg blood flow (all P<.001 versus baselines)
were observed in both groups of subjects without significant changes in
arterial K+ concentration,
PaCO2,
PaO2, or pH.
Compared with control subjects, at
peak exercise, patients
presented higher and respiratory rate and
lower
CO2 and
O2 levels (all
P<.001)
(Table 2).
For matched work duration (3-minute handgrip), in comparison with control subjects, patients also showed higher diastolic pressure (98.8±3.0 versus 90.1±3.0 mm Hg, P<.01), heart rate (92.6±2.5 versus 85.5±3.4 beats per minute, P<.01), and leg vascular resistance (96.5±6.2 versus 81.5±5.2 units, P<.01), with reduced leg blood flow (1.4±0.1 versus 1.7±0.1 mL·100 mL-1·min-1, P<.001).
Within each group of subjects, the changes in the
spectral
analysis parameters observed during the two
handgrip runs were similar, with reductions of RR variability and its
HF component, without significant changes in the LF component (Table
2). The LF component rose as a percentage of the total
variability, and
the HF component fell in both groups. Systolic and
diastolic pressure variability increased, with concomitant
increases in LF but no changes in HF components. During exercise, CHF
patients still showed lower RR, systolic and
diastolic variability, LF, and HF compared with control
subjects (Table 2).
Ergoreflex Contribution
Four subjects out of 12 CHF and 2 control subjects out of 10 felt
slight discomfort when the cuff was inflated after exercise, but none
of them described this as pain; in all, the sensation immediately
disappeared when the cuff was released.
In both CHF and control groups,
the ergoreflex activation (by PH-RCO)
prolonged the increased systolic and diastolic
blood pressures, , respiratory rate, and leg
vascular
resistance, but with no concomitant changes in heart rate: these
contributions were evident both in absolute and also in percentage
values (Table 3). These differences could not be
attributed to any significant differences in
CO2,
O2, arterial
K+ concentration, pH, PaCO2,
or PaO2 (Table 3).
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In both CHF and
control subjects, ergoreceptor activation increased the
power spectral indexes of sympathetic tone (elevation of LF in RR and
systolic and diastolic variability), with a fall in
the vagal index (HF of RR variability); systolic and
diastolic variability also increased (Table 3).
The
ergoreflex contributions to exercise responses were higher in
patients than in control subjects in both absolute and percentage
values with regard to the systolic (42.4±8.2 versus 25.6±11.3
mm Hg, P<.01; 89.0±8.1% versus 53.5±9.7%,
P<.001) and the diastolic (23.5±3.9 versus
15.9±4.3 mm Hg, P<.01; 97.8±10.3% versus
53.5±9.7%,
P<.001) pressures, the ventilatory responses to exercise as
(11.5±1.7 versus 3.2±1.0 L/min,
P<.01;
86.5±7.1% versus 54.5±8.6%, P<.001) and respiratory
rate (11.5±1.8 versus 3.0±1.0 breaths per minute,
P<.01;
84.3±12.7% versus 48.6±24.7%, P<.01), leg vascular
resistance (47.0±10.0 versus 32.1±6.4 units, P<.05;
108.1±6.5% versus 48.9±6.0%, P<.001), and blood flow
(1.0±0.2 versus 0.5±0.1 mL·100
mL-1·min-1,
P<.01; 101.2±13.1% versus 57.3±13.4%,
P<.001). CHF patients did not show any differences in the
changes of autonomic parameters compared with control
subjects.
Fig 3 compares the
, diastolic blood
pressure, and leg vascular resistance responses in CHF patients and
control subjects during the two handgrip runs without and with
PH-RCO.
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Assessments 2 and 3: Training Versus Detraining
Nine of 12
CHF and 9 of 10 control subjects completed the training
regimen, with 95% compliance: 2 patients and 1 control subject did not
complete it because of work commitments, and 1 patient found it too
difficult to follow.
Rest
There were no changes in the
resting values induced by either
training or detraining in either group of subjects. No significant
weight loss occurred in either group.
Handgrip
Within each group of subjects, no differences in the exercise
duration were seen between the two exercise runs, with and without
PH-RCO. After training compared with after detraining, the two groups
showed longer durations of forearm exercise (CHF: 8.0±0.5 versus
4.8±0.4 minutes, P<.001; control subjects: 9.0±0.3
versus
6.5±0.1 minutes, P<.001) and increased peak work rates
(CHF: 78.5±1.1 versus 64.9±1.7 kg, P<.05; control
subjects: 85.0±2.6 versus 76.9±3.1 kg, P<.005).
Thus,
even after training, CHF patients exercised less than control
subjects.
After training versus detraining, CHF and control subjects
increased
peak exercise CO2 (CHF:
422.0±31.3
versus 348.8±25.8 mL/min, P<.01; control subjects:
463.4±16.5 versus 404.6±11.0 mL/min, P<.05) and
O2 (450.0±25.2
versus 396.5±19.1
mL/min, P<.01; 480.8±15.4 versus 463.9±17.0 mL/min,
P<.05).
