Invited editorial
European Journal of Preventive
Exercise intolerance and skeletal muscle
metaboreflex activity in chronic heart
failure: Do we need to recruit more
muscle in exercise training?
Ioannis D Laoutaris
The haemodynamic hypothesis was dominant in
chronic heart failure for most of the last century.
This hypothesis attributes exercise intolerance charac-
terized by exertional dyspnoea and/or muscle fatigue
to impairment in ventricular performance. The more
recent neurohormonal, muscle and immunohumoral
hypotheses describe chronic heart failure not only in
terms of haemodynamic adaptations, but also by neu-
rohormonal overactivation associated with a sympa-
thetic overdrive, activation of the immune response,
systemic inflammation and a catabolic state with
muscle atrophy, which may be enhanced by disuse
and immobilization in advanced stages of disease.
Current paper
In the current issue of this journal, Angius and
Crisafuli1 review the literature for the role of an exag-
gerated feedback from group III/IV muscle afferents in
the genesis of fatigue by bringing forward the muscle
hypothesis. The muscle hypothesis describes changes in
skeletal muscle metabolism, structure and function
where an increased activation of metaboreceptors
(and chemoreceptors responding to changes in blood
gas concentrations) sensitive to the metabolic changes
occurring during exercise produces an exaggerated
feedback from group III/IV muscle afferents (termed
the metaboreflex). The metaboreflex has been associat-
ed with increased sympathetic activity, abnormal
responses to exercise and with the progression of the
syndrome.2,3
Although central fatigue needs to be further illumi-
nated in patients with chronic heart failure (CHF), a
vasoconstriction-mediated response to peripheral sig-
nals originating from type III/IV muscle afferents in
the muscle potentially restrains muscle perfusion and
probably contributes to the early development of
Cardiology
2020, Vol. 27(17) 1858–1861
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Cardiology 2020
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peripheral muscle fatigue and exercise intolerance
shown by patients CHF.2–6
Although Angius and Crisafuli1 focus on muscle
fatigue, another aspect that needs to be reported is
the role of the metaboreflex in the genesis of dyspnoea,
which appears to be at least partially responsible for
exercise intolerance in patients with CHF. The reflex
network arising from the exercising muscle not only acti-
vates autonomic circuits, but also medullary ventilatory
centres resulting in an excessive ventilatory response to
exercise that presents as exertional dyspnoea.3,4
Most interestingly, muscle fatigue, dyspnoea and
exercise intolerance appear to be closely associated
not only with the limb muscle, but also with respiratory
muscle dysfunction,7 expressed by decreases in inspira-
tory muscle strength (PImax), but also mainly by the
inability of the diaphragm to sustain inspiratory pres-
sure over time, known as sustained PImax (SPImax), i.e.
inspiratory work capacity.8 Thus, the tension–time
index of the diaphragm (TTIdi) at peak exercise was
0.10 in patients with advanced CHF compared with
0.03 in healthy participants, suggesting a potential
early respiratory muscle fatigue for patients with
CHF.7 Furthermore, reducing the increased work of
respiratory muscles with a ventilator during exercise
resulted in a decrease in sympathetic activity and an
increase in limb blood flow in patients with CHF, sug-
gesting the modification of an increased diaphragmatic
metaboreflex activity,9 similar to the limb muscles. In
addition, another study showed that non-invasive
Onassis Cardiac Surgery Center, Athens, Greece
Corresponding author:
Ioannis D Laoutaris, Cardiac Rehab Laboratory, Onassis Cardiac Surgery
Centre, 356 Sygrou Boulevard, Athens, 176 74, Greece.
Email: ylaoutaris@yahoo.gr
Laoutaris 1859

