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1868
Editorial Comment
Reduced Aerobic Enzyme Activity in Skeletal
Muscles of Patients With Heart Failure
A Primary Defect
or a
Result of Limited Cardiac Output?
Karlman Wasserman, MD
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Anumber of important contributions to the
pathophysiology of heart failure have come
from the exercise laboratory at Duke University. In their most recent report, which appears in
this issue of Circulation, Sullivan et al1 report that
skeletal muscle oxidative enzyme activity is reduced
in heart failure and attribute parts of the increased
anaerobiosis and lactate production at low work rates
observed in these patients to this mechanism. They
suggest that the reduction in enzyme activity contributes to the reduced exercise capacity and lactic
acidosis in heart failure. But is the reduction in
aerobic enzyme activity in the skeletal muscle a
primary disturbance accompanying heart failure,
which adds to exercise limitation, or simply atrophy
of skeletal muscle, which accompanies decreased
exercise tolerance without contributing to it?
See p 1597
These investigators also examined skeletal muscle
phosphocreatine decrease and lactate increase as
potential mechanisms of fatigue. They concluded
that neither could account for fatigue. But one
important function in the fatigue mechanism, which
was not measured, is the rate of aerobic regeneration
of high energy phosphate (ATP). This factor is
reflected in the rate of Vo2 increase in response to
the work rate stimulus. To what degree does heart
failure impair oxygen supply to the muscles, thereby
limiting the rate of ATP regeneration from aerobic
metabolism? An inadequate rate of increase in oxygen supply forces more energy to be derived from
anaerobic mechanisms, or, if the latter is inadequate,
fatigue must occur. When addressing exercise fatigue
and adaptive mechanisms in heart failure, limited
perspective is gained by measuring only some comThe opinions expressed in this editorial comment are not necessarily those of the editors or of the American Heart Association.
From the Department of Medicine, Division of Respiratory and
Critical Care Physiology and Medicine, Harbor-UCLA Medical
Center, Torrance, Calif.
Address for correspondence: Karlman Wasserman, MD, Department of Medicine, Division of Respiratory and Critical Care
Physiology and Medicine, Harbor-UCLA Medical Center, 1000 W.
Carson St., Torrance, CA 90509.
ponents in the bioenergetic process. The oxygen
supply-demand balance must be considered.
Changing Rate of Oxygen Consumption
in Response to Constant Work Load
Exercise and Fatigue
At the highest work rate performed by the heart
failure patients of Sullivan et al,' the Vo2 was unexpectedly low. It can be calculated from either total
body Vo2 or by oxygen consumption calculated from
leg blood flow and arteriovenous oxygen difference,
that the exercising muscles of the heart failure group
had an oxygen consumption of only about 70% of
normal at the submaximal cycle ergometer work of
300 kpm/min. Aerobic ATP regeneration therefore
was taking place at only about 70% of the normal
rate.
Patients with heart failure do not have increased
bioenergetic efficiency. Therefore, the failure of
these patients to increase Vo2 appropriately, in response to the work load, may reflect inability of their
circulation to transport oxygen fast enough to regenerate the ATP required, that is, oxygen supplydemand imbalance.
An oxygen supply inadequate to regenerate ATP
aerobically may cause a delay in Vo2 steady-state
time.2 Vo2 reaches a steady-state by 3 minutes when
performing constant exercise without a lactic acidoSiS.3 The slow rate of rise in Vo2 after 3 minutes that
accompanies lactic acidosis might result from muscle
hypoxia-stimulated vasodilating agents and lactic acidosis acting to shift the oxygen dissociation curve to
the right, thereby facilitating unloading of oxygen
from hemoglobin. Since the work duration for each
level of work performed by the heart failure and
normal subjects was 3 minutes in Sullivan et al's
study,' the reduced Vo2 in the heart failure subjects
could be interpreted as an increased oxygen deficit
and failure to reach steady-state aerobic ATP regeneration. This mechanism is likely a major contributing factor to exercise fatigue in heart failure.
Additional factors that may play a role in the
fatigue mechanism are the H' buffering capacity and
volume changes of the exercising muscle cells. Muscle cell pH is about 7.0.4 Thus, the bicarbonate
concentration in these cells can be estimated to be
Wasserman Reduced Aerobic Enzyme Activity in Skeletal Muscles
about 12 meq/l. Experimental data support that
HCO3 is the major intracellular buffer of lactic
acid.5 Since HCO3 is volatile, minimal change in pH
results when HCO3 takes up the H' of lactic acid
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and leaves the cell as CO2. But nonvolatile buffers
must take up H' when intracellular lactate increases
sufficiently to exhaust the volatile HCO3 buffer. The
pH decrease must then accelerate. But also intracellular osmolality should increase when lactate accumulates without a simultaneous loss of an intracellular anion. Thus, both cell swelling and rapidly
decreasing cell pH might contribute to muscle fatigue. The reduced work capacity and peak lactate at
the point of fatigue in normal subjects exercising at
high altitude6 may be explained in part by oxygen
supply-demand imbalance and the reduced blood
and therefore cell HCO3 concentration found in
high-altitude acclimatized subjects. Thus, it might be
predicted that lactate could not increase much beyond the buffering capacity of the volatile HCO3
buffer.