Changes in matched work duration (3-minute
handgrip) were compared
after detraining and after training (Table 4): in both
groups, conditioning reduced systolic and diastolic
pressures, ,
O2,
CO2, and leg vascular
resistance
with increased blood flow. The reduction in heart rate and respiratory
frequency did not reach statistical significance in the CHF group. In
comparison with control subjects, after training, patients still showed
higher hemodynamic and ventilatory responses to
exercise at matched work duration (Table 4).
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Ergoreflex Contribution
After detraining, both
groups of subjects showed the same
ergoreflex-driven responses in all variables as the baseline
test (assessment 1).
In the CHF group, training significantly reduced
the
ergoreflex contributions (by PH-RCO) to (1) the systolic and
diastolic pressure changes, (2) the ventilatory response to
exercise (both and respiratory rate), and (3)
leg vascular
resistance changes with an increased leg blood flow (Table 5).
Reduced sympathetic activation was also seen,
as assessed by power spectral analysis of systolic and
diastolic pressure variability LF components.
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In the control subjects,
training reduced the ergoreflex contributions
to blood pressure, ventilatory, leg vascular resistance, and blood flow
responses to exercise, although this effect was significant only for
(as a percentage) and leg vascular resistance.
Reduced
sympathetic activation of the circulation was also evident in control
subjects (LF components of systolic and diastolic
pressure variability) (Table 5).
After training, no
significant differences were observed in
CO2 and
O2 data in both groups. The
differences
between CHF patients and control subjects in the percentage
contribution of the ergoreceptors to the responses to exercise were
less marked after training than after detraining: systolic
(23.5±12.3% versus 31.2±10.3%, P<.05) and
diastolic (4.9±13.1% versus 33.5±14.5%,
P<.05, Fig 4) blood pressures,
(16.7±11.3% versus 49.7±9.9%, P<.05), respiratory
rate
(4.8±15.8% versus 33.9±26.7%, P=NS), leg
vascular
resistance (12.2±8.9% versus 64.1±8.7%, P<.01), and
leg
blood flow (24.9±18.9% versus 61.9±17.8%, P<.01).
The
autonomic parameters showed no significant differences
between control subjects and CHF patients (Table 5).
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P<.05 detraining vs
training;
*P<.05 control subjects versus patients).
Fig
5 compares the training effect on
,
diastolic pressure, and leg vascular resistance responses
in CHF patients and control subjects during the two handgrips without
and with PH-RCO after training.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Background
A determinant role for the skeletal muscle
abnormalities in the
limited exercise performance in established CHF has been
hypothesized. Initially, a reduction in blood flow to exercising limbs
during both submaximal and maximal exertion was
demonstrated.30 Subsequently, altered skeletal muscle
morphology and metabolism were described. Biopsy studies
reported decreased oxidative enzyme activity and muscle fiber
atrophy.3 4 5 Using 31P
nuclear magnetic
resonance spectroscopy, Wilson et al31 demonstrated
excessive depletion of PCr and greater acidosis in the forearm muscles
during submaximal exercise in CHF patients compared with normal
subjects. These findings were later confirmed by Massie et
al,6 who also found a relation between the degree of
skeletal muscle alterations in the forearm during exercise and the
clinical severity of CHF. Furthermore, these changes were unrelated to
limb blood flow and were present during ischemic as well as
aerobic exercise.32 Therefore, there is little evidence
that an impairment of blood flow is the primary cause of these
metabolic changes.33 Instead, leg muscle
volume correlates with exercise limitation in CHF.34
These studies suggested that an alteration in the muscle itself might be a major cause of exercise intolerance, with consequent exertional fatigue and dyspnea. The frequent coexistence of dyspnea and fatigue and the delay in resolution of dyspnea after hemodynamic improvement raise the possibility that structural skeletal muscle changes may be involved in the generation of dyspnea as well as fatigue. Dyspnea and increased ventilation could also be manifestations of changes in respiratory musculature similar to those seen in skeletal muscle.35 36 An alternative explanation is that skeletal muscle signals contribute directly to the perception of both muscle fatigue and dyspnea via an exaggerated neural signal from the muscle. Indeed, we have shown no objective difference in characteristics of patients limited by fatigue compared with those limited by dyspnea.37
Deconditioning may be responsible for a part of
the skeletal muscle
abnormalities: several studies on the beneficial effects of exercise
training on muscle function in heart failure have suggested that
inactivity may play a role in the peripheral abnormalities.
