1. health and fitness
2. exercise

Review
European Heart Journal (2007) 28, 673–678
doi:10.1093/eurheartj/ehl404
Exercise ventilation inefficiency in heart failure:
pathophysiological and clinical significance
´rard2*
Gabriele Tumminello1, Marco Guazzi1, Patrizio Lancellotti2, and Luc A. Pie
1
Cardiopulmonary Unit, Cardiology Division, University of Milano, San Paolo Hospital, 20142 Milano, Italy and 2 Department
`ge, Belgium
of Cardiology, University Hospital Sart Tilman, Boite 35 CHU, B-4000 Lie
Received 24 May 2006; revised 8 September 2006; accepted 7 November 2006; online publish-ahead-of-print 23 November 2006
KEYWORDS
Heart failure;
Ventilation;
Exercise;
Periodic breathing
Introduction
Heart failure (HF) is a complex syndrome characterized by
myocardial dysfunction and an impaired regulatory function
of multiple organ systems. Exercise ventilation inefficiency
is a hallmark manifestation of HF that provides additive
clinical and prognostic value.1 The abnormal ventilatory
response to exercise is identified by an increased slope of
ventilation vs. CO2 production (VE/VCO2) to incremental
workload.2 The origin of an increased and inefficient ventilatory response to incremental exercise is multifactorial
and no definitive agreement on its pathogenetic bases has
yet been provided. Recently, interest has also been
addressed to the clinical significance of an oscillatory ventilatory and gas exchange kinetics; a pattern that resembles
Cheyne Stokes respiration during sleep.3
This article highlights current proposed pathogenetic
views for an abnormal ventilatory response to exercise in
patients with left ventricular (LV) dysfunction, with emphasis on their clinical correlates and potential perspectives.
Increased VE/VCO2 slope
Measuring VE/VCO2 slope is of peculiar clinical relevance
because this variable has been repeatedly identified as a
strong and independent prognostic marker in a large
subset of HF patients with exercise limitation of mild-tointermediate severity.4–12 Mathematically, the VE/VCO2
* Corresponding author. Tel: þ32 4 366 71 94; fax: þ32 4 366 71 95.
E-mail address: lpierard@chu.ulg.ac.be
slope is determined by three factors: the amount of CO2
produced (VCO2), the physiological dead space/tidal volume
ratio (VD/VT), and the arterial CO2 partial pressure (PaCO2)
˙E ¼ 863 V
˙CO2/
according to the following equation: V
[PaCO2 (1–VD/VT)]. Three different mechanisms for an
increased ventilatory requirement to a given CO2 production
have been reported (Figure 1): (i) increased dead space and
consequent waste ventilation;10,11,13 (ii) early occurrence of
haematic lactic acidosis,11 and (iii) abnormal chemoreflex
and/or metaboreflex activity.14,15
In HF patients, a reduction in static lung mechanics (i.e.
reduced vital capacity and forced expiratory volume in 1 s)
is a common finding.11 The occurrence of restrictive lung
changes is implicated in a lower rate of increase in tidal
volume (VT), higher respiratory rate (RR), and dead space
to tidal volume ratio (VD/VT) for a given workload.13
Consonant with an increased dead space ventilation is the
demonstration that lung interstitial fibrosis and remodelling
of alveolar-capillary membrane are additional features of
changes occurring at the lung level.16,17 Thus, the abnormalities in alveolar gas membrane conductance along with the
occurrence of ventilation/perfusion mismatch due to the
combination of impaired regional lung perfusion and abnormal increase in pulmonary capillary pressure seem to be
implicated in the increased ventilatory requirement during
exercise.18
A limited increase in cardiac output is certainly the initial
determinant of exercise intolerance and muscle fatigue in
these patients. The imbalance between cardiac output and
metabolic request by working muscles explains the development of early lactic acidosis during exercise, favoured by
& The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
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Heart failure (HF) is a complex syndrome characterized by myocardial dysfunction and a poor prognosis.
