Download Skeletal muscle contractile characteristics and fatigue resistance in

European Heart Journal (1996) 17, 896-901
Skeletal muscle contractile characteristics and
fatigue resistance in patients with chronic heart
failure
S. D. R. Harridge, G. Magnusson and A. Gordon*
Department of Physiology and Pharmacology, Physiology III, Karolinska Institute; Stockholm, Sweden;
*Department of Medicine, Huddinge Hospital, Huddinge, Sweden
Whole muscle contractile characteristics and fatigue resistance were studied in male patients with chronic heart failure
(n = 6) and in healthy control subjects (n = 6). Maximum
voluntary isometric strength in the major muscle groups of
leg (plantar flexors and knee extensors) and arm (elbow
extensors and elbow flexors), was found to be similar for
both groups of subjects. However, a faster isometric twitch
time course was observed in the plantar flexor and knee
extensor muscles of heart failure chronic patients. The poor
resistance to fatigue in the knee extensors of chronic heart
failure patients was confirmed in the present study, but
using twitch interpolation this was shown not to be due to
poor activation. The plantar flexors of chronic heart failure
patients also showed a tendency to be less resistant to
fatigue, even when the muscle was activated by direct
electrical stimulation.
Introduction
lady type lib fibres15'61. Since type II fibres are inherently
less resistant to fatigue than type I fibres'71 it is possible
that the reduced ability of patients with chronic heart
failure to maintain force output during repeated contractions'3'8'91 is due to alterations in fibre distribution
and to changes in the metabolic profile of the working
muscles'4"61. However, the lower fatigue resistance in
these patients may also be as a result of poor motivation,
due to a fear of over-exertion. The reduced endurance of
the tibialis anterior in chronic heart failure patients
recently reported by Minotti et a/.'91 was partly a result
of central fatigue, but the patients were no different to
controls in this respect. However, with maximal exercise
of the larger muscle groups such as the knee extensors a
greater physiological challenge is presented to these
patients, with potentially more relevance to the fear of
over-exertion.
The aim of the present investigation was thus to
determine muscle strength in the major muscle groups of
the arm and leg in chronic heart failure patients, to
determine any differences in the time course of the
muscle twitch and to establish whether muscle force
production during maximal single and repeated contractions of major muscle groups was affected by poor
activation.
Whole body exercise tolerance is markedly reduced in
patients with chronic heart failure, with a decrease in
muscle strength and an increase in local muscle fatigability being implicated as potential causes1'1. To establish whether muscle strength per se is a contributory
factor to reduced whole body exercise capacity, it is
important that strength is measured in a number of
major muscle groups covering both the upper and lower
extremities. Lower muscle strength in chronic heart
failure patients has partly been attributed to their
smaller muscle mass'2'31, but impairment of the descending motor pathways and an inability to activate the
muscle fully during maximum voluntary contraction
cannot be excluded. Independent of muscle strength, it is
possible that the skeletal muscles of patients with
chronic heart failure may contract faster due to a
significantly higher proportion of type II141 and particuRevision submitted 29 August 1995, and accepted 20 September
1995.
Correspondence- S. D. R. Harridge, University Department of
Geriatric Medicine, Royal Free Hospital School of Medicine, Pond
Street, London NW3 2QG, U.K.
0195-668X/96/060896 + 06 $18.00/0
The present study shows that independent of muscle
strength, patients with chronic heart failure may possess
muscles that are faster to contract and less resistant to
fatigue. However, it seems this increased fatigability is not
due to poor muscle activation.
(Eur Heart J 1996; 17: 896-901)
Key Words: Heart failure, muscle contraction, fatigue,
activation.
© 1996 The European Society of Cardiology
Skeletal muscle and fatigue resistance in patients with CHF
Table 1 Physical characteristics of the subjects
Patients
(n = 6)
Age (years)
55-7
±8-8
Weight (kg)
Height (cm)
Ejection fraction (%)
VO 2 max (ml. kg ~ ' . min ~ ')
84-8
± 11-6
178-8
±5-9
32
± 12
17-5*
±2-4
Controls
(n=6)
62-7
±2-6
80-2
±81
179 7
±5-4
—
33-3
±4-2
'Patients with chronic heart failure significantly different
controls.
