Scand J Med Sci Sports 2015: 25 (Suppl. 4): 53–59 ª 2015 John Wiley & Sons A/S.

doi: 10.1111/sms.12619 Published by John Wiley & Sons Ltd

Review

Regulation of cardiac output in hypoxia

Christoph Siebenmann1, Carsten Lundby2
1
Department of Environmental Physiology, School of Technology and Health, Royal Institute of Technology, Solna, Sweden,
2
Center for Integrative Human Physiology, Institute of Physiology, University of Z€
urich, Z€
urich, Switzerland
Corresponding author: Dr. Christoph Siebenmann, Department of Environmental Physiology, KTH Technology and Health,
Berzelius v€
ag 13, 171 65 Solna, Sweden, Tel.: +46 (0)8 524 839 65, Fax: +46 (0)8-33 09 23, E-mail: [email protected]
Accepted for publication 14 October 2015

This brief review addresses the regulation of cardiac output consequence of a decrease in SV whereas tachycardia
(Q) at rest and during submaximal exercise in acute and persists. The diminished SV reflects a lower left ventricular
chronic hypoxia. To preserve systemic O2 delivery in acute end-diastolic volume which is primarily related to hypoxia-
hypoxia Q is increased by an acceleration of heart rate, generated reduction in plasma volume. Hypoxic pulmonary
whereas stroke volume (SV) remains unchanged. vasoconstriction may contribute by increasing right
Tachycardia is governed by activation of carotid and aortic ventricular afterload and thus decreasing its ejection
chemoreceptors and a concomitant reduction in arterial fraction. In summary, the Q response to hypoxia is the
baroreflex activation, all balancing sympathovagal activity result of a complex interplay between several physiological
toward sympathetic dominance. As hypoxia extends over mechanisms. Future studies are encouraged to establish the
several days a combination of different adaptive processes individual contributions of the different components from
restores arterial O2 content to or beyond sea level values an integrative perspective.
and hence Q normalizes. The latter however occurs as a

In acute hypoxia, arterial O2 content (CaO2) decli- and submaximal exercise only. Readers interested in
nes in parallel with oxyhemoglobin saturation the mechanisms for and the relevance of the reduced
(SaO2), requiring a higher cardiac output (Q) for the maximal Q are referred to another review (Wagner,
preservation of convective O2 transport. Q is 2000).
increased by an acceleration of heart rate (HR),
whereas stroke volume (SV) remains unchanged
Acute hypoxia
(Talbot et al., 2005). As hypoxia extends over sev-
eral days haematological and ventilatory acclimati- The magnitude of the increase in Q is related to the
zation processes restore CaO2 to or above sea level severity of hypoxia. While in moderate hypoxia it is
values (Siebenmann et al., 2015a). Subsequently, Q usually sufficient to preserve systemic O2 delivery
is normalized by a decrease in SV while tachycardia (Naeije et al., 1982; Lador et al., 2008), this may not
persists, at least in resting conditions (Klausen, be the case in severe hypoxia (Wolfel et al., 1998;
1966). During submaximal exercise, the response is Lador et al., 2008), particularly during exercise,
less clear as HR is reported higher than in normoxia where pulmonary O2 diffusion limitation aggravates
in some (Saltin et al., 1968; Lundby & Van Hall, hypoxemia (Calbet et al., 2008). In this case, tissue
2002), but not all (Wolfel et al., 1998; Calbet et al., O2 supply requires larger O2 extraction (Wolfel
2003), studies. et al., 1998).
The mechanisms mediating these responses have
been the subject of extensive research and the scope
Tachycardic response
of this review is to summarize our present under-
standing. The discussion is divided into “acute The direct effect of acute hypoxia on cardiac pace-
hypoxia”, denoting the time period preceding the maker cells of animals is a reduction in depolariza-
normalization of CaO2, and “chronic hypoxia”, tion rate (Senges et al., 1979; Stowe et al., 1985) and
referring to the time thereafter. indirect evidence suggests the same in humans
A further consequence of (severe) hypoxia is a (Kobayashi et al., 1992). Tachycardia must hence be
reduction in maximal exercise HR and Q. However, related to an indirect effect of hypoxia. HR is regu-
due to space limitations this review focuses on rest lated by balancing the sympathetic and vagal inputs.