Training not only improves o2max
(even though
central hemodynamics do not improve) but also causes a
number of significant changes in the exercising limbs, including
increases in O2 uptake and arteriovenous O2
difference at maximal exercise and a decrease in lactate accumulation
at submaximal exercise with an increase in blood flow.29
Surprisingly, a strictly localized forearm training, with no systemic
effects, improved both metabolic and functional capacity in
CHF patients:23 38 the trained forearm demonstrated a
greater submaximal endurance and a lower ratio of inorganic phosphate
to PCr, without associated changes in muscle blood flow or systemic
hemodynamic response. This result reflects an improved
oxidative capacity of the muscle. Physical training in CHF induces
reductions in PCr depletion and increases in ADP during exercise, with
enhanced rates of PCr resynthesis in recovery, indicating a substantial
correction of the impaired oxidative capacity of skeletal muscle in
heart failure.15
Afferents sensitive to skeletal muscle work appear to be responsible for hemodynamic, autonomic, and ventilatory changes during exercise in animal models and in humans.19 20 21 23 We hypothesize that the beneficial effect of physical training may be mediated by a reduction of the activity of the muscle ergoreflex, either directly or via reduction of the metabolic signal activating the ergoreceptors.
Present Study
The major finding of this controlled study was
that the
contribution of the ergoreceptors to the autonomic,
hemodynamic, and respiratory responses to exercise is
enhanced in CHF patients: therefore, the heightened sympathetic,
vasoconstrictor, and ventilatory drives characteristic of heart failure
may be partially explained by an exaggerated ergoreflex contribution
during exercise. Physical training not only improved the exercise
capacity of the trained forearm but also partially reversed the
abnormal responses to exercise via a reduction of this reflex
excitation. This benefit was seen in both CHF patients and control
subjects, but with training, the responses to the enhanced ergoreflex
of CHF patients were brought closer to those of the normal
subjects.
We used three different assessment phases: baseline, detraining, and training. Both untrained periods showed similar values for respiratory, hemodynamic, and autonomic variables. In both physiological and pathological conditions, the muscle ergoreflex, together with the baroreflex,39 seems to be a determinant of the exercise-induced rises in systolic and diastolic blood pressures and in the redistribution of the blood flow by increasing the vascular resistance in the nonexercising limbs. These responses could also have been mediated by sympathetic overactivity to the heart and circulation and concomitant vagal withdrawal as a result of the known baroreflex abnormalities in CHF.40 These effects were shown by spectral analysis data of RR-interval and blood pressure variability: increases in the LF components of RR and blood pressure variability and falls in the HF components of RR-interval variability. However, the improvement seen with training of such a small muscle mass leads us to believe that the abnormality in the muscle reflex secondary to the metabolic changes in skeletal muscle in CHF gives the dominant role to the ergoreflex.
Ventilatory responses to exercise
are also mediated by the muscle
afferents: increases in respiratory frequency and ventilation
correlated with ergoreflex activity; these responses could not be
explained by any difference in
CO2,
O2, arterial blood
gases, or potassium concentrations, although one would not have
expected those to change, since the trained, exercising muscle was
small (Table 2).
At peak exercise, CHF patients
demonstrated higher ventilatory
responses than control subjects, with more marked abnormality of the
autonomic variables (Table 2). At similar exercise durations
(3-minute handgrip), CHF patients presented greater
hemodynamic (diastolic pressure, leg
vascular resistance) and ventilatory (minute
and respiratory
rate) responses and responses to exercise, despite working at the same
percentage of maximal handgrip strength. The ergoreflex was more
evident in the CHF group with regard to the control of nonexercising
limb blood flow and vascular resistance, systolic and
diastolic blood pressures, and ventilation, suggesting a
major contribution of these receptors in the abnormal responses to
exercise (Table 3).
Perhaps surprisingly, we found no differences between CHF and control subjects in the ergoreflex contribution to the autonomic response to exercise. Spectral analysis techniques showed only very low values of variability at baseline, during exercise, and at recovery in the CHF group, and thus they may have been unable to identify any differences in autonomic balance with respect to control subjects.
After training, exercise tolerance improved in both CHF and control
subjects: prolonged exercise duration with higher workloads were
accompanied by higher peak
O2. At
matched work duration, however (3-minute handgrip), local conditioning
reduced systolic and diastolic blood pressures,
,
CO2,
O2, and nonexercising
vascular
resistance and consequently raised the blood flow, suggesting a more
efficient response to exercise (Table 4). These beneficial
changes of
training were associated with reduced ergoreflex responses in blood
pressure, ventilation, and leg blood flow changes, despite a greater
workload achieved (and increased work duration). Reduced sympathetic
activation was also seen (LF components of power spectral
analysis of systolic and diastolic pressure
variability).
A localized physical training period of only the muscles
of one forearm
brought the responses to exercise of the patient group closer to those
of the subjects with normal left ventricular function: the
differences between CHF patients and control subjects in the ergoreflex
contribution to the responses to exercise were less marked after
training in regard to blood pressure (Fig 5), leg vascular
resistance,
leg blood flow, , and the autonomic responses.