to
Methods
Patients
Six male patients with chronic heart failure as a result of
left ventricular systolic dysfunction participated in the
study. Four patients had idiopathic dilated cardiomyopathy and two had heart failure based on previous
myocardial function. Five patients were in New York
Heart Association Functional Class II and one in Class
III. Left ventricular ejection fraction as determined by
echocardiography ranged from 18-45%. Physical characteristics are given in Table 1. All of the patients were
medicated with ACE inhibitors and diuretics. Four were
taking digoxin, two atenolol and one warfarin. The
patients had suffered from the disease for 6-3 ± 4-5
(1-11) years and had been clinically stable for at least 1
month prior to the study. They exercised by walking or
cycling at least 2 h a week. Six healthy age-matched men
volunteered as control subjects. All had a normal electrocardiograph response to exercise and none was taking
medication. They were also habitually active, walking
for a couple of hours per week.
Muscle testing
All measurements were made on the dominant limb. To
test contractile properties and voluntary strength of the
knee extensors, the subjects were seated upright in a
rigid chair with knee flexed to an angle of 90° (see1'01).
The lower leg was strapped in a steel brace attached by
a rigid bar to a strain gauge load cell (Bofors KRG-4,
2 kN, Nobel Electronic, Sweden). Percutaneous stimulating electrodes (15 x 6 cm Tenzecare-3M) were placed
over the proximal and distal portions of the quadriceps
femoris.
To test the plantar flexors, the subjects were
seated upright in a purpose-built dynamometer with the
thigh horizontal and the ankle positioned at an angle of
85"1"1. A specially shaped clamp placed over the distal
portion of the thigh close to the kiiee prevented heel lift
897
during contractions. The ankle joint was aligned with
the centre of rotation of a footplate 0-3 m from a load
cell (see above). Stimulating electrodes ( 6 x 1 0 cm) were
placed over the belly of the soleus ( - ve) and over the
heads of the gastrocnemius (+ve).
To test the elbow flexors and extensors the
subjects were seated upright in a tall-backed rigid chair,
firmly attached with steel pins to a fixed bench. The
shoulder was positioned so that the upper arm was in a
horizontal position and the elbow was flexed to 90°. The
elbow joint was fixed to a purpose-built dynamometer
fixed on the bench. The wrist was clamped between two
steel brackets to the lever arm of the dynamometer, and
movement in the shoulder region was prevented with an
adjustable clamp. The dynamometer was designed such
that all force resulting from elbow extension and flexion
was transmitted through a 015 m lever system to a load
cell (see above). Four chronic heart failure patients
and an equal number of controls performed this part of
the study. No electrically evoked contractions were
performed on the arm muscles.
The torque signals from the load cell were
amplified (BKJ-5 Nobel Electronik, Sweden and
Gould, U.S.A.) and processed by an analogue-to-digital
converter (Cambridge Electronic Etesign 1401, U.K.)
attached to a personal computer, which sampled the
data at a rate of 4 kHz for twitch and 2 kHz for the
maximum voluntary contraction measurements. All
muscle contractions were evoked using direct current
square wave pulses of 0-5-10 ms duration delivered by a
battery powered stimulator1'21, where a PC controls
output from a Krone-Hite (Avon, MA, U.S.A.) waveform generator. Maximum voluntary grip strength of
the hand was tested using a handgrip dynamometer
(Cardionics, AB Sweden) with the arm in a straightened
position.
Test procedure
For the plantar flexors and the knee extensors each
procedure began with the determination of the maximal
twitch response. A maximal twitch was defined where
a stepwise increment in voltage delivered every 30 s
resulted in no further increase in torque. Three maximal
twitches were performed and the average values for peak
torque (PJ, time to peak torque (TPT) and half relaxation time (1/2RT) were used for analysis. One chronic
heart failure patient did complete the knee extensor
twitch protocol and one control subject did not complete
the plantar flexor twitch protocol. Following a short
rest, 4-5 maximum voluntary contractions were performed where the subjects were asked to generate their
maximum force as fast as possible and maintain the
contraction for 2-3 s. At least 1 min of rest was taken
between contractions. During the final two maximum
voluntary contractions of the knee extensors and plantar
flexors a maximal electrical impulse was delivered to the
muscle in an attempt to monitor the ability of the
subjects to activate fully each respective muscle.
