Physical deconditioning may be a mechanism for the skeletal muscle energy phosphate metabolism abnormalities in chronic heart failure

Heart Failure

Physical deconditioning may be a mechanism for the skeletal muscle energy phosphate metabolism abnormalities in chronic heart failure Z u k a / C h a t i , MD, a, b, c Fa~ez Zannad, MD, PhD, a Claude Jeandel, MD, b Brigitte Lherbier, DSc, c Jean-Marie Escanye, PhD, c Jacques Robert, MD, c and Etienne Aliot, MD a Nancy, France

The aim of our study was to investigate the contribution of physical deconditioning in skeletal muscle metabolic abnormalities in patients with chronic heart failure (CHF). Phosphate metabolism was studied in the leg muscle at rest and during exercise by using phosphate 31 nuclear magnetic resonance spectroscopy in a group of 14 patients with New York Heart Association class II and III CHF and left ventricular ejection fraction <40% and in two groups of agematched healthy volunteers: one group of 7 sedentary and another of 7 trained subjects. Phosphocreatine depletion rate, intracellular pH, and adenosine diphosphate levels in the muscle during exercise were not statistically different in the CHF patients and in the sedentary healthy subjects, but both groups were statistically different from the trained healthy subjects, who had slower phosphocreatine depletion rates, as well as less intracellular acidosis and lower adenosine diphosphate levels during exercise (p= 0.02; analysis of variance). Our results suggest that metabolic changes occurring in the skeletal muscle of patients with CHF may contribute to the limitation of exercise capacity and are most likely to be a consequence of physical deconditioning because they are very similar to what is observed in sedentary and otherwise healthy subjects as compared with trained subjects. (AM HEART J 1996;131:560-6.)

Muscle fatigue and exercise capacity limitations a r e common symptoms of chronic heart failure (CHF). 1 Several previous studies have described metabolic, histologic, and biochemical changes in the skeletal From the Departments of ~Cardiology, bGeriatrics, and CBiophysics Laboratory, University of Nancy. This work was performed in the Centre d'Investigation Clinique (CIC) INSERM-CHU of Nancy. Received for publication Feb. 22, 1995; accepted July 25, 1995. Reprint requests: Zuka~ Chati, MD, Service de Cardiologie, HSpita] Central, 29 Avenue de Mar6chal de Lattre de Tassigny, 54035 Nancy Cedex, France. Copyright © 1996 by Mosby-Year Book, Inc. 0002-8703/$5.00 + 0 4/1/68571

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muscle of patients with CHF and suggest that these m a y contribute to the limitation of exercise capacity. 2-4 The mechanisms leading to such changes in the skeletal muscle are unknown. Because some of these changes m a y be at least partly reversed after physical training, it has been speculated t h a t they may be a consequence of physical deconditioning.5"7 However, reversal of metabolic abnormalities by training m a y also be related to mechanisms other t h a n physical deconditioning, such as changes in ventricular function. To ascertain the role of physical deconditioning, we compared skeletal muscle metabolism in CHF patients with muscle metabolism in sedentary but otherwise healthy subjects and in trained healthy subjects. We studied the skeletal muscle metabolism, assessed by phosphate 31 nuclear magnetic resonance spectroscopy (31p MRS), in a group of patients with CHF and in two groups of healthy subjects with different levels of physical training status (i.e., a group of untrained sedentary subjects and another of trained fit subjects). In the CHF group, we also studied the relation between clinical severity, peak oxygen consumption, and muscle metabolic 31p MRS indexes. METHODS Subject selection. Ambulatory patients were selected of

either sex, aged younger than 75 years, with CHF resulting from ischemic heart disease or primitive dilated cardiomyopathy, belonging to the New York Heart Association classes II and III, with left ventricular ejection fraction <40% and sinus rhythm. They were in stable clinical condition for at least 2 months before the study and took their usual medications, which consisted of diuretics and vasodilators with or without digoxin. Control subjects were healthy volunteers with unknown