Because the ergoreceptors are sensitive to the metabolic changes related to skeletal muscle work, it may be hypothesized that in conditions of higher workloads or durations, the production of metabolites may be greater, with a consequent greater ergoreflex activation. In agreement with this idea, Sterns et al41 reported a higher contribution of ergoreflex to muscle sympathetic nerve activity during PH-RCO after exercise at 40% than at 30% maximal voluntary contraction in small groups of CHF and control subjects. Gandevia and Hobbs,42 evaluating the pressor responses to handgrip and to 3- to 4-minute PH-RCO in normal humans, observed that the responses increased in parallel as the duration (from 45 to 120 seconds) and the intensity (from 33% to 50% of maximal voluntary contraction) of exercise increased.
In our study, however,
the control subjects compared with CHF patients
and also both groups of subjects after training showed higher
O2max and exercise duration
but lower
ergoreflex contribution compared with the detraining phase (Table
5,
Figs 4 and 5), suggesting a nondirect relation
between exercise level
and ergoreflex contribution. The link between workload and ergoreflex
seems to be mediated by the metabolic products of
muscle work. After training, the improved muscle
metabolism, by delaying the onset of anaerobic
metabolism,23 38 could have reduced the
production of those metabolites that activate the
ergoreceptors, with a resultant lower activity of the reflex
effects.
Previous reports of the ergoreceptor reflex control of sympathetic efferent activity in CHF have been conflicting. Sterns et al,41 using a lower exercise load than our study (30% maximal voluntary capacity performed for 2 minutes), reported that during PH-RCO, mean blood pressure and muscle sympathetic nerve activity remained above baseline values for both CHF and control subjects, but only for control subjects were these increases significant. They concluded that the sympathetic nervous response to ergoreceptor activation in CHF was blunted; however, the vastly different baseline levels of sympathetic tone in the two patient groups in that study made it difficult to interpret the incremental effect of metabolic reflex activation. More recently, the same group of workers43 evaluated the muscle ergoreflex at a lower workload (25% maximal voluntary capacity) but for a longer period of time (20 minutes), which was not tolerated by all CHF patients: an increased metabolic reflex activation in CHF was observed. The longer time of exercise performed with perhaps more exercise metabolites produced may have allowed a greater stimulation of the ergoreflex sufficient to differentiate their activity in the two groups of subjects studied.
On the basis of the reported observations and our own experience,21 we chose handgrip exercise at 50% maximal voluntary contraction until exhaustion to highlight the differences of the ergoreflex contribution to exercise in physiological and pathological conditions, such as CHF.
Limitations of the Study
No direct measurements of muscle
metabolic activity,
muscle mass, or muscle circumference were performed that could have
given information regarding the triggers of the ergoreflex activation.
However, the metabolic improvements induced by a physical
training program similar to the program used in our study suggest that
reduced PCr depletion and the acidification of the muscle during
exercise24 may be responsible for the reversed ergoreflex
overactivation.
Although the method of using the same maximal voluntary contraction to normalize the workload in different group of subjects is well established,41 43 we cannot exclude the possibility that CHF patients were using more muscle than control subjects, which could be responsible for the enhanced ergoreflex activation, or that a smaller mass of muscle was working harder per unit muscle. Thus, after training, the partially reversed overactivity of this reflex could be related to more efficient muscle work or to increased working muscle mass.
To focus on a small muscle group, we studied only forearm exercise rather than exercise that might be more relevant to the effort intolerance of the CHF syndrome. However, a similar protocol (PH-RCO) after leg exercise has been used for studies in normal subjects and also demonstrated the contribution of the ergoreceptors.44 Complete circulatory occlusion would be less certain during leg exercise because of the larger and deeper vessels of the lower limbs and the shape of the thigh, and it was for this reason that we chose the forearm in this study.
Four patients and two control subjects felt slight discomfort during PH-RCO, but there was no correlation between pain and the ergoreflex activity to the hemodynamic, autonomic, or ventilatory responses. Some of the most striking increases in blood pressure, ventilation, and leg vascular resistances occurred in three control subjects and four CHF subjects who did not experience any discomfort. However, a contribution from pain receptors could not be excluded. Small, unmyelinated pain afferents with C fibers may also be similar to or even the same as the skeletal muscle afferents evaluated in this research. This does not preclude their participation in a physiologically relevant reflex response.
The overactivation of this receptor may not be specific to CHF but rather may be common to all conditions of altered muscle metabolism associated with muscle wasting, such as detraining, chronic lung diseases, chronic liver diseases, or neoplastic cachexia. In particular, the cachexia of neoplastic disease has some similarities with cardiac cachexia, and this syndrome too can be associated with unexplained dyspnea.45 In all these situations, effort intolerance could be partially related to an enhanced ergoreflex activation due to an abnormality in the peripheral muscle.