Eur Heart J, Vol. 17, June 1996
898 S. D. R. Harridge et al.
Muscle activation following fatiguing
exercise
Fatiguing exercise of the knee extensor muscles was
performed using an isokinetic dynamometer (Cybex II,
Lumex Inc, N.Y., U.S.A.). Stimulating electrodes in
the form of conductive silicon rubber pads (5 x 10 cm)
were placed over the proximal and distal portions of
the quadriceps femoris. Following a brief warm-up,
where the subjects cycled at 50 watts on a cycle
ergometer for 5 min and then performed some light
stretching exercise, the subjects performed 50 consecutive maximal concentric contractions. Contractions
were performed at an angular velocity of 180" s~' and
repeated approximately once per second. Fatigue was
denned as the decline in peak torque (mean of the
torque generated on the best three of the last five
contractions expressed as a percentage of the mean of
the best three out of the first five contractions). Immediately following the final contraction, the leg was
rapidly positioned and locked at an angle of approximately 60°. The subjects were then instructed to push
isometrically as hard as possible for 3 s. The time
taken to reposition the leg and to initiate the isometric
contraction was 1-2 s. A supramaximal impulse (delivered from a stimulator, Medlec, Surrey, U.K.) was
then delivered to the muscle to determine the degree of
activation in the fatigued state. Five of the chronic
heart failure patients took part in this stage of the
study and were compared with control subjects from a
previous experiment[3]
Electrically evoked fatigue
For the plantar flexor fatigue test, the triceps surae was
activated by direct electrical stimulation and stimulated
for 300 ms once per second for 2 min at a frequency of
20 Hz1"1. The muscle was considered to be maximally
activated when prior stepwise increments in voltage (a
300 ms contraction at 20 Hz delivered once per minute)
resulted in a plateau in the torque response. Of the six
chronic heart failure patients tested, only two were able
to tolerate a supramaximal stimulus. Three subjects were
unable to tolerate a supramaximal stimulus and the test
was performed at what was estimated to be 70-90% of
maximum. One subject did not tolerate even mild tetanic
stimulation and did not perform the test. A fatigue index
was calculated as the mean of the isometric torque
generated on the final three contractions expressed as a
percentage of the mean torque generated by the first
three contractions. The data from the patients were
compared with data from a further five healthy agematched controls (mean age 57-4 ± 8-7 years), tested in
very similar apparatus1"1, using exactly the same test
protocol and where a maximal stimulus was tolerated in
all subjects.
All testing of the chronic heart failure patients
took place under clinical supervision.
Eur Heart J, Vol. 17, June 1996
Table 2 Isometric twitch characteristics of the knee
extensors and plantar flexors
Knee extensors
Patients
Controls
P,
TPT
(Nm)
(ms)
1/2RT
(ms)
314
±91
250
±60
81
±5
78
±7
76*
±15
94
±8
Plantar flexors
P,
(Nm)
190
±3-1
18-2
±3-6
TPT
(ms)
1/2RT
(ms)
127*
± 11
146
± 11
91
±22
114
± 10
P, = peak torque, TPT = time to peak torque, l/2RT=halfrelaxation time.
•Patients significantly different from controls (/><005). Patients:
n = 6 for plantar flexors, n = 5 for knee extensors. Controls. n = 6 for
knee extensors and n = 5 for plantar flexors.
Statistics
Values are expressed as mean ± SD in the text and
Tables and ± SE in the figures. Comparisons between
the chronic heart failure patients and control subjects
were made using independent Student t-tests. / ) <005
was taken as the level of statistical significance.
Results
Peak torque generated by the maximal twitch in the
plantar flexors and the knee extensors was similar for
chronic heart failure patients and controls (Table 2). In
the knee extensors, time to peak tension did not differ
between the two groups, but a significantly faster half
relaxation time was observed (/ ) <005) in the chronic
heart failure patients. In the plantar flexors, both time to
peak tension (F<005) and half relaxation time (P<006)
were faster in chronic heart failure patients when
compared with controls.
Maximum voluntary torque production in the
chronic heart failure patients averaged 126-8 ± 30-8,
1680 ± 4 0 , 53-9 ±15-7 and 57-7 ± 20-9 Nm for the
plantar flexors, knee extensors, elbow extensors and
elbow flexors respectively (Fig. 1). Similar values were
obtained from the four muscle groups of the control
subjects. This was also the case for hand grip strength
where the patients generated 478-7 ± 77-1 N and the
control subjects 4659±45-9N of force, but no differences in the ability to activate the plantar flexor and
knee extensor muscles were observed between the
chronic heart failure patients and control subjects.
