Progress in Cardiovascular Diseases 52 (2010) 456 – 466

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Physiological Adaptation of the Cardiovascular System to High Altitude

Robert Naeije⁎
Erasme University Hospital, Brussels, Belgium

Abstract Altitude exposure is associated with major changes in cardiovascular function. The initial
cardiovascular response to altitude is characterized by an increase in cardiac output with
tachycardia, no change in stroke volume, whereas blood pressure may temporarily be slightly
increased. After a few days of acclimatization, cardiac output returns to normal, but heart rate
remains increased, so that stroke volume is decreased. Pulmonary artery pressure increases
without change in pulmonary artery wedge pressure. This pattern is essentially unchanged with
prolonged or lifelong altitude sojourns. Ventricular function is maintained, with initially
increased, then preserved or slightly depressed indices of systolic function, and an altered
diastolic filling pattern. Filling pressures of the heart remain unchanged. Exercise in acute as well
as in chronic high-altitude exposure is associated with a brisk increase in pulmonary artery
pressure. The relationships between workload, cardiac output, and oxygen uptake are preserved in
all circumstances, but there is a decrease in maximal oxygen consumption, which is accompanied
by a decrease in maximal cardiac output. The decrease in maximal cardiac output is minimal in
acute hypoxia but becomes more pronounced with acclimatization. This is not explained by
hypovolemia, acid-bases status, increased viscosity on polycythemia, autonomic nervous system
changes, or depressed systolic function. Maximal oxygen uptake at high altitudes has been
modeled to be determined by the matching of convective and diffusional oxygen transport
systems at a lower maximal cardiac output. However, there has been recent suggestion that 10% to
25% of the loss in aerobic exercise capacity at high altitudes can be restored by specific pulmonary
vasodilating interventions. Whether this is explained by an improved maximum flow output by an
unloaded right ventricle remains to be confirmed. Altitude exposure carries no identified risk of
myocardial ischemia in healthy subjects but has to be considered as a potential stress in patients
with previous cardiovascular conditions. (Prog Cardiovasc Dis 2010;52:456-466)
© 2010 Elsevier Inc. All rights reserved.

Keywords: High altitude; Physiologic adaptation; Cardiovascular system; Cardiac failure; Exercise; Pulmonary hypertension; Hypoxia

You cannot fool Mother Nature. Jack Reeves, 1976
High-altitude exposure has long been recognized as a
cardiac stress. Early accounts of alpine climbs include
Statement of Conflict of Interest: see page 465.
⁎ Address reprint requests to Robert Naeije, Laboratory of
Physiology, Erasme Campus, CP 604, Lennik road, 808, B-1070
Brussels, Belgium.
E-mail address: rnaeije@ulb.ac.be.
mention of tachycardia, palpitations, and shortness of
breath as a symptoms of “cardiac fatigue.”1 Heart failure
syndromes have been reported at high altitudes, including
“brisket disease” in cattle brought to high-altitude pastures
in Utah and Colorado,2 “Monge's disease” in the
inhabitants of the South American altiplano,3 “subacute
mountain sickness” or “chronic mountain sickness” in the
Himalayas,4,5 and “high-altitude right heart failure” in
occasional high-altitude travelers.6 On the other hand,
there is the notion that the myocardium has a good toler-
ance to hypoxia and that the prevalence of cardiovascular

0033-0620/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.pcad.2010.03.004 456
 R. Naeije / Progress in Cardiovascular Diseases 52 (2010) 456–466 457