Muscle Hypothesis
As a result of these experiments and other
studies,20 44 a "muscle hypothesis" is
proposed as
the basis of the generation of the exercise intolerance in CHF. The
metabolic state of skeletal muscle is centrally monitored
by the activation of ergoreceptors, whose fibers, traveling in the
lateral spinothalamic tract, increase ventilation and
sympathetic outflow, producing vasoconstriction in distant
nonexercising vascular beds, with consequent effects on blood pressure
and possibly a small increase in heart rate. They are sensitive to the
metabolic state of the muscle, but their triggers are still
unclear. They have the properties necessary to link the skeletal muscle
abnormality to the fatigue, dyspnea, hyperpnea, and sympathoexcitation
characteristic of CHF. This hypothesis proposes another cycle of
deterioration similar to those of neuroendocrine activation (Fig
6). A reduction in left ventricular function
sets in motion a series of metabolic events that leads to
wasting of skeletal muscle and resultant abnormalities of muscular
metabolism and function. In response to early
metabolic distress in exercising muscle, an exaggerated
ergoreflex activation occurs that is perceived by the patient as both
muscle fatigue and dyspnea and that leads reflexly to excessive
sympathetic vasoconstrictor drive to nonexercising beds and an
excessive ventilatory response to exercise.
|
Symptomatic improvements after treatments for CHF and the exaggerated reflex responses will depend on the resolution of skeletal muscle abnormalities; therefore, they will be delayed after hemodynamic correction and would be most marked in therapies associated with a specific improvement in muscle function or exercise responses.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
Dr Piepoli is a European Society of Cardiology Research Fellow. Dr Clark is a Robert Luff Research Fellow. Dr Coats is the British Heart Foundation and Viscount Royston Senior Lecturer in Cardiomyopathy. We gratefully acknowledge the advice and support of Dr James Conway and Dr Theo E. Meyer and the expertise of Dr Luciano Bernardi.
Received June 13, 1995; revision received September 20, 1995; accepted October 4, 1995.
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References |
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S. A. Smith, M. A. Williams, J. H. Mitchell, P. P.A. Mammen, and M. G. Garry The Capsaicin-Sensitive Afferent Neuron in Skeletal Muscle Is Abnormal in Heart Failure Circulation, April 26, 2005; 111(16): 2056 - 2065. [Abstract] [Full Text] [PDF]
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A. Houssiere, B. Najem, A. Ciarka, S. Velez-Roa, R. Naeije, and P. van de Borne Chemoreflex and metaboreflex control during static hypoxic exercise Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1724 - H1729. [Abstract] [Full Text] [PDF]
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M. Guazzi, G. Reina, G. Tumminello, and M. D. Guazzi Exercise ventilation inefficiency and cardiovascular mortality in heart failure: the critical independent prognostic value of the arterial CO2 partial pressure Eur. Heart J., March 1, 2005; 26(5): 472 - 480. [Abstract] [Full Text] [PDF]
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A. J.S. Coats Why ventilatory inefficiency matters in chronic heart failure Eur. Heart J., March 1, 2005; 26(5): 426 - 427. [Full Text] [PDF]
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A. Momen, D. Bower, J. Boehmer, A. R. Kunselman, U. A. Leuenberger, and L. I. Sinoway Renal blood flow in heart failure patients during exercise Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2834 - H2839. [Abstract] [Full Text] [PDF]
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M. Guazzi, S. Belletti, G. Tumminello, C. Fiorentini, and M. D. Guazzi Exercise hyperventilation, dyspnea sensation, and ergoreflex activation in lone atrial fibrillation Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2899 - H2905. [Abstract] [Full Text] [PDF]
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J. Li, A. N. Sinoway, Z. Gao, M. D. Maile, M. Pu, and L. I. Sinoway Muscle Mechanoreflex and Metaboreflex Responses After Myocardial Infarction in Rats Circulation, November 9, 2004; 110(19): 3049 - 3054. [Abstract] [Full Text] [PDF]
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H. R. Middlekauff, J. Chiu, M. A. Hamilton, G. C. Fonarow, W. R. MacLellan, A. Hage, J. Moriguchi, and J. Patel Muscle mechanoreceptor sensitivity in heart failure Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H1937 - H1943. [Abstract] [Full Text] [PDF]
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J. P Fisher and M. J White Muscle afferent contributions to the cardiovascular response to isometric exercise Exp Physiol, November 1, 2004; 89(6): 639 - 646. [Abstract] [Full Text] [PDF]