53
Siebenmann & Lundby
Sympathoexcitation occurs in acute hypoxia as tive, but not the HR response to hypoxia supporting
demonstrated by recordings of muscle sympathetic that aortic chemoreceptors chiefly govern the tachy-
nerve activity (mSNA) (Saito et al., 1988). The cardic response, whereas the carotid bodies control
response of vagal activity is less understood as no the ventilatory and vascular responses (Niewinski
direct measurement method is available for humans. et al., 2014). Other results however indicate that the
Spectral analysis of HR variability however indicates carotid receptors are vital for the tachycardic
that vagal tone decreases, at least during resting con- response to hypoxia as the ventilatory response that
ditions (Perini et al., 1996; Princi et al., 2008). they trigger reduces vagal traffic to the heart through
A functional approach to assess the relative con- activation of pulmonary stretch receptors (Kato
tributions of sympathoexcitation and vagal with- et al., 1988). In line with this, carbon monoxide
drawal is pharmacological inhibition of b- inhalation, which reduces CaO2 but not PaO2 and
adrenergic and muscarinic receptors. At rest indi- hence should specifically stimulate aortic chemore-
vidual inhibition of either receptor type does not ceptors, increases mSNA but does not facilitate
affect the tachycardic response to hypoxia, whereas hyperventilation and tachycardia (Hanada et al.,
combined inhibition abolishes it (Koller et al., 2003). Aside from the indirect effect on vagal activ-
1988; Siebenmann et al., 2015b). This indicates that ity, sympathoactivation governed by carotid bodies
sympathoexcitation and vagal withdrawal are both may further accelerate HR through circulating cate-
involved and rules out other mechanisms. The cholamines.
unchanged tachycardic response during separate In summary, hypoxic activation of the peripheral
inhibition of either receptor type probably reflects chemoreceptors leads to sympathoactivation and
compensatory adjustment of the antagonistic arm indirectly to vagal withdrawal, both of which con-
of the autonomic nervous system. During submaxi- tribute to tachycardia. The functional differences
mal exercise hypoxia accelerates HR even during between carotid and aortic chemoreceptors are to
combined inhibition of b-adrenergic and muscarinic date incompletely understood.
receptors (Siebenmann et al., 2015b). In that study,
the magnitude of the tachycardic response was
Role of the arterial baroreflex
unaffected by b-adrenergic inhibition, whereas mus-
carinic inhibition reduced the response by ~50%. Reduced baroreflex activation contributes to the
The lack of an effect of separate b-adrenergic inhi- respective in- and decrease in sympathetic and vagal
bition and the partial persistence of tachycardia activity in acute hypoxia. This is brought about via
despite combined inhibition supports the idea that two mechanisms: First, hypoxia shifts the baroreflex
cardiac a-adrenergic receptors constitute an alterna- set-point to higher pressures, so that for a given arte-
tive pathway for sympathetic traffic to the heart rial pressure activation is lower (Halliwill et al.,
(Hopkins et al., 2003). 2003; Querido et al., 2011). The exact mechanism for
In summary, the tachycardic response to acute the resetting is unclear, but it seems to be a conse-
hypoxia at rest is related to simultaneous sympa- quence of the activation of the peripheral chemore-
thoexcitation and vagal withdrawal. The same is ceptors (Halliwill et al., 2003). Second, hypoxia-
probably true with exercise, although a contribution induced dilation of peripheral vascular beds tends to
of an unknown, non-autonomic mechanism cannot reduce arterial pressure, although this is overridden
be ruled out. Next, we discuss how the shift in auto- by sympathetically-induced global vasoconstriction,
nomic control is regulated. so that arterial pressure remains largely unchanged
(Calbet et al., 2014). The vasodilatory effect of acute
hypoxia is however appreciable in asthmatic patients
Role of the peripheral chemoreflex
after carotid body resectioning. There, the chemore-
Peripheral chemoreceptors are the main hypoxia flex-mediated sympathoactivation is blunted and a
sensors in the arterial blood. Carotid bodies are pri- reduction in arterial pressure occurs (Lugliani et al.,
marily sensitive to arterial O2 tension (PaO2), 1973).
whereas aortic chemoreceptors are mainly respon-
sive to changes in CaO2 (Lahiri et al., 1981).
Role of the muscle metaboreflex
Hypoxic activation of peripheral chemoreceptors
increases both sympathetic and parasympathetic Hypoxia reduces O2 availability in exercising mus-
nervous activity (Chapleau & Sabharwal, 2011). cles which accelerates the accumulation of fatigue-
However, in dogs, the hypoxia-induced increase in related metabolites (Hogan & Welch, 1986) and
sympathetic traffic directed specifically to the heart could hence increase HR by activating the muscle
is governed by activation of aortic chemoreceptors metaboreflex. Nevertheless, inhibition of neural
(Karim et al., 1980). In humans, removal of the car- feedback from exercising muscles has demonstrated
otid bodies blunts the ventilatory and vasoconstric- that the muscle metaboreflex does not play an