diseases is lower in high-

Abbreviations and Acronyms
altitude dwellers than in
IVRT = isovolumic sea level inhabitants. 7
relaxation time Hypoxia induces an in-
LV = left ventricular crease in pulmonary vas-
PAP = pulmonary artery cular resistance, but
pressure resulting pulmonary hy-
pertension is most often
RV = right ventricular
moderate. 8 However,
TAPSE = tricuspid annular there has been recent sug- Fig 2. Mean heart rate (HR), cardiac output (Q), and stroke volume during
plane systolic excursion gestion that specific pul- the first days of acclimatization to the altitude of 3800 m in 8 healthy
volunteers. Both Q and HR increased initially. After 8 days of altitude
TDI = tissue Doppler imaging monary vasodilating exposure, Q was back to prehypoxic normal, but stroke volume remained
interventions to unload decreased and heart rate increased. After study by Klausen.11
the right ventricle might improve aerobic exercise capacity
at altitude.9
or slightly below in a few days.11,12 Heart rate remains
increased, so that stroke volume is decreased. This is
Stroke volume and heart rate at rest
illustrated in Fig 2 that depicts the evolution of cardiac
output, stroke volume, and heart rate in 5 subjects during
Immediately after exposure to hypoxia, normobaric or
the first 8 days of exposure to an altitude of 3800 m.11
hypobaric, the resting cardiac output increases. A typical
This situation then remains stable over time. Resting
response in 24 subjects acutely breathing a fraction of
cardiac output in long-term sojourners and high-altitude
inspired oxygen of 0.12 to decrease arterial PO2 to 40 ±
natives is not different from that of sea level controls but
1 mm Hg is illustrated in Fig 1.10 Cardiac output
with somewhat higher heart rate and lower stroke
increased by 22%, and this was entirely explained by an
volume.13-15 Interestingly, there seems to be no relation
18% increase in heart rate. Stroke volume did not
between the altitude and cardiac output. Because cardiac
change. It is remarkable that the increase in cardiac
output returns to baseline a few days of hypoxic
output exactly matched the decrease in arterial oxygen
exposure before the onset of polycythemia, there has to
content, so that the product of both, or the oxygen
be an increased oxygen extraction. Why it takes a few
delivery to the tissues, remained unchanged. This
days for the body to select increased extraction over
observation has been repeatedly confirmed and suggests
increased delivery to preserve the oxygen uptake is not
that oxygen delivery to the tissues is tightly matched by
exactly known. Maintenance of cardiac output with
immediate cardiac output changes to peripheral demand
decreased stroke volume and increased heart rate may be
in normal subjects at rest.
related to the development of respiratory alkalosis with
However, this cardiovascular response to hypoxia is
progression of the hypoxic ventilatory response during
transient, as cardiac output returns to normoxic baseline
acclimatization, although this would decrease over the
years.16 Another possible explanation is that increased
heart rate and decreased stroke volume allow for an
improved coupling of the right ventricle to the
pulmonary circulation in the presence of even mild
hypoxic pulmonary hypertension, through an adaptive
decrease in the oscillatory component of pulmonary
arterial hydraulic load.17