In support of increased lactic acid as a mechanism
of fatigue, Sahlin7 postulated that the intracellular
acidosis accompanying the increase in lactate may
block excitation-contraction coupling by inhibiting
the rephosphorylation of cytosolic ADP. In further
support is the observation that endurance time decreases the higher the lactate concentration.8
Fatigue can be viewed as a condition in which the
sum of the rates of aerobic metabolism, reflected by
Vo2, and anaerobic metabolism, reflected by the rate
of lactate increase, cannot meet the rate of ATP
regeneration required by muscles to sustain work.
The increase in blood lactate during exercise is
correlated with the degree of slowing of oxygen
uptake kinetics.9 That the total energetic requirement is not being met by aerobic plus anaerobic
mechanisms is suggested by the failure of Vo2 and
lactate to reach steady states.
Aerobic mechanisms allow for continual regeneration of energy during sustained exercise, without
disturbing the internal environment, except for a
gradual reduction in energy substrate. The amount of
energy that can be generated by anaerobic mechanisms is small. The oxygen stores (oxyhemoglobin
and oxymyoglobin) and the anaerobic mechanisms
(splitting of phosphocreatine and reoxidation of cytosolic NADH by pyruvate to form lactate) are quantitatively limited, being equal to no more than several
liters of oxygen.
Sullivan et all concluded that neither increase in
lactate nor decrease in phosphocreatine could totally
account for the fatigue of their patients because
neither changed as much in the patients as in the
normal subjects at their respective maximal work
rates. However, it is clear from their data that lactate
increased and phosphocreatine decreased more rapidly in the patients than the normal subjects when
related to work rate. While different mechanisms
could have contributed to the fatigue of the patient
and normal groups, reduced aerobic ATP regenera-
1869
tion was likely the major factor contributing to the
fatigue in the heart failure patients.
Decreased Skeletal Muscle Aerobic Enzyme
Activity in Heart Failure: A Primary
Maladaptation Reducing Exercise Performance
or a Response to Inactivity?
The peripheral circulation is controlled by local
factors that optimize matching of blood flow to the
tissue metabolic rate. This matching accounts for the
uniformity in the Vo2 cardiac output relation in
normal trained and sedentary subjects.'0 However,
patients with heart failure may not transport adequate oxygen to skeletal muscle during exercise.
Because a partial pressure gradient is needed for
diffusion of oxygen from blood to mitochondria,
oxygen extraction cannot be total. Since 5 1 of blood
contain only 1 1 of oxygen, when the hemoglobin
concentration is normal and maximally saturated
with oxygen, it is clear that an excess of 5 1 of blood
per minute must be delivered to the exercising muscles to perform work requiring 1 1 of oxygen per
minute. While the lowest end-capillary Po2 that can
be achieved during exercise without anaerobiosis is
unknown, the micro Po2 electrode studies of BylundFellenius et all' suggest that it must exceed 8-10
mm Hg.
Heart failure limiting oxygen transport to muscles
would obligate the patient to a reduced maximal
oxygen consumption, reducing the needed level of
muscle aerobic enzymes. Thus, the reduction in
mitochondrial oxidative enzymes found in heart failure patients might represent matching to the decreased oxygen transport, that is, atrophy of the
muscle aerobic energy-generating mechanism due to
symptom-enforced inactivity.'
Sullivan et all suggest that reduced aerobic enzyme
activity is mechanistically important in mediating the
reduction in maximal oxygen uptake and increased
anaerobic metabolism at low work rates in their heart
failure patients. If true, this must be considered to be
a maladaptation of the metabolic processes, which
worsens exercise tolerance beyond that dictated by the
cardiac lesion. But their study did not differentiate
between a deficiency in aerobic enzyme activity and
inadequate oxygen transport (cardiac output) as the
cause of the reduced peak Vo2 performed by their
patients. If the cardiac output increase is limited, then
the transport of oxygen to the tissues is limited and the
maximal Vo2 would be reduced. Thus a reduced
ability to increase cardiac output and oxygen transport
might result in a pari passu decrease in the concentration of enzymes that catalyze the aerobic-energygenerating mechanisms.