54
 Cardiac output in hypoxia
appreciable role in the tachycardic response to & Grover, 1983; Boussuges et al., 2000) and during
hypoxia (Kjaer et al., 1999). supine exercise (Stembridge et al., 2015). Potential
explanations for this include (i) reduced central
blood volume; (ii) diminished right ventricular SV
Preservation of stroke volume
due to the increase in afterload that results from
At rest and during exercise in acute hypoxia SV is hypoxic pulmonary vasoconstriction; and (iii)
preserved despite the higher HR (Calbet et al., 2003; impaired diastolic function (Stembridge et al.,
Talbot et al., 2005; Siebenmann et al., 2015b), indi- 2014b). Central blood volume may decline as a con-
cating enhanced venous return. This could be related sequence of the reduced PV. Restoration of PV by
to the vascular effect of hypoxia-induced sympa- isotonic Dextran infusion has indeed normalized
thoactivation, to the higher ventilation and/or the resting SV after three weeks at altitude (Siebenmann
accelerated HR itself which increases the occurrence et al., 2013). In contrast, in another study, expansion
of negative pressure in the right atrium (Bendjelid, of PV at altitude by infusion of one liter of Dextran
2005). did not affect resting SV but induced a substantial
increase in HR (Calbet et al., 2004), which, accord-
ing to the authors, may have been facilitated by the
Chronic hypoxia
Bainbridge reflex (Bainbridge, 1915). Whatever the
After weeklong exposure to moderate hypoxia, the mechanism, the increase in HR may have counter-
increase in CaO2 is primarily related to a reduction in acted the beneficial effect of PV expansion on right
PV and a partial restoration of SaO2 due to ventila- ventricular preload so that SV remained unchanged.
tory acclimatization, whereas the contribution of red During exercise at altitude, PV expansion did not
cell volume expansion is small (Siebenmann et al., affect SV (Calbet et al., 2004), presumably as in that
2015a). However, if hypoxia is severe and exposure study SV (prior to the PV expansion) was not
time extends to over several months, red cell volume reduced compared to sea level. Decreased central
expansion may become more pronounced and con- blood volume is further supported as explanation for
tribute to the increase in CaO2 more substantially the reduced SV in chronic hypoxia, at least at rest,
(Pugh, 1964). The subsequent normalization of Q is by the finding that progressive whole body head-
usually initiated by a reduction in SV and not by down tilt increases SV at altitude to the same plateau
reversion of tachycardia. Nevertheless, although the as at sea level (Siebenmann et al., 2013). This
evidence for HR to remain elevated is wide (Wolfel occurred despite a >40% elevation in systolic pul-
et al., 1994; Hansen & Sander, 2003; Siebenmann monary artery pressure, suggesting that hypoxic pul-
et al., 2013; Dhar et al., 2014), a normalization has monary vasoconstriction does not reduce resting SV.
also been reported (Wolfel et al., 1998; Bao et al., The latter is further supported by the notion that
2002). hypoxic pulmonary vasoconstriction occurs within
the first hours of hypoxic exposure, whereas the
reduction in SV requires days to occur. Echocardiog-
Reduced stroke volume
raphy has also indicated that right ventricular sys-
At rest, a reduced SV is a universal finding in chronic tolic function at rest is unchanged (Huez et al.,
hypoxia (Klausen, 1966; Siebenmann et al., 2013; 2009), although others have recently reported
Stembridge et al., 2015). During submaximal exer- impaired systolic function (Stembridge et al., 2014a).
cise, the situation is less clear as most (Sutton et al., The divergent findings could relate to the severity of
1988; Wolfel et al., 1998; Stembridge et al., 2015), hypoxic pulmonary vasoconstriction which was
but not all (Calbet et al., 2004), studies have more pronounced in the second study (Stembridge
observed a lower SV than in normoxia. The determi- et al., 2014a). In line with this, treatment with pul-
nants of SV are myocardial contractility, left ventric- monary vasodilators has demonstrated that hypoxic
ular preload and afterload. Left ventricular ejection pulmonary vasoconstriction may limit SV during
fraction is preserved or increased in chronic hypoxia, exercise, where cardiac output is higher and the
both at rest and during exercise (Reeves et al., 1987; increase in pulmonary artery pressure further aggra-
Suarez et al., 1987), excluding reductions in myocar- vated (Ghofrani et al., 2004; Hsu et al., 2006). This
dial contractility. Together with the observation that is however not always the case because, as indicated,
reducing blood viscosity by isovolemic hemodilution others have observed normal values of SV during
does not restore exercise SV to normoxic levels (Cal- exercise in chronic hypoxia (Calbet et al., 2003).
bet et al., 2002), the unchanged left ventricular ejec- Impaired left and right ventricular diastolic func-
tion fraction also rules out a higher left ventricular tions have been observed at altitude (Huez et al.,
afterload as an explanation. In contrast, a decrease 2009). More recent evidence however indicates that
in left ventricular end-diastolic volume, as a measure diastolic function is preserved or even improved,
of preload, has been detected both at rest (Alexander thus supporting that the reduction in SV is entirely