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cardiac or other diseases and with normal cardiac echocardiograms. Sedentary subjects had a sedentary life and had not performed any physical training for a period >1 year before the study. Trained subjects had to be performing > 14 hours per week of physical training for periods > 1 year before the study. Physical fitness of the healthy subjects was assessed by a graded 20 W/2 min-increment cycle exercise with measurements of the total duration of exercise performed before 31p MRS in the geriatrics department by the same investigation. Respiratory gas analysis was not ]performed in the healthy subjects. All three groups were age matched. Informed consent was obtained in all pa1;ients and subjects, and the protocol was approved by the ethics committee of the University Hospital of Nancy. 31p MRS measurements Study protocol. After the patient was installed in the semiseated position with both legs stretched out horizontally, the test began with the recording of a 31p MRS spectrum of the left calf muscle at rest. Exercise consisted of successive plantar flexions by pressing on a pedal connected to a known load. The exercise was progressive, beginning with a 3 kg weight with 2 kg increments each 3 minutes. Exercise increments were interrupted by 3-minute rest periods. Termination of the test, at the end of a given increment, was decided when either the patient was tired or high, almost total creatine phosphate depletion was achieved. Workload is expressed as: Workload (watts) = Weight (kilograms) x g (newtons x kilogram -1) x Distance traveled (meters) x Number of flexions/Time (seconds). (Weight from 3 to 13 kg; g = 10 N x kg-1; Distance, 0.2 m; Number of flexions/3 rain = 78; Time, 180 seconds.) The exercise spectra were recorded during the last 25 seconds of each workload. After the final increment, five spectra were recorded to study the recovery phase. All patients underwent two successive 31p MRS tests 48 hours apart. The first one familiarized the subject with the test. We used the results of the second test for this study. Processing of spectra. This study was conducted by using a Bruker Biospec BMT 100 spectrometer (multinuclear spectrometer equipped with a horizontal superconducting magnet with a 2.4 T field strength and a 40 cm opening, Karfsruhe, Germany). The surface coil (a single-coil 5 cm in diameter) with double tuning allows signal acquisition for both phosphorus and hydrogen (proton), which makes it possible to adjust the uniformity of the magnetic field. Acquisition of phosphorus spectra occurs at a frequency of 40.6 MHz by using a single pulse sequence with quadrature reception and four-phase cycling (Cyclops). A spectrum is obtained by the accumulation of 200 free induction decays in a resting subject and only 20 free induction decays during exercise and the recovery period. The repetition time equals 1 second. The pulse used corresponds to a flip angle of approximately 70 degrees for maximum signal. We took into consideration the relaxation differential of the different peaks studied, and We applied measured correction factors (phosphate monoesters [PME], 0.244; inorganic phosphorus [Pi], 0.264; phosphodiesters [PDE], 0.317, creatine phosphate [PCr], 0.225; adenosine triphos-

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phate-T [ATPT], 0.256; ATP~, 0.284; ATP~, 0.241). The spectral window used was 2000 MHz. A Fourier transformation was performed after differential convolution (by an exponential function 200 Hz wide) for baseline correction, and exponential multiplication (15 Hz wide). For our results, we took into consideration the area under the spectra for measurement of concentrations of each metabolite. IntracellularpH was measured from the chemical shift (~) between the spectral peak of Pi and that of PCr. We used the following formulaS: pH = 6.88 x logl0((r- 3.35/ 5.60 - (r). The rate of PCr depletion during exercise was determined by using the following indexes: Pi/PCr ratio changes at each workload level; PCr linear depletion slope in the Pi/PCr versus stimulation frequency relation up to a fixed workload of 6 W (7 kg) (Pi/PCr slope 0 to 6 W); workload at the transition from a linear to a nonlinear relation between the Pi/PCr ratio and workload ("threshold workload"); graphical determination of the workload corresponding to the ratio Pi/PCr = 0.5. ATP levels were expressed as the sum of ATP (a, ~, T/sum of phosphorus ratio versus workload (~ATP/~P), and adenosine diphosphate (ADP) levels were evaluated from the PCr/ATP~ ratio to which they are negatively correlated. 9 PCr recovery rate was studied by the course of the Pi/PCr ratio during the 125 seconds after cessation of exercise (five spectra) and calculation of the slope of monoexponential recovery (Pi/PCr ratio vs time: Pi/PCr = A x e sl°pe x time). Exercise test with measurement ofpeak V02. At <48-hour intervals after the 31p MRS test, patients underwent an exercise test on an ergometric bicycle with data analyzed on an IBM AT computer connected to a rapid cycle-by-cycle respiratory gas analyzer (Medical Graphics Desktop diagnostics/CPX, St. Paul, Minn.). A protocol using an increasing workload was selected with increments of 20 W for 2 minutes, allowing the measurement of peak Vo2, total duration of exercise, and the anaerobic threshold (determined graphically)} ° Exercise was continued until the patient was exhausted (dyspnea, fatigue). All patients were familiarized with this test to obtain performance that could be reproduced (within a margin of 15%) before participating in this study. All tests were run in the morning before the patient took his or her usual medications. Statistics. Results are expressed as mean values _+ SEM. For comparisons, we used these three tests: analysis of the variance for comparison either of several groups with only one variable (unpaired series) or of three groups with repetitive measurements of each variable (paired series). We used linear regression analysis to determine possible correlations between the measured variables. We chose a value ofp < 0.05 for the significance threshold.