Relevant to the question of whether a shortage of
aerobic enzymes or oxygen transport determines the
work capacity in normal subjects are the studies on
maximal one- and two-legged exercise reported by
Davies and Sargeant.'2 They provide evidence that
the muscle aerobic enzyme activity exceeds that
required to perform cycle ergometer exercise so that
1870
Circulation Vol 84, No 4 October 1991
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the maximal VoJkg for one-legged exercise was
more than one half of that for two-legged cycle
exercise. Similarly, in studies on oxygen uptake and
blood flow of the knee extensor muscles of one leg
during maximal knee extension exercise, Anderson
and Saltin13 found that the maximal blood flow and
oxygen uptake per kilogram of the active muscle was
considerably higher than would be present if larger
muscle groups were simultaneously active. They concluded that when a large fraction of the muscle mass
is actively engaged in exercise, the capacity of the
skeletal muscles to consume oxygen exceeds the
capacity of the central circulation to supply it with
blood and oxygen.
Similarly, one- and two-legged exercise might be
studied in heart failure patients to discriminate between aerobic enzyme and muscle blood flow limitations. If the patient's reduced Vo2 max resulted from
reduced aerobic enzyme activity, then the increase in
Vo2 for maximal one-legged exercise should be one
half of that for two-legged exercise. However, if
oxygen flow were limiting, the increase in maximal
Vo2 for one-legged exercise should be more than one
half of the Vo2 increase for two-legged exercise.
That the muscles adapt to the aerobic capacity of
the subject may be an important concept to keep in
mind when evaluating the benefits of pharmacological therapy in chronic heart failure patients. Exercise
capacity would not be expected to improve to any
great degree immediately, even with successful heart
failure therapy, because of the chronic atrophic
changes in muscle induced by inactivity. Thus to
determine the true benefits of treatment, training
may be required to regenerate aerobic enzymes to
match the patient's improved cardiovascular function. If the cardiovascular transport of oxygen in
support of muscle aerobic metabolism improves, it
would be seen more quickly if the skeletal muscle
aerobic capacity were simultaneously stimulated to
accounting for reduced aerobic enzymes in the skeletal muscle of heart failure patients, similar to that
found in normal subjects undergoing experimental
detraining,14 is perhaps a more reasonable explanation than a coexisting primary skeletal muscle disturbance, acting to impair the patient beyond that caused
by their reduced cardiac function.
References
1. Sullivan MJ, Green HJ, Cobb FR: Altered skeletal muscle
metabolic response to exercise in chronic heart failure: Relationship to skeletal muscle aerobic enzyme activity. Circulation
1991;84:1597-1607
2. Wasserman K: New concepts in assessing cardiovascular function. Circulation 1988;78:1060-1071
3. Whipp BJ, Wasserman K: Oxygen uptake kinetics for various
intensities of constant load work. J Appl Physiol 1972;33:
351-356
4. Wilson JR, McCully KK, Mancini DM, Boden B, Chance B:
Relationship of muscular fatigue to pH and diprotonated Pi in
humans: A31P-NMR study. JAppl Physiol 1988;65:2333-2339
5. Beaver WL, Wasserman K, Whipp BJ: Bicarbonate buffering
of acid generated during exercise. J Appl Physiol 1986;60:
472-478
6. Edwards HT: Lactic acid in rest and work at high altitudes.
Am IPhysiol 1936;116:367-375
7. Sahlin K: Muscle fatigue and lactic acid accumulation. Acta
Physiol Scand 1986;128(suppl 556):83-91
8. Wasserman K: The anaerobic threshold measurement to
evaluate exercise performance. Am Rev Respir Dis 1984;1 16:
367-375
9. Roston WL, Whipp BJ, Davis JA, Effros RM, Wasserman K:
Oxygen uptake and lactate kinetics during exercise in man.Am
Rev Respir Dis 1987;135:1080-1084
10. Rowell LB: Human Circulation Regulation During Physical
Stress. New York, Oxford University Press, Inc, 1986, p 215
11. Bylund-Fellenius AC, Walker PM, Elander A, Holm S, Holm
J, Schersten T: Energy metabolism in relation to oxygen
partial pressure in human skeletal muscle during exercise.
Biochem J 1981;200:247-255
increase.
The concept of a primary aerobic enzyme deficiency
limiting exercise capacity in heart failure appears to
12. Davies CTM, Sargeant AJ: Physiological responses to one and
two leg exercise breathing air and 45% oxygen. JAppl Physiol
1974;36:142-148
13. Anderson P, Saltin B: Maximum perfusion of skeletal muscle
in man. JAppl Physiol 1985;366:233-249
14. Saltin B, Gollnick PD: Skeletal muscle adaptability: Significance for metabolism and performance, in Handbook of
Skeletal Muscle. Bethesda, Md, American Physiological Society, 1988, pp 589-596
denigrate the importance of the underlying defect in
heart failure patients. Rather, enforced detraining
KEY WORDS * heart failure * exercise * Editorial Comments
Reduced aerobic enzyme activity in skeletal muscles of patients with heart failure. A
primary defect or a result of limited cardiac output?
K Wasserman
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
Circulation. 1991;84:1868-1870
doi: 10.1161/01.CIR.84.4.1868
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1991 American Heart Association, Inc. All rights reserved.
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