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A. C. Scott, R. Wensel, C. H. Davos, P. Georgiadou, L. Ceri Davies, A. J.S. Coats, D. P. Francis, and M. F. Piepoli Putative contribution of prostaglandin and bradykinin to muscle reflex hyperactivity in patients on Ace-inhibitor therapy for chronic heart failure Eur. Heart J., October 2, 2004; 25(20): 1806 - 1813. [Abstract] [Full Text] [PDF]
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K. K.A. Witte and A. L. Clark The effect of aspirin on the ventilatory response to exercise in chronic heart failure Eur J Heart Fail, October 1, 2004; 6(6): 745 - 748. [Abstract] [Full Text] [PDF]
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H. T. Robertson, R. Pellegrino, D. Pini, J. Oreglia, S. DeVita, V. Brusasco, and P. Agostoni Exercise response after rapid intravenous infusion of saline in healthy humans J Appl Physiol, August 1, 2004; 97(2): 697 - 703. [Abstract] [Full Text] [PDF]
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A. I. Larsen and K. Dickstein Can sedentary patients with heart failure achieve the beneficial effect of exercise training without moving? Eur. Heart J., January 2, 2004; 25(2): 104 - 106. [Full Text] [PDF]
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R. U. Pliquett, K. G. Cornish, K. P. Patel, H. D. Schultz, J. D. Peuler, and I. H. Zucker Amelioration of depressed cardiopulmonary reflex control of sympathetic nerve activity by short-term exercise training in male rabbits with heart failure J Appl Physiol, November 1, 2003; 95(5): 1883 - 1888. [Abstract] [Full Text] [PDF]
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K K A Witte, S D R Thackray, N P Nikitin, J G F Cleland, and A L Clark The effects of {alpha} and {beta} blockade on ventilatory responses to exercise in chronic heart failure Heart, October 1, 2003; 89(10): 1169 - 1173. [Abstract] [Full Text] [PDF]
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F. Roveda, H. R. Middlekauff, M. U. P. B. Rondon, S. F. Reis, M. Souza, L. Nastari, A. C. P. Barretto, E. M. Krieger, and C. E. Negrao The effects of exercise training on sympathetic neural activation in advanced heart failure: A randomized controlled trial J. Am. Coll. Cardiol., September 3, 2003; 42(5): 854 - 860. [Abstract] [Full Text] [PDF]
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S. A. Smith, P. P.A. Mammen, J. H. Mitchell, and M. G. Garry Role of the Exercise Pressor Reflex in Rats With Dilated Cardiomyopathy Circulation, September 2, 2003; 108(9): 1126 - 1132. [Abstract] [Full Text] [PDF]
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J. J. Leite, A. J. Mansur, H. F. G. de Freitas, P. R. Chizola, E. A. Bocchi, M. Terra-Filho, J. A. Neder, and G. Lorenzi-Filho Periodic breathing during incremental exercise predicts mortality in patients with chronic heart failure evaluated for cardiac transplantation J. Am. Coll. Cardiol., June 18, 2003; 41(12): 2175 - 2181. [Abstract] [Full Text] [PDF]
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T Tomita, H Takaki, Y Hara, F Sakamaki, T Satoh, S Takagi, Y Yasumura, N Aihara, Y Goto, and K Sunagawa Attenuation of hypercapnic carbon dioxide chemosensitivity after postinfarction exercise training: possible contribution to the improvement in exercise hyperventilation Heart, April 1, 2003; 89(4): 404 - 410. [Abstract] [Full Text] [PDF]
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I. L. Pina, C. S. Apstein, G. J. Balady, R. Belardinelli, B. R. Chaitman, B. D. Duscha, B. J. Fletcher, J. L. Fleg, J. N. Myers, and M. J. Sullivan Exercise and Heart Failure: A Statement From the American Heart Association Committee on Exercise, Rehabilitation, and Prevention Circulation, March 4, 2003; 107(8): 1210 - 1225. [Full Text] [PDF]
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A. C. Scott, R. Wensel, C. H. Davos, P. Georgiadou, M. Kemp, J. Hooper, A. J.S. Coats, and M. F. Piepoli Skeletal Muscle Reflex in Heart Failure Patients: Role of Hydrogen Circulation, January 21, 2003; 107(2): 300 - 306. [Abstract] [Full Text] [PDF]
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U. Corra, A. Giordano, E. Bosimini, A. Mezzani, M. Piepoli, A. J. S. Coats, and P. Giannuzzi Oscillatory Ventilation During Exercise in Patients With Chronic Heart Failure* : Clinical Correlates and Prognostic Implications Chest, May 1, 2002; 121(5): 1572 - 1580. [Abstract] [Full Text] [PDF]
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P. P. Ponikowski, T. P. Chua, D. P. Francis, A. Capucci, A. J.S. Coats, and M. F. Piepoli Muscle Ergoreceptor Overactivity Reflects Deterioration in Clinical Status and Cardiorespiratory Reflex Control in Chronic Heart Failure Circulation, November 6, 2001; 104(19): 2324 - 2330. [Abstract] [Full Text] [PDF]