55
Siebenmann & Lundby
the result of reduced left ventricular filling pressure (a)
(Stembridge et al., 2015). These divergent findings
indicate that further research is required for a
complete understanding of the effects of chronic
hypoxia on diastolic function.
It should be considered whether the lower SV
could simply reflect reduced diastolic filling time due
to tachycardia. However, b-antagonists normalized
HR at rest and decreased it during exercise at alti-
tude but did not enhance SV (Wolfel et al., 1998),
although this could have also been related to the neg-
ative inotropic effect of b-antagonists. Nevertheless,
in acute hypoxia SV is preserved despite tachycardia,
arguing against shortened diastolic filling time as the
cause for the reduced SV.

Preserved tachycardia
Individual inhibition of b-adrenergic (Hughson
et al., 1994) and muscarinic receptors (Boushel et al.,
2001) fails to abolish tachycardia in chronic hypoxia.
As simultaneous inhibition has never been conducted
in chronic hypoxia it remains to be established
whether other mechanisms than altered autonomic
control are involved. Nevertheless, mSNA record- (b)
ings have indicated that after the acute response sym-
pathoactivation further increases throughout
weeklong hypoxic exposure (Hansen & Sander,
2003). The carotid chemoreceptors act as the pri-
mary mediators of the sympathetic response to
hypoxia and are sensitive to PaO2, which improves
little with acclimatization (Lundby et al., 2004). Fur-
thermore, the carotid bodies are sensitized during
acclimatization so that a given reduction in PaO2
evokes stronger activation (Hansen & Sander, 2003).
As a result, circulating norepinephrine concentra-
tions at rest and during exercise are higher in chronic
than in acute hypoxia (Mazzeo et al., 1995), which
may at least partially explain the persistence tachy-
cardia. In contrast, specific activation of cardiac
sympathetic fibers seems to be mainly governed by
aortic chemoreceptors, which are sensitive to CaO2.
It can hence be speculated that direct sympathetic
traffic to the heart triggered by chemoreceptor acti-
vation is less important in chronic than with acute
hypoxia.
Surprisingly, acute re-oxygenation only leads to a Fig. 1. Regulation of cardiac output in acute (a) and
minor reduction in mSNA in chronic hypoxia (Han- chronic (b) hypoxia. Note that the figure represents merely a
sen & Sander, 2003). While this could to some extent general overview as the regulation may change with exercise
and/or postural changes. Furthermore, not all mechanisms
relate to carotid body sensitization it also supports a are fully understood and some aspects are omitted for the
contribution of other mechanisms, potentially sake of better clarity. PaO2, arterial O2 pressure; CaO2, arte-
reduced activation of the baroreflex. The latter could rial O2 content.
result from the shift in baroreflex set-point that