Following 50 isokinetic contractions of the knee
extensor muscles by five of the chronic heart failure
patients at 180° s~', peak torque had declined to
46 ± 13% of that generated at the onset of exercise (Fig.
2). When a maximal electrical stimulus was delivered to
the muscle during a maximal isometric contraction
performed immediately after the final isokinetic contraction, no further increase in torque was observed in any
of the five subjects (Fig. 3).
Skeletal muscle and fatigue resistance in patients with CHF
Plantar
Knee
Elbow
Elbow
flexors extensors extensors flexors
Figure 1 Muscle strength values for the knee extensor
and plantar flexor muscle groups of the leg and the elbow
flexors and extensors of the arm. Data expressed in the
form of torque about the joint (n=6 for leg muscles and
n=4 for arm muscles in both groups).
0 = chronic heart failure; • = controls.
CHF patients
Controls
Figure 2 Fatigue of the knee extensor muscles in chronic
heart failure patients compared to controls taken from
Magnusson et aL (1994) expressed as a percentage (n = 5
chronic heart failure patients, n = 8 controls).
*Patients significantly different from controls (/ > <0 > 05).
The mean fatigue index obtained from the electrically evoked fatigue test in the plantar flexor muscle
group of the chronic heart failure patients was lower
(63 ±13%), but not significantly so, when compared
with control subjects (76 ± 15%, Fig. 4).
Discussion
Patients with chronic heart failure in the present study
were similar to control subjects in terms of voluntary
strength, but exhibited different contractile properties of
the leg muscles as determined by the twitch response.
The high degree of fatigability of the knee extensor
muscles was confirmed in chronic heart failure patients,
which could not be attributed to poor neural drive. Even
when the muscle, in this case the plantar flexors, was
899
involuntarily activated by direct electrical stimulation,
chronic heart failure patients were found to be generally
more fatiguable than control subjects.
As a consequence of their condition, heart failure
patients may hesitate to make a maximal effort during
strength and endurance testing procedures for fear of
over-exerting themselves. In order to investigate whether
or not this was the case, the twitch interpolation technique was used to determine whether the chronic heart
failure patients and the control subjects were able to
activate fully the knee extensor and plantar flexor muscles during maximum isometric contractions. Although
there was some evidence of poor activation in both the
plantar flexor and knee extensor muscle groups no
differences were observed between chronic heart failure
patients and controls. In some studies muscle strength in
patients with chronic heart failure has been reported to
be lower than for controls'3'13'41. This would seem to be
the result of a smaller muscle mass in the subjects in
these studies, as no changes in force per unit area have
been reported'3131. However, in the present study
chronic heart failure patients showed comparable
strength with controls in all three muscles, which is in
accordance with the observations of unaltered strength
in the knee extensors and ankle dorsiflexors in chronic
heart failure patients in other studies'2'8'91. The lack of a
decline in strength in the present study is unlikely to be
explained by the duration of the disease, since three of
the chronic heart failure patients had suffered with the
condition for approximately 10 years. However, it is
likely that the more advanced and the longer the duration of heart failure, the more inactive patients become,
resulting in a greater degree of muscle wasting and thus
greater deterioration of muscle function.
The muscle twitch provides a useful measure of
involuntary muscle function which has been shown to
reflect muscle composition'151. In the present study, time
to peak tension in the knee extensors was similar for
both groups, however, a significantly faster half relaxation time (/><005) was observed in chronic heart failure
patients. The twitch time course of the plantar flexors
was markedly prolonged in both groups of subjects
when compared to the knee extensors. This is no doubt
a reflection of difference in the composition of the two
muscle groups as the knee extensors, as represented by
the vastus lateralis, comprise a relatively even mixture of
fast (type II) and slow (type I) fibres (at least in healthy
young adults)'71, whilst the plantar flexors comprise both
the gastrocnemius and soleus muscles, the latter of
which is dominated by type I fibres'161. Observations of
the plantar flexors revealed a markedly faster time to
peak tension (f<0-05) and half relaxation time (/><0-06)