RESULTS Patients' and subjects' characteristics. D e m o g r a p h i c a n d o t h e r clinical characteristics of p a t i e n t s a n d h e a l t h y subjects are s u m m a r i z e d in Table I. A m o n g p a t i e n t s with CHF, eight h a d ischemic h e a r t disease, a n d six h a d dilated c a r d i o m y o p a t h y . Seven were in

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Per

Pi

~

Pi/PCr 2"

ATP

p= 0.009 (bg) p= 0.0001 (ig)

~-~

Sedentary / ~ ~ i

, ~ j ~

,

,

sCed.e%tary

.{, 0 pH 7.3-

Fig. 1. Illustrative 31p MRS spectra, at peak exercise, in a patient with CHF, in a healthy sedentarysubjeet, and in a healthy trained subject. Decrease of the Per spectra and increase of the Pi spectra are more rapid in the CHF patienic and in the sedentary subject than in the trained subject.

Workload (W) Rest i

3

5

p= 0.003 (bg) p= 0.01 (ig)

*

**

*

**

*

7.27.17.0. 6.9-

Table I. Demographic and clinical characteristics of CHF patients and healthy sedentary and trained subjects CHF (n =14)

Sedentary (n = D

Age (yr) 55 ± 3 (35-74) 58 ± 7 (30-74) Sex (M/F) 12/2 4/3 H R (beats/ 77 ± 6 73 +_ 4 rain) S B P (ram Hg) 122 +_ 10 137 ± 5 DBP(mmHg) 70±5 78_+5 Vo2 (ml/kg/ 16.7 ± 1.8 ---

R~st i

Trained (n = D 50 ± 7 (30-74) 3/4 68 _+ 3

~

s

p= 0.02 (bg) p= 0.0001 (ig)

PCr/ATPfl 5

4 125 ± 6 75_+5 --

min) A T (ml/kg/ 10.0 _+ 1.1 rain) Exercise t i m e 575 ± 75* (see)

6.8

3

-2

719 ± 74*

1120 ± 53

Sedentary, Healthy sedentary subjects; Trained, healthy trained subjects; HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure; AT, anaerobic ventilatory threshold. *p < 0.05 between CHF patients and trained subjects. ~p < 0.05 between sedentary and trained subjects (analysis of variance).

N Y H A class II and seven in class III. Radionuclide left v e n t r i c u l a r ejection fraction was 29 _+ 2% (range 15 to 40). P a t i e n t s were t a k i n g l o o p diuretics (n = 14), n i t r a t e s (n = 14), angiotensin-converting e n z y m e inhibitors (n = 10), calcium antagonists (n = 6), and digoxin (n = 8). A d e m o n s t r a t i v e 31p s p e c t r u m recorded in a C H F patient, a s e d e n t a r y subject, and a t r a i n e d subject is illustrated in Fig. 1. PCr depletion rate, e x p r e s s e d by the Pi/PCr ratio changes, was f a s t e r in the C H F p a t i e n t s and in the s e d e n t a r y h e a l t h y subjects as c o m p a r e d with t h a t in the h e a l t h y t r a i n e d subjects (p < 0.02; Fig. 2). O t h e r

Workload (W) 1

Rest

i

i

s

÷

Fig. 2. Mean changes in Pi/PCr ratio and intracellular pH and PCr/ATP[3 ratio produced by incremental exercise. p(bg), p between groups; p(ig), p intragroup (analysis of variance); *, p < 0.05 between CHF patients and trained subjects; t, p < 0.05 between sedentary and trained subjects.