occurs in acute hypoxia or from a lower circulating
blood volume secondary to the reduction in plasma ing head-up tilt (Siebenmann et al., 2013). In the
volume. In support of the latter, the HR difference same study, the transition from head-down to head-
to normoxia is lower during head-down tilt than dur- up tilt induced a steeper increase in HR at altitude

56
 Cardiac output in hypoxia
than at sea level, but this was normalized after ings), a potential explanation for these conflicting
restoration of PV by Dextran infusion. On the other results is that chronic hypoxia may increase the den-
hand, baroreceptor loading by infusion of 1 L of sal- sity of muscarinic receptors so that a given vagal
ine did not decrease mSNA at altitude to a large tone has a larger effect on HR (Kacimi et al., 1993),
extent (Hansen & Sander, 2003). It should however although this remains to be verified in humans.
be considered that such a large saline volume reduces
CaO2, which may counteract the negative effect of
Summary
baroreceptor loading on mSNA by activating aortic
chemoreceptors. Figure 1 illustrates an overview of the main mecha-
The effect of progressive sympathoactivation at nisms involved in the Q response to acute and
altitude may be attenuated by a down-regulation of chronic hypoxia.
cardiac b-adrenergic receptor density as demon-
strated in animals (Kacimi et al., 1993). In line with
Perspective
this, the HR response to b-adrenergic stimulation by
isoproterenol is blunted at altitude in humans As hypoxia is not only present at high altitude but
(Richalet et al., 1988). Reduced b-adrenergic recep- also a symptom of various diseases, there is a main-
tor density could explain the normalization of HR tained interest in its effects on the human body. With
that has occurred during altitude acclimatization in regard to the Q response, past work has generated a
some studies (Wolfel et al., 1998; Bao et al., 2002). comprehensive but yet incomplete understanding of
As in acute hypoxia vagal activity is not well the various mechanisms that are involved. Studies
understood in chronic hypoxia. Pharmacological are now required that investigate the interplay of
inhibition of muscarinic receptors has increased HR these mechanisms from an integrative perspective.
at altitude more than at sea level, both at rest (Bao This is complicated by the redundancy of the
et al., 2002) and during exercise (Boushel et al., involved mechanisms as inhibition of one mechanism
2001), indicating higher cardiac vagal modulation. may lead to a compensatory adjustment of an ago-
On the other hand, analysis of HR variability sug- nistic or antagonistic mechanism.
gests vagal withdrawal even after 18 months at alti-
tude (Dhar et al., 2014). Aside from methodological Key words: Chemoreflex, hypoxemia, exercise, para-
differences (with HRV including several shortcom- sympathetic, rest, vagal.

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