Among multiple markers of severity, an exercise ventilation inefficiency has important clinical and prognostic value. The pathophysiology determining exercise ventilatory inefficiency is complex and not definitively clarified. Three different mechanisms have been identified: (i) increased dead space, (ii) early
occurrence of lactic acidosis, and (iii) abnormal chemoreflex and/or metaboreflex activity. Besides its
prognostic value, abnormal ventilation can be influenced by pharmacological and non-pharmacological
therapies such as b-blockers, selective cyclic 30 –50 guanosine monosphosphate phosphodiesterase inhibitors, physical training, and nocturnal continuous positive airway pressure. There is an increasing interest for the exercise periodic breathing, which is frequently associated with HF syndrome and has
prognostic importance. The precise mechanisms sustaining exercise periodic breathing are not fully
defined but ventilatory and metabo-haemodynamic hypotheses have been proposed.
674
G. Tumminello et al.
Figure 1
concomitant muscle deconditioning and increased type IIb
muscular fibres expression.19 Early lactic acidosis may
explain the occurrence of an increased inefficient ventilation since the early stages of exercise. It has been demonstrated that patients with severe HF exhibit a significant
PaCO2 reduction at peak exercise8,12,20,21 and even during
a submaximal constant workload at 50 W.22
Evidence for a major putative role of lactic acidosis in the
augmented ventilatory response is supported by the finding
of reduced PaCO2 levels in HF compared with control subjects. PaCO2 is stable or gradually increase during an incremental exercise up to the beginning of respiratory
compensation for lactic acidosis. Subsequently, for the
higher levels of developing lactic acidosis, PaCO2 decreases
accordingly until exercise termination. The demonstration
that patients with a lower PaCO2 at peak exercise are
those exposed at a high risk of death10 supports this hypothesis. This mechanism is nevertheless debated. Wensel
et al.23 recently showed that during the recovery phase of
exercise, high levels of lactate do not correlate with VE/
VCO2 slope. Moreover, the decrease in PaCO2 may also be
primarily related to the hyperventilatory response necessary
to overcome ventilation–perfusion mismatch and high dead
space ventilation.11,24
There is, however, no doubt that most of the pathophysiological evidence for an increase in the ventilatory response
to exercise is related to an impaired breathing control.
This may occur at several levels and involve the peripheral25
and/or central26 chemoreflex control as well as the
increased neural reflexogenic activity arising from working
muscle ergoreceptors.27 Chemoreflex deregulation may
occur early in the natural history of HF. In 60 patients14
with ischaemic heart disease without overt HF, VE/VCO2
slope was found to correlate with the level of central
chemosensitivity. Changes in VE/VCO2 slope correlated
with an improved chemoreflex sensitivity after a 3-month
period of exercise training. Although an increased chemoreflex activation in patients with overt HF is well established,
the relative contributory role of central vs. peripheral
activation is still undefined. Interestingly, Ciarka et al.15
have recently reported that in heart transplant recipients,
central chemoreflex activity may reverse to normal despite
persistent peripheral impairment, which correlates positively
with the increased VE/VCO2 during exercise.
Overactivaton of ergoreceptors (amielinic fibres located
in the skeletal muscles) to metabolic products such as Kþ
and Hþ triggers a series of reflex responses such as sympathetic activation, vasoconstriction, and hyperventilation.27
Ergoreflex activation independently correlates with VE/
VCO2 slope and inversely with exercise tolerance in HF
patients.28 The central nervous system processing involvement in the deregulated ventilatory response to exercise
has been evaluated. Rosen et al.29 did not report major
differences between the regional brain activation at rest,
after exercise, and during isocapnic hyperventilation in HF
patients and controls. Leptin, an hormone that may be
involved in the control activity of central chemosensitivity,
was found be a marker of increased VE/VCO2 slope.30
Impaired ventilation during exercise is a common finding
in HF patients even in right HF due to primary pulmonary
hypertension (PPH). PPH patients present a ventilation
profile similar to HF patients, consisting in increased VE/
VCO2 slope, ventilated dead space, and concomitant
reduced PaCO2. The difference between the two patterns
is the underlying pathophysiological mechanisms.
PPH results primarily from the abnormalities of pulmonary
vasculature consisting in intimal fibrosis, medial hypertrophy leading to increased pulmonary vascular resistances,
and loss of the physiological vasodilator response to
exercise. These changes determine a ventilation/perfusion
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Mechanisms involved in the genesis of increased VE/VCO2 slope and EPB. PaCO2, arterial partial pressure of CO2; for details see text.