ventilatory support combined with aerobic and resis-
tance training provided additional benefits for
dyspnoea and quality of life in this population.10
This response seems to be mediated by the metabolic
stimulation of small afferent fibres types III and IV
from the respiratory muscles, especially from the
diaphragm (Figure 1).
Angius and Crisafuli1 correctly include recent studies
reporting increased activation of the metaboreflex in
patients using beta blockers11,12 compared with previous
studies (beta blockers in 30% of patients).3,4,6 Based on
ventilatory responses to exercise in patients with
CHF,13 a finding that appears to be mediated by a
reduction in the exaggerated metaboreflex.3 A recent
study showed that aerobic training resulted in an
improvement in muscle metaboreflex and mechanore-
flex control of muscle sympathetic nerve activity, which
was associated with an improvement in peak oxygen
consumption (peakVO2).14 However, a number of
studies are increasingly adding either resistance train-
ing or inspiratory muscle training (IMT) to aerobic
training (moderate intensity or high-intensity interval),

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the consideration that the metaboreflex is mediated by
the sympathetic nervous system and that beta blockers
are adrenergic blockers, they could affect their hyperac-
tivation by decreasing the sympathetic tonus, potentially
influencing the metaboreflex activation.
These findings, in conjunction with the evidence of
the metaboreflex activity arising from the diaphragm,
support the muscle hypothesis and the role of the
metaboreflex as a contributor to exercise intolerance
in patients with CHF on optimum medical therapy.
Exercise training and skeletal muscle
metaboreflex activity
Modification of the exaggerated metaboreflex activity
with aerobic training has been suggested as one of the
main mechanisms of improvement in exercise tolerance
and quality of life in patients with CHF. Aerobic train-
ing has been shown to improve the sympathovagal and
reporting significantly enhanced benefits in exercise tol-
erance in patients with CHF.
Selective IMT has been shown to result in the ame-
lioration of dyspnoea15,16 and there is increasing evi-
dence for an IMT-induced delay in diaphragmatic
metaboreflex activity and an increase in limb blood
flow in patients with CHF.17,18 Another study reported
decreased sympathetic activity after IMT19 and there is
evidence for improvements in peakVO2 when IMT is
performed at a higher training intensity as a percentage
of inspiratory muscle work capacity (SPImax) or in
patients with severe inspiratory muscle weakness.15–17
The randomized multicentre Vent-HeFT trial demon-
strated that combined aerobic training/IMT provided
additional benefits in SPImax, dyspnoea and in func-
tional and serum biomarkers in patients with moderate
CHF.20 Selective resistance training of moderate inten-
sity resulted in improvements in heart rate variability,
limb blood flow, the mitochondrial ATP production

Dyspnoea

Sympathetic activity
Vasoconstriction
Muscle fatigue

Activity of type III/IV afferents

Metabolites
muscle fatigue

Figure 1. Skeletal muscle (limb and respiratory) metaboreflex activated during fatiguing muscle work due to the accumulation of
metabolites and increased activity of type III/IV afferents ,resulting in dyspnoea and increased sympathetic activity and vasocon-
striction, exacerbating muscle fatigue and contributing to exercise intolerance.
1860
rate and peakVO2,21,22 whereas combined aerobic
training/resistance training resulted in additional bene-
fits not only in muscle strength and function, but also
in flow-mediated vasodilation and ventilatory and met-
abolic efficiency in patients with CHF.23,24 Whether
these changes are associated with a potential attenua-
tion of metaboreflex activity needs to be investigated.
The triple combination of aerobic training/resistance
training/IMT (ARIS hypothesis) resulted in enhanced
benefits in dyspnoea, respiratory and limb muscle func-
tion, cardiopulmonary exercise parameters and quality
of life in patients with CHF.25,26
Based on these observations, the recruitment of
more muscle in exercise training appears to be associ-
ated with enhanced benefits in patients with CHF, with
the attenuation of metaboreflex hyperactivity arising as
an attractive mechanism for improvement. However,
Angius and Crisafuli1 rightfully suggest that further
studies are needed to evaluate the effect of metabore-
flex activity in producing exaggerated ventilatory
responses, central and peripheral fatigue in patients
with CHF, and also its potential attenuation in
response to different and combined exercise training
modalities.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of
this article
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
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