variables assessing the P C r depletion r a t e showed the same difference, w h e t h e r it was the Pi/PCr slope or the initial slope up to a 6-watt workload, the t h r e s h o l d workload, or the workload producing the p r e d e t e r m i n e d level of Pi/PCr = 0.5 (p < 0.05, analysis of variance; Table II). S e d e n t a r y subjects a n d C H F p a t i e n t s h a d no statistically significant differences. Workload producing the p r e d e t e r m i n e d level of Pi/PCr = 0.5 was positively correlated with p e a k

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Table II. Comparison of 31p MRS indexes during exercise

in patients with CHF and in healthy sedentary and trained subjects CHF

Sedentary

W o r k l o a d (W) P i / P C r = 0.5 10

563

r= 0.72 p= 0.003

Trained 8

Initial Pi/PCr 0.159 -+ 0.030* 0.098 -+ 0.010 0.053 -+ 0.006 slope Threshold 5.61 -+ 0.56* 6.29 -+ 0.794 8.51 _+ 0.60 w o r k l o a d (W) W o r k l o a d for Pi/ 4.41 -+ 0.68* 5.61 -+ 1.51t 9.95 -+ 1.78 P C r = 0.5 (W)

o

o

6

/°

4

o

o

2

o

Peak V02 (ml/kg/min)

e

Sedentary, Healthy sedentary subjects; Trained, healthy trained subjects. *p < 0.05 between CHF patients and trained subjects. Sp < 0.05 between sedentary and trained subjects (analysis of variance).

oxygen consumption (r = 0.72; p = 0.003), anaerobic ventilatory threshold (r = 0.54; p -- 0.04), and exercise total time (r = 0.71; p = 0.004) in patients with CHF (Fig. 3). None of the 31p MRS variables or of the exercise-capacity variables was significantly correlated with the left ventricular ejection fraction. Intracellular p H decreased significantly in all three groups (p--0.01) during exercise. Betweengroup comparison shows a more pronounced de,crease in the CHF-patient group, which was statistically significant only against the trained-subject group (p < 0.05; Fig. 2). It was correlated negatively to the Pi/Pcr ratio (r = -0.38;p = 0.03) and positively to the PCr/ATP~ ratio (r = 0.51; p = 0.0008) at any work]load in all the patients and healthy subjects (Fig. 4). PCr/ATP[t ratio decreased significantly during exercise in all groups (p = 0.0001). Between-group comparison showed again t h a t CHF patients were significantly different from the trained subjects only (p < 0.05) and exhibited a more pronounced decrease in this ratio (Fig. 2). ZATP/EP ratio did not change significantly during exercise in any group. PCr recovery rate expressed as the monoexponential slope of the Pi/PCr versus time curve was similar in CHF patients (0.273 _+ 0.028), sedentary subjects (0.270 _+0.026), and trained subjects (0.239 _+0.021). DISCUSSION

31p MRS is a useful tool for the noninvasive in vivo assessment of intracellular skeletal muscle metabolism during exercise. It has been used both in animal models of CHF 11 and in patients with this condition 3, 4, 12; it has consistently shown significant abnormalities of the energy-rich phosphate metabolism. Other investigators have shown several biochemical and morphologic changes in the skeletal muscle of patients with CHF, consisting of alterations of the oxidative metabolism and type I oxidative fibers relative to the glycolytic ones. 1-3 However, the mechanisms responsible for these changes are

o

0 10 W o r k l o a d (W) P i f P C r = 0.5 10"

20

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r=0.54 p= 0.04 0

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o 0

oo

A T (ml/kg/min)

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r= 0.71 p= 0.004 o

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OO 40

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O E x e r c i s e Ti me (See)

200

400

600

800

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1200

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Fig. 3. Positive correlation between workload at Pi/PCr = 0.5 and exercise capacity (peak V02, anaerobic threshold [AT], exercise time) in patients with CHF. still not well understood. In some studies, faster PCr depletion in patients with CHF was weakly correlated with the muscle hypotrophy,3 and in another study, it had no significant relation to the changes in the muscle enzyme activity. 4 On the other hand, physical deconditioning has been postulated as the most likely explanation of these metabolic abnormalities. Fleg and L a k a t t a 13 showed that muscle hypotrophy as a result of physical deconditioning was related to exercise capacity. Several metabolic, biochemical, and histologic changes that have been