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A. J S Coats HEART FAILURE: What causes the symptoms of heart failure? Heart, November 1, 2001; 86(5): 574 - 578. [Full Text] [PDF]
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Y. Goso, H. Asanoi, H. Ishise, T. Kameyama, T. Hirai, T. Nozawa, S. Takashima, K. Umeno, and H. Inoue Respiratory Modulation of Muscle Sympathetic Nerve Activity in Patients With Chronic Heart Failure Circulation, July 24, 2001; 104(4): 418 - 423. [Abstract] [Full Text] [PDF]
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L TAVAZZI and P GIANNUZZI Physical training as a therapeutic measure in chronic heart failure: time for recommendations Heart, July 1, 2001; 86(1): 7 - 11. [Full Text] [PDF]
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M. Cicoira, L. Zanolla, L. Franceschini, A. Rossi, G. Golia, M. Zamboni, P. Tosoni, and P. Zardini Skeletal muscle mass independently predicts peak oxygen consumption and ventilatory response during exercise in noncachectic patients with chronic heart failure J. Am. Coll. Cardiol., June 15, 2001; 37(8): 2080 - 2085. [Abstract] [Full Text] [PDF]
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C. T. Pu, M. T. Johnson, D. E. Forman, J. M. Hausdorff, R. Roubenoff, M. Foldvari, R. A. Fielding, and M. A. F. Singh Randomized trial of progressive resistance training to counteract the myopathy of chronic heart failure J Appl Physiol, June 1, 2001; 90(6): 2341 - 2350. [Abstract] [Full Text] [PDF]
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A.I Larsen, T Aarsland, M Kristiansen, A Haugland, and K Dickstein Assessing the effect of exercise training in men with heart failure. Comparison of maximal, submaximal and endurance exercise protocols Eur. Heart J., April 2, 2001; 22(8): 684 - 692. [Abstract] [PDF]
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C. F. Notarius, D. J. Atchison, and J. S. Floras Impact of heart failure and exercise capacity on sympathetic response to handgrip exercise Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H969 - H976. [Abstract] [Full Text] [PDF]
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C. E. Negrao, M. U. P. B. Rondon, T. Tinucci, M. J. N. Alves, F. Roveda, A. M. W. Braga, S. F. Reis, L. Nastari, A. C. P. Barretto, E. M. Krieger, et al. Abnormal neurovascular control during exercise is linked to heart failure severity Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1286 - H1292. [Abstract] [Full Text] [PDF]
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R. L. Johnson Jr Gas Exchange Efficiency in Congestive Heart Failure II Circulation, February 20, 2001; 103(7): 916 - 918. [Full Text] [PDF]
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P. Ponikowski, D. P. Francis, M. F. Piepoli, L. C. Davies, T. P. Chua, C. H. Davos, V. Florea, W. Banasiak, P. A. Poole-Wilson, A. J. S. Coats, et al. Enhanced Ventilatory Response to Exercise in Patients With Chronic Heart Failure and Preserved Exercise Tolerance : Marker of Abnormal Cardiorespiratory Reflex Control and Predictor of Poor Prognosis Circulation, February 20, 2001; 103(7): 967 - 972. [Abstract] [Full Text] [PDF]
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Recommendations for exercise testing in chronic heart faliure patients Eur. Heart J., January 1, 2001; 22(1): 37 - 45. [PDF]
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C. A. Carrington, W. J. Fisher, M. K. Davies, and M. J. White Is there a relationship between muscle fatigue resistance and cardiovascular responses to isometric exercise in mild chronic heart failure? Eur J Heart Fail, January 1, 2001; 3(1): 53 - 58. [Abstract] [Full Text] [PDF]
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A. C Scott, D. P Francis, L C. Davies, P. Ponikowski, A. J S Coats, and M. F Piepoli Contribution of skeletal muscle 'ergoreceptors' in the human leg to respiratory control in chronic heart failure J. Physiol., December 15, 2000; 529(3): 863 - 870. [Abstract] [Full Text] [PDF]
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K. T. Spencer, K. Collins, C. Korcarz, R. Fentzke, R. M. Lang, and J. M. Leiden Effects of exercise training on LV performance and mortality in a murine model of dilated cardiomyopathy Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H210 - H215. [Abstract] [Full Text] [PDF]
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N G Mahon, S Sharma, P M Elliott, M K Baig, M W Norman, S Barbeyto, and W J McKenna Abnormal cardiopulmonary exercise variables in asymptomatic relatives of patients with dilated cardiomyopathy who have left ventricular enlargement Heart, May 1, 2000; 83(5): 511 - 517. [Abstract] [Full Text]