Exercise ventilation inefficiency in HF
mismatch and increased VD/VT ratio, due to hypoperfusion
of ventilated alveoli, resulting in an increased VE/VCO2
ratio.31 Another trigger for the increased ventilatory
response to exercise is the early lactic acidosis at low
work rate32 and the consequent production of CO2 due to
the bicarbonate dissociation, as it buffers the newly
formed lactic acid. The last mechanisms are the arterial
hypoxemia and failure in delivering the requested O2 to
the exerting muscles due to: (i) reduced pulmonary capillary
bed with short red blood cell transit, (ii) possible
right-to-left shunt through a patent foramen ovale,33 and
(iii) failure in cardiac output.32 The right ventricle is
unable to increase the pulmonary and consequent systemic
blood flow against the elevated vascular resistance.
Interestingly, the role of an impaired chemoreflex and ergoreflex control in PPH has not been tested.34 Nevertheless, in
PPH patients, VE/VCO2 better correlates with the NYHA
class than the resting pulmonary haemodynamics.32 The
ventilatory pattern is also important for unmasking the presence of a right-to-left shunt as evidenced by an abrupt
decrease in end-tidal CO2 with concomitant increase in endtidal O2 and respiratory exchange ratio (RER).33
VE/VCO2 slope: prognostic relevance
and therapeutic implications
VE/VCO2 slope appears to be favourably influenced by
beta-blockade, an intervention that improves prognosis
despite unchanged exercise performance and peak VO2.41
In a retrospective analysis performed in 614 HF patients,
an association was found between b-blocker administration
and an improved ventilatory efficiency.42 Multiple explanations have been proposed for this favourable interaction.
b-Blockers may attenuate catecholamine activation of
central and peripheral chemoreceptors.43 Moreover, HF is
associated with cardiac b-adrenoceptor desensitization
and the process may also involve the pulmonary system;44
a resensitization receptor process induced by b-blockers
may favourably influence pulmonary ventilation–perfusion
matching and haemodynamics during exercise, leading to a
more efficient ventilation during exercise. An intriguing
hypothesis is the postulated effects of b-blockers on metabolic activity.45 In the early and intermediate exercise
stages, energy is supplied predominantly by fatty acids
while at further exercise stages, it is supplied by carbohydrates. Fatty acid oxidation yields to an RER, which is
given by VCO2/VO2 ratio of 0.7 compared with 1.0 when
glucose is the only energy substrate. Sympathetic nervous
system activation during exercise shifts the metabolic substrate towards carbohydrate utilization pathway. b-Blockers
may delay the switch from fatty acid to carbohydrate substrate utilization keeping exercise VCO2/VO2 ratio at lower
levels. As a result, for a given O2 consumption, less CO2 is
produced. In other words, an improved ventilation efficiency
could be driven by a lower CO2 production due to a prolonged utilization of fatty acid substrate.
Modulation of the nitric oxide pathway by selective cyclic
30 250 guanosine monophosphate phosphodiesterase inhibition, such as sildenafil, has provided evidence for a VE/
VCO2 slope lowering effect. This therapeutic effect was
found to correlate with an improvement in alveolarcapillary membrane conductance.39
Non-pharmacological therapy that directly influences the
inefficient ventilation includes physical training and nocturnal continuous positive airway pressure (CPAP). Treating
central sleep apnoea with CPAP improves inefficient ventilation46 probably through a combined positive effect on LV
ejection fraction,47 sympathetic activity, and chemosensitivity.48 Similarly, exercise-training programs improve inefficient ventilation by several mechanisms: (i) reduced
sympathetic nerve activity and catecholamine concentration,49 (ii) restoration of normal muscular metabolism,50
(iii) reduction in metabolic mediators involved in ergoreflex
activation,51 and (iv) improved alveolar-capillary membrane
diffusion properties.40
Exercise periodic breathing
Figure 2 Examples of ventilatory response to exercise: ( S ) healthy subject:
maximal oxygen consumption is 40 mL/min/kg, VE/VCO2 slope 24; () mild HF
patient (NYHA class 2) with preserved exercise capacity and ventilation:
maximal oxygen consumption 29 mL/min/kg, VE/VCO2 slope 25; (V) severe
HF patient (NYHA class 3) with reduced exercise capacity and hyperventilation: maximal oxygen consumption 16 mL/min/kg, VE/VCO2 slope 41.