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pH 7.4 ]

r=- 0.51 p= 0.0008

pH

r=- -0.45 p= 0.0001

7.4

1

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~

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72

p

A~ 7.0 ~

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6.6 J J

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PffPCr .--,- .-I-, 4 5 6

6.4

PCr/ATPB 0

1

2

3

4

5

6

7

Fig. 4. Correlation between intracellular pH and Pi/PCr and PCr/ATP~ ratios in all the patients and in healthy subjects. described in CHF were found also in healthy sedentary subjects but not in trained subjects. 14 Moreover, physical training could reverse 31p MRS changes in the skeletal muscle of patients with CHF. 5, 6 To our knowledge, our study is the first to compare 31p MRS in patients with CHF and in healthy subjects with sedentary lives, most likely to be physically deconditioned, and in others well trained and thus physically fit. Our hypothesis was that if physical deconditioning is one mechanism for the metabolic abnormalities in patients with CHF, the same abnormalities should also be present in subjects with minimal daily exercise activity b u t not in trained subjects. Indeed, our results support this hypothesis. The PCr depletion rate, whatever the method we used to express it, was similarly accelerated in CHF patients and in sedentary subjects. An interesting finding is that this depletion rate was significantly correlated with exercise capacity as evaluated by several ergometric variables, such as peak oxygen consumption, in our CHF patients. Consistently in CHF patients, Adamopoulos et al. 5 showed that this depletion rate could be slowed after a period of 8 weeks of endurance bicycle training. Minotti et al.6 reached the same conclusion by using segmental training of one arm in which PCr depletion rate tended to recover as compared with the contralateral untrained arm in which it remained unchanged. Free ADP concentrations in the muscle play a major role in the oxidative metabolism during exercise. 15 In our study, we assessed ADP levels as a function of the PCr/ATP~ ratio, to which it is negatively correlated, 9 and found that it tended to accumulate during exercise in the muscle of CHF patients, as well as of sedentary subjects. This is not surprising because the Pi/PCr ratio is related to free A D P . 16 In a previous study, we showed that ADP accumulation was more pronounced in the most se-

verely deconditioned patients, having the lowest peak V02, as compared with those of less severely deconditioned patients. 17 In the work of Adamopoulos et al.,5 the training protocol produced a significant decrease in free ADP levels in the muscle at peak exercise workload. ATP levels remained unchanged during exercise in all groups of this study. Actually, it has been suggested that ATP levels should not change in the muscle during exercise because of its rapid resynthesis from ADP. is However, very heavy exercise may produce a small but significant decrease of muscle ATP levels, even in normal subjects. 19Massie et al. 2° also described a 10% to 20% decrease in muscle ATP levels at peak exercise workload in patients with CHF. In addition, in a previous work, we showed a similar depletion but only in a subset of patients with severe CHF having the poorest exercise capacity. 17 In this study, it is likely that the patients' condition was not severe enough or they did not exercise heavily enough to produce an ATP depletion or both. Intracellular pH level is the result of the opposed effects of lactic acid production and the buffering permitted by the proton consumption during PCr hydrolysis.21 A rapid onset ofintracellular acidosis is the consequence of an early shift toward anaerobic metabolic pathways. 2° Consistent with a rapid PCr depletion, intracellular pH decreased in this study more rapidly (i.e., for smaller workloads) in the CHF patients, as well as in the sedentary subjects, when compared with the trained subjects. Nevertheless, Adamopoulos et al.5 did not show any improvement in intracellular pH, in spite of a slowing of PCr depletion in the patients after physical training. They suggested that this m a y be related to an increased lactate synthesis produced by training. On the other hand, Sahlin 22 showed that muscular aci-