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P. Ponikowski, M. Piepoli, T.P. Chua, W. Banasiak, D. Francis, S.D. Anker, and A.J.S. Coats The impact of cachexia on cardiorespiratory reflex control in chronic heart failure Eur. Heart J., November 2, 1999; 20(22): 1667 - 1675. [Abstract] [PDF]
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L. dalla Libera, R. Zennaro, M. Sandri, G. B. Ambrosio, and G. Vescovo Apoptosis and atrophy in rat slow skeletal muscles in chronic heart failure Am J Physiol Cell Physiol, November 1, 1999; 277(5): C982 - C986. [Abstract] [Full Text] [PDF]
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W J Fisher and M J White Training-induced adaptations in the central command and peripheral reflex components of the pressor response to isometric exercise of the human triceps surae J. Physiol., October 15, 1999; 520(2): 621 - 628. [Abstract] [Full Text] [PDF]
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A. A. Smith, P. J. Cowburn, M. E. Parker, M. Denvir, S. Puri, K. R. Patel, and J. G. F. Cleland Impaired Pulmonary Diffusion During Exercise in Patients With Chronic Heart Failure Circulation, September 28, 1999; 100(13): 1406 - 1410. [Abstract] [Full Text] [PDF]
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C. Opasich, N. Ambrosino, G. Felicetti, R. Aquilani, E. Pasini, D. Bergitto, A. Mazza, F. Cobelli, and L. Tavazzi Heart failure-related myopathy. Clinical and pathophysiological insights Eur. Heart J., August 2, 1999; 20(16): 1191 - 1200. [Abstract] [PDF]
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K. Narkiewicz, C. A. Pesek, P. J. H. van de Borne, M. Kato, and V. K. Somers Enhanced Sympathetic and Ventilatory Responses to Central Chemoreflex Activation in Heart Failure Circulation, July 20, 1999; 100(3): 262 - 267. [Abstract] [Full Text] [PDF]
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J. K. Shoemaker, H. L. Naylor, C. S. Hogeman, and L. I. Sinoway Blood Flow Dynamics in Heart Failure Circulation, June 15, 1999; 99(23): 3002 - 3008. [Abstract] [Full Text] [PDF]
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R.P. Wielenga, I.A. Huisveld, E. Bol, P.H.J.M. Dunselman, R.A.M. Erdman, M.R.P. Baselier, and W.L. Mosterd Safety and effects of physical training in chronic heart failure. Results of the Chronic Heart Failure and Graded Exercise study (CHANGE): (CHANGE) Eur. Heart J., June 2, 1999; 20(12): 872 - 879. [Abstract] [PDF]
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N. Francis, A. Cohen-Solal, and D. Logeart Peripheral muscle ergoreceptors and ventilatory response during exercise recovery in heart failure Am J Physiol Heart Circ Physiol, March 1, 1999; 276(3): H913 - H917. [Abstract] [Full Text] [PDF]
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R. Hambrecht, E. Fiehn, C. Weigl, S. Gielen, C. Hamann, R. Kaiser, J. Yu, V. Adams, J. Niebauer, and G. Schuler Regular Physical Exercise Corrects Endothelial Dysfunction and Improves Exercise Capacity in Patients With Chronic Heart Failure Circulation, December 15, 1998; 98(24): 2709 - 2715. [Abstract] [Full Text] [PDF]
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M. V. Kamath, S. Hollerbach, A. Bajwa, E. L. Fallen, A. R.M. Upton, and G. Tougas Neurocardiac and cerebral responses evoked by esophageal vago-afferent stimulation in humans: effect of varying intensities Cardiovasc Res, December 1, 1998; 40(3): 591 - 599. [Abstract] [Full Text] [PDF]
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J. K. Shoemaker, A. R. Kunselman, D. H. Silber, and L. I. Sinoway Maintained exercise pressor response in heart failure J Appl Physiol, November 1, 1998; 85(5): 1793 - 1799. [Abstract] [Full Text] [PDF]
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A. B. Evans, L. W. Tsai, D. A. Oelberg, H. Kazemi, and D. M. Systrom Skeletal muscle ECF pH error signal for exercise ventilatory control J Appl Physiol, January 1, 1998; 84(1): 90 - 96. [Abstract] [Full Text] [PDF]
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S. Mostoufi-Moab, E. J. Widmaier, J. A. Cornett, K. Gray, and L. I. Sinoway Forearm training reduces the exercise pressor reflex during ischemic rhythmic handgrip J Appl Physiol, January 1, 1998; 84(1): 277 - 283. [Abstract] [Full Text] [PDF]
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R. P Wielenga, A. J S Coats, W. L Mosterd, and I. A Huisveld The role of exercise training in chronic heart failure Heart, November 1, 1997; 78(5): 431 - 436. [Full Text] [PDF]
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P. Ponikowski, T. P. Chua, M. Piepoli, D. Ondusova, K. Webb-Peploe, D. Harrington, S. D. Anker, M. Volterrani, R. Colombo, G. Mazzuero, et al. Augmented Peripheral Chemosensitivity as a Potential Input to Baroreflex Impairment and Autonomic Imbalance in Chronic Heart Failure Circulation, October 21, 1997; 96(8): 2586 - 2594. [Abstract] [Full Text]
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