There is an increasing interest for an abnormal breathing
disorder, identified as exercise periodic breathing (EPB),
which may be observed in HF patients (Figure 3). Since
1986, Weber described a particular ‘saw-toothed’ ventilatory response to exercise in some HF patients.52 EPB ventilation is characterized by oscillations in ventilation, VO2
and VCO2, with a period and amplitude that may be quite
different across HF populations. Its definition and classification remain quite arbitrary and definitive criteria are
still needed. Kremser et al.53 classified the periodism as
an oscillation of 1 min, a .15% amplitude of the resting
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VE/VCO2 slope (Figure 2) has repeatedly emerged as an
independent powerful prognostic marker in HF patients
with intermediate exercise limitation. Following the landmark paper published by Mancini et al.35 in the early
1990s, the prognostic superiority of VE/VCO2 slope over
peak VO2 has been progressively documented and strengthened by a series of studies. As originally proposed by Chua
et al.,4 the large majority of these studies have identified
and confirmed the prognostic value of a cut-off of 34.
Remarkably, VE/VCO2 slope provides incremental prognostic
value in patients with preserved peak VO2 (.18 mL/min/
kg)36 and in patients with diastolic HF.37 Although the exercise ventilation inefficiency is not considered as a specific
target of HF therapeutic strategies, an improvement in
VE/VCO2 slope has been demonstrated after several therapeutic approaches.38–40
675
676
G. Tumminello et al.
severe sleep-disordered breathing (apnoea–hypopnea
index . 30/h). In this study, a tight pathogenic link
between EPB and oscillatory sleep-disordered breathing
was observed. The finding of EPB may, therefore, help in
the decision making for further investigations, such as
screening for a sleep apnoea syndrome. However, several
questions on this ventilatory abnormality remain unanswered, such as the real incidence of this phenomenon,
the uncertain criteria for EPB definition, its prognostic
importance compared with VE/VCO2 slope, and the most
effective therapeutic approach.64
Figure 3
Example of EPB in a HF patient.
value, and a duration of up to 66% of the exercise protocol.
Leite et al.54 diagnosed EPB based on the presence of
frequent (at least three cycles), regular (standard deviation
of three consecutive cycle lengths within 20% of their
average), and ample (minimal amplitude of 5 L/min)
minute ventilation oscillations.
EPB pathophysiology and prognostic relevance
HF is frequently associated with functional mitral regurgitation (MR), which can be due to several mechanisms such as
valve annular dilatation, LV distortion, and mitral deformation.65 MR yields to a significant rise in pulmonary
venous, capillary, and arterial pressures.66,67 MR quantification is usually performed at rest and despite a relevant
and compelling pathophysiological background, it is often
overlooked that MR may abruptly rise during exercise.
Notably, the degree of MR at rest is not predictive of
exercise-induced changes in MR65 and a strong correlation
has been reported between MR exercise-induced changes
and transtricuspid pressure gradient.68 The excessive rise
in pulmonary wedge pressure18 and pulmonary artery
pressure69 is likely related to an increased ventilation
during exercise and dyspnoea sensation. Many HF patients,
without significant MR at rest, may develop a functional
MR during exercise resulting in worsening of dyspnoea and
hyperventilation.69 In order to better quantify the role of
functional MR in the development of dyspnoea during exercise in the individual patient, the appreciation of functional
MR may be integrated with a contemporary evaluation of the
effective ventilation during exercise. Remarkably, the
occurrence of exertional hyperventilation may potentially
suggest the presence of functional MR, which could play a
role in the hyperventilatory response. Finally, the presence
of functional MR is a further relevant marker for the prognostic stratification of HF patients by predicting the occurrence of acute pulmonary oedema70 and guarded
prognosis.71
Conclusions
HF syndrome is a complex syndrome involving several organ
systems. Exercise limitation is a typical manifestation that is
accompanied by increased significant dyspnoea and ventilation inefficiency. Characterization of abnormalities in
exercise ventilation may help clinicians to better define
clinical condition and risk stratification.
Conflict of interest: none declared.
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