in the chronic heart failure patients as compared to
control subjects. It is likely that these results are a
reflection of an altered muscle composition, specifically
a higher proportion of type II[4] and particularly lib
fibres which have been shown to occur in the vastus
lateralis'61 and in the gastrocnemius muscles of chronic
heart failure patients'51. These data are, however, in
contrast to the results of studies on isolated bundles of
Eur Heart J, Vol. 17, June 1996
900
S. D. R. Harridge et al.
Angle
trace
Stimulus
Torque
trace
Figure 3 An original record of a chronic heart failure patient performing maximum isokinetic contraction at 180° s ~ ' . The record shows the
final contraction followed by a rapid repositioning of the leg followed by
a maximum isometric contraction. The arrow indicates the delivery of a
maximal stimulus with no effect on torque production, suggesting full
activation can occur whilst the muscle is in the fatigued state.
CHF patients Controls
Figure 4 The fatigue index data from the plantar flexors
resulting from electrically evoked isometric contractions
(=5).
skeletal muscle fibres from the type II fibre dominated
extensor digitorum longus muscle of rats with
infarction-induced chronic heart failure1'71, where twitch
time course has shown to increase. This phenomenon
was shown to be closely coupled to changes in sarcoplasmic reticulum Ca 2+ kinetics, which also seemed to
be the cause of the ~ 50% reduction in specific tension
observed during a maximal tetanus.
It is evident that chronic heart failure patients
have markedly reduced muscular endurance138'9''31 despite similar absolute strength as control subjects'8'91.
Minotti et a/.'81 using dynamic and sustained isometric
contractions of the dorsiflexors, reported that neural
drive was a limiting factor to force production during
Eur Heart J, Vol. 17, June 1996
fatiguing exercise, but that patients with chronic heart
failure were no worse in this regard than normal healthy
subjects. Compared to the dorsiflexors, the physiological
demands of repeated knee extensor exercise are potentially much greater given the larger muscle mass. Thus it
is possible that these patients may be more susceptible to
impaired activation under these conditions. However,
following 50 maximal isokinetic knee extensions the
subjects appeared to be able to activate their muscle
mass fully, as shown by no evidence of an interpolated
twitch superimposed on an isometric contraction immediately following dynamic exercise (Fig. 3). The decline
in torque over this period was in close agreement with
values previously reported for chronic heart failure
patients and which are markedly lower than those of
healthy controls'31.
By activating the muscle through direct electrical
stimulation it is possible to determine its fatigue resistance completely independent of subject volition. In the
present study the plantar flexors were stimulated intermittently at a frequency of 20 Hz for 2 min. The decline
in torque production was more pronounced in the
patients with chronic heart failure than in the control
subjects. However, in contrast to all of the control
subjects, only two of the chronic heart failure patients
were able to tolerate a supramaximal stimulus. Since
these two showed the biggest decline in torque production, it may explain why this difference was not at the
level of statistical significance, when the whole patient
group was considered.
The results of the fatigue experiments on the
knee extensor and plantar flexor muscle groups would
Skeletal muscle and fatigue resistance in patients with CHF
seem to support the argument that local muscle fatigue
in patients with chronic heart failure is due to peripheral,
rather than central factors. The aetiology of muscle
fatigue is complex and depends on the type and duration
of the exercise performed (see1181 for review). In the
present study a relatively short duration high intensity
exercise protocol was used. In this regard, lower muscle
pH and higher inorganic phosphate concentrations have
been observed in chronic heart failure patients following
intense exercise when compared to controls'5'19', factors
known to contribute to impaired force generation'201.
In addition lower oxidative enzyme capacity15'6'21' and
lower capillary density161 may also contribute to the early
onset of fatigue, even during relatively short exercise
periods.
In conclusion, voluntary strength in the major
muscle groups of the arm and leg was well maintained in
patients with chronic heart failure when compared with
age-matched healthy individuals in the present study.
However, a faster twitch response and greater fatigability were observed in the leg muscles of chronic
heart failure patients. The latter finding could not be
attributed to poor muscle activation, adding further
weight to the argument that the decrease in local skeletal
muscle fatigue resistance in patients with chronic heart
failure is due to muscular and not to central limitations.
The authors would like to thank Eddy Karlsson and Georg
Goertz for their technical assistance.
References
[1] Coats AJS, Clark AL, Piepoli M, Volterrani M, Poole-Wilson
PA. Symptoms and quality of life in heart failure: the muscle
hypothesis. Br Heart J 1994; 72 (Suppl): S36-9.