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dosis blocks the excitation-contraction coupling in muscle fibers by inhibiting ADP rephosphorylation. Consistently, in our study as well as in a previous one, 17 we showed that intracellular pH was negatively correlated with the Pi/PCr ratio, as well as with the ADP levels, in all patients and in healthy subjects. PCr recovery rate was unchanged in CHF patients and in sedentary subjects when compared with t h a t in trained subjects. This conflicts with the findings of Adamopoulos et al.,5 who showed t h a t PCr recovery half-time was diminished after physical training in CHF patients. Nevertheless, however important it may be as an index of energetic metabolism, 3, 5 the investigation of the PCr resynthesis rate by 31p MRS is technically unreliable and has led to conflicting results, as we have pointed out previously. 17 How physical deconditioning may lead to muscle metabolic abnormalities. Changes in the muscle metabolism associated with physical deconditioning or physical training or both may be the result of local or systemic mechanisms or both. Interestingly, segmental, local training limited to an arm, 6 as well as general systemic training on a bicycle,5 produced similar partial correction of 31p MRS changes in patients with CHF. This may be taken as an indication of the involvement of both local and systemic mechanisms, even though important interactions m a y exist between these two mechanisms. Among the systemic factors, physical deconditioning may decrease, and physical training may improve exercise left ventricular ejection fraction and cardiac output in healthy subjects. 23 But it has consistently been demonstrated that there is no correlation between indexes of left ventricular systolic function and 31p MRS abnormalities in CHF. 5, ~, 17 In addition, these abnormalities remained unchanged in spite of significant improvement of left ventricular performance induced by dobutamine, for example. 24 Muscle blood flow may be another contributing factor. However, in healthy subjects, 14 as well as in CHF patients, 25 muscle blood flow does not necessarily increase after physical training. In addition, limitation of muscle perfusion in patients with CHF was not found to be critical to the muscle metabolic changes. 12 These changes may be corrected after segmental training of a limited group of muscles, without any significant modification of muscle blood flow.6 For local factors, loss of muscle mass was suggested as a possible mechanism contributing to the rapid PCr depletion in patients with CHF. 3 But PCr depletion rate m a y be slowed by physical training without any significant change in muscle mass or

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thickness. 6 Mitochondrial content and oxidative enzymatic activity of the muscle are more likely to play an important role, because both can be enhanced by physical training in parallel to the correction of 31p MRS changes. Indeed, Dudley et al. 15 showed an increased mitochondrial content in the muscle of hypothyroid rats after training, and Adamopoulos et al., 7 in a preliminary work in a model of experimental heart failure, demonstrated a training-induced increase in muscle concentrations of citrate synthase and glutamate-pyruvate aminotransferase. Similarly, Plourde et al. 26 described increased activity of the muscle nicotinamide adenine dinucleotide-isocitrate dehydrogenase produced by training. Among other local factors, impaired neuromuscular junction transmission (as well as, on the systemic side, abnormality of the central motor drive) as a possible cause of muscle fatigue in patients with CHF has been ruled out in a study of the group of Minotti et al. 27 in which CHF patients were compared with normal control subjects. Enhanced sympathetic nervous system activity is present in sedentary untrained normal subjects, 2s as well as in patients with CHF, 29 and muscle metaboreceptors response is attenuated in CHF. 3° However, because it was found t h a t muscle nerve activity during static exercise was similar in CHF patients and in normal controls, it was suggested t h a t factors other t h a n metaboreceptor impairment contribute to the enhanced sympathetic nervous system activity. More locally, ~-adrenoceptors in the skeletal muscle may be involved in the muscle metabolic impairment, as suggested by Plourde et al., 26 who described in normal rats a significant increase of ~-adrenoceptor density in the predominantly oxidative skeletal muscles, such as the soleus muscle or the red part of the vastus lateralis, occurring after physical training, together with an increased oxidative enzyme activity. Consistently, in a dog model of pacing-induced heart failure, Frey et al. 31 showed a significant loss of ~-adrenoceptor density with a diminished adenylate cyclase activity in the gastrocnemius and in the semitendinosus muscles. Study limitation. The small number of healthy subjects enrolled in this study may have led to a type II error, which we cannot totally rule out. There was a strong trend toward more abnormal response in the patients as compared with sedentary subjects. However, even if the difference between those two groups was indeed significant, this does not negate our hypothesis. The same trend is observed also in exercise capacity, which was even lower in CHF patients (total exercise time, 575 ___75 seconds vs 719 _+ 74 sec-

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onds; not significant). This suggests that, indeed, the level of typical deconditioning is the principal factor determining muscle metabolic changes. Conclusion. We have been able to show that physical deconditioning associated with sedentary habits in untrained subjects may lead to skeletal muscle metabolic impairments similar to those observed in patients with CHF. This is a strong indication of the implication of physical deconditioning in the pathogenesis of muscle metabolic abnormalities and consequently of exercise capacity limitation. However, the nature of the relation between deconditioning and metabolic changes (cause, consequence, or covariates of a single common pathophysiologic mechanism) and the mechanisms leading from the former to the latter cannot be answered by our study and are matters for further investigations. In any case, this study adds more rationale to the use of physical training in patients with CHF as a therapeutic means to improve functional capacity.

12.

13. 14.

15. 16.

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