[2] Minotti JR, Pillay P, Oka R, Wells L, Christoph 1, Massie
BM. Skeletal muscle size: relationship to muscle function in
heart failure. J Appl Physiol 1993; 75: 373-81.
[3] Magnusson G, Isberg B, Karlberg K-E, Sylven C. Skeletal
muscle strength and endurance in chronic congestive heart
failure secondary to idiopathic dilated cardiomyopathy. Am J
Cardiol 1994; 73: 307-9.
[4] Drexler H, Riede U, Munzel T, Konig H, Funke E, Just H.
Alterations of skeletal muscle in chronic heart failure. Circulation 1992; 85: 1751-9.
[5] Mancini DM, Coyle E, Coggan A et al Contribution of
intrinsic skeletal muscle to 3 T NMR skeletal muscle metabolic abnormalities in patients with chronic heart failure.
Circulation 1989; 80: 1338-46.
901
[6] Sullivan MJ, Green HJ, Cobb FR. Skeletal muscle biochemistry and histology in ambulatory patients with long-term
heart failure. Circulation 1990; 81: 518-27.
[7] Saltin B, Gollnick PD. Skeletal muscle adaptability, significance for metabolism and performance. In: Handbook of
physiology, section 10, Skeletal muscle. Bethesda/Baltimore:
Williams and Wilkins 1983: 555-663.
[8] Minotti JR, Christoph I, Weiner MW, Wells L, Massie BM.
Impaired skeletal muscle function in patients with congestive
heart failure. J Clin Invest 1991; 88: 2077-82.
[9] Minotti JR, Pillay P, Chang L, Wells L, Massie B. Neuromuscular assessment of skeletal muscle fatigue in patients with
congestive heart failure. Circulation 1992; 86: 903-8.
[10] Edwards RHT, Young A, Hosking GP, Jones DA. Human
skeletal muscle function: description of tests and normal
values. Clin Sci 1977; 52: 283-290.
[11] Davies CTM, Mecrow IK, White MJ. Contractile properties
of the human triceps surae with some observations on the
effects of temperature and exercise. Eur J Appl Physiol 1982;
49: 255-69.
[12] Duvoisin MR, Reed HE, Doerr DF, Dudley GA, Buchanan
P. A newly developed EMS unit. IEEE Trans Biomed Eng
1988; 10: 677-8.
[13] Lipkin DP, Jones DA, Round JM, Poole-Wilson PA. Abnormalities of skeletal muscle in patients with chronic heart
failure, Int J Cardiol 1988; 18: 187-95.
[14] Buller NP, Jones DA, Poole-Wilson PA,. Direct measurement
of skeletal muscle fatigue in patients with chronic heart
failure. Br Heart J 1991; 65: 20-4.
[15] White MJ, Harridge SDR, Carrington CA, Goodman M,
Cummins P. The relationship between isometric contractile
characteristics and isomyosin composition of the young and
elderly human triceps surae. J Physiol 1994; 475: 27P.
[16] Gollnick PD, Sjodin B, Karlsson J, Jansson E, Saltin B.
Human soleus muscle: a comparison of fibre compositions and
enzyme activities with other leg muscles. Pflug Arch 1974; 348:
247-55.
[17] Perreault CL, Gonzalez-Serratos, H, Liwin SE, Sun X,
Franani-Armstrong C, Morgan JP. Alterations in contractility and intracellular Ca 2+ transients in isolated bundles of
skeletal muscle fibers from rats with chronic heart failure. Circ
Res 1993; 73: 405-12.
[18] Fitts RH. Cellular mechanisms of fatigue. Phys Rev 1994; 74:
49-94.
[19] Arnolda L, Conway M, Dolecki M et al. Skeletal muscle
metabolism in heart failure; a 3 I P nuclear magnetic resonance
spectroscopy study of leg muscle. Clin Sci 1990; 79: 583-9.
[20] Cooke R, Franks K, Luciani GB, Pate E. The inhibition of
skeletal muscle contraction by hydrogen ions and phosphate.
J Physiol 1988; 395: 77-97.
[21] Ralston MA, Merola JA, Leir CV. Depressed aerobic enzyme
activity of skeletal muscle in severe chronic heart failure. J Lab
Clin Med 1991; 117: 370-2.
Eur Heart J, Vol. 17, June 1996