Effects of exercise

Fig 1. Mean ± SE percent (%) changes in cardiac output (Q), heart rate
(HR), stroke volume (SVI), arterial PO2 (PaO2), and oxygen delivery
(TO2) in 24 subjects submitted to a brief period of normobaric hypoxic
breathing with a fraction of inspired oxygen of 12.5% (FIO2)—full
columns in normoxia, empty columns in hypoxia. Arterial PO2
decreased to 40 mm Hg, but the decrease in arterial O2 saturation
was limited to 79%. Cardiac output increased because of an increased
heart rate. Oxygen delivery to the tissues was maintained. Redrawn
from Naeije et al.10
Altitude exposure is associated with a decrease in
maximal oxygen uptake (VO2max) that parallels the
decrease in barometric pressure or the inspired partial
pressure of oxygen (PO2) and is thus essentially
explained by a decreased oxygenation of the blood.18
However, both maximal stroke volume and heart rate are
decreased. Initially, there is a higher cardiac output at
any workload, so that maximum cardiac output and heart
458 R. Naeije / Progress in Cardiovascular Diseases 52 (2010) 456–466
Fig 3. Cardiac output (Q) as a function of workload (W) or oxygen uptake
(VO2) in 4 healthy volunteers at the altitude of 5800 m and at sea level.
The relationships between Q, W, and VO2 were preserved at high altitude
but reaches a peak at lower maximal VO2 (after study by Pugh23).
rate are either maintained or only slightly reduced.19-22
With acclimatization, the relationship between cardiac
output, workload, and oxygen uptake is not different
from that measured at sea level, but it reaches a peak at
lower VO2max, workload, cardiac output, and heart
rate.13-15,23-26 This is illustrated in Fig 3, which represents
cardiac output, workload, and oxygen uptake measure-
ments in 4 subjects at sea level and again after
acclimatization at the altitude of 5800 m,23 and in Fig 4,
which shows the increased resting but decreased maximal
heart rate as a function of increased altitude.24
Typical changes were reported by Alexander et al20
in normal subjects exposed for 3 weeks at 3100 m.
Maximal oxygen uptake decreased by 25% during the
first days of altitude exposure with no subsequent
improvement. There was a fall in arterial oxygen
saturation at maximal exercise but minimally so. Heart
rate increased at all levels of exercise, but maximal
heart rate was unchanged. Stroke volume was decreased
at rest and at all levels of exercise. Maximal cardiac
output was decreased. The authors discussed possible
contributions of increased pulmonary vascular resis-
tance, sympathetic nervous system activity, decreased
plasma volume, and alluded to a possible depressant
effect of alkalosis but favored the idea of a myocardial
depressant effect of moderate hypoxia.20 This is
intriguing because stroke volume was decreased with
hardly any change in arterial oxygen saturation.
Furthermore, supplemental oxygen to correct hypoxemia
at higher altitudes does not immediately correct the fall
in stroke volume.13,23,24
Mechanisms of decreased maximal cardiac output at
high altitudes
Sympathetic nervous system activation
The pattern of change in cardiac output on acute high-
altitude exposure is at least in part related to an activation
of the sympathetic nervous system. This is reflected by an
increase in plasma and urine catecholamines27,28 and has
been confirmed by microneurographic recordings.29,30
Sympathetic nervous system activation is also responsible
for an increased metabolic rate.11 On the other hand, there
has been evidence of diminished heart rate responses to
isoproterenol31 together with reduced β-adrenergic recep-
tor activity32 and of increased muscarinic receptor
activity.33 Although none of these changes explains an
increase in heart rate at rest, each of them could contribute
to decrease maximal heart rate at altitude. However, the
immediate reversibility of maximal heart rate with pure
oxygen breathing, and similar effects of infused isopro-
terenol in acute and chronic hypoxia, while heart rates are
different, argue against autonomic nervous system
changes playing a role in reduced maximal cardiac output
at altitude. A parasympathetic block with atropine or
glycopyrrolate restores maximum heart rate but not
maximal cardiac output or VO2max.28,34,35 β-Adrenergic
blockade with propranolol decreases maximal heart rate
without any effect on maximal cardiac output or
VO2max.28,36 Therefore, how a sympathetic-parasympa-
thetic nervous system imbalance could account for
tachycardia at rest, but decreased maximal heart rate at
exercise remains difficult to understand. On the other
hand, the absence of changes in VO2max by pharmaco-
logic manipulations of the autonomic nervous system
indirectly suggest that a decreased chronotropic reserve
does not contribute to decreased exercise capacity
at altitude.
Myocardial depressant effects of hypoxia
It has long been thought that the myocardium may self-
limit its pump function because of decreased oxygen
availability, thereby, preventing potentially fatal hypoxia-
induced arrhythmia or failure.20,37 Hypoxia has been
reported to exert negative inotropic effects in intact animal
preparations38 and in isolated myocardial fibers. 39
Fig 4. Mean cardiac output (Q) as a function of oxygen uptake (VO2) or
heart rate (HR) in 8 subjects at progressively increased simulated altitudes
with barometric pressures (PB) of 760 mm Hg (full circles, n = 8), 380
mm Hg (empty triangles, n = 6), and 282 mm Hg (full triangles, n = 4).
The relationships between Q and VO2 are preserved but interrupted at a
maximal VO2 decreased in proportion to decreased PB. There is an
increase in resting HR and a decrease in maximal HR with altitude (after
study by Reeves et al24).
 R. Naeije / Progress in Cardiovascular Diseases 52 (2010) 456–466
Fig 5. Increased ratio of maximal LV systolic pressure to end-systolic
volume at rest and at exercise at altitude. Abbreviation: PB, barometric
pressure (after study by Suarez et al40).
Possible effects of hypoxia would require several days to
become manifest and are not immediately reversible
because oxygen breathing in acclimatized subjects does
not rapidly modify the relation of heart rate to stroke
volume.13,23,24 However, stroke volume as a function of
right or left heart filling pressures have been reported to be
well maintained at extremely high simulated altitudes,
indicating preserved contractility.24 This has been con-
firmed by measurements of left ventricular (LV) peak
systolic vs end-systolic volume relationships, as illustrated
in Fig 5.40
Hypocapnia
More than a century ago, Angelo Mosso hypothesized
that much of the symptoms of high altitude intolerance
could be accounted for by hypocapnia instead of hypoxia.1
Accordingly, stroke volume could be depressed as a
consequence of alkalosis because of altitude-induced
increased ventilation and associated fall in arterial partial
pressure of carbon dioxide (PCO2). This was actually tested
by Grover et al,41 who exposed 8 normal subjects to
hypobaric conditions, with a barometric pressure of 440
mm Hg and with 3.7% inspired carbon dioxide in 5 of
them. The results of these experiments are shown in Fig 6.
Supplemental carbon dioxide allowed for the arterial pH
and PCO2 to remain unchanged and stroke volume to be
preserved. However, VO2max decreased by 32% instead
of 29% in subjects without supplemental carbon dioxide,
and this was explained by a lower arterial PO2 as predicted
by the alveolar gas equation, decreasing oxygen delivery
to the tissues. Supplemental carbon dioxide prevented the
usual acute hypoxia-related increase in hematocrit,
suggesting maintained plasma volume. The authors
thought that maintained stroke volume by supplemental
carbon dioxide in hypoxic subjects at exercise could be
explained by the combined effects of increased plasma
volume and sympathetic nervous system activation. These
experiments have not been repeated, even though the
results reported by Grover et al41 were obtained in a
limited number of subjects, with perhaps insufficient
matching in baseline conditions.
459
Hypovolemia
Plasma volume decreases with exposure to high
altitudes.13,42-44 Hypoxia acutely increases hemoglobin
concentration, implying an escape of water out of the
vascular space.45 Further decrease of plasma volume is
explained by loss of water by increased ventilation,
perspiration, and urine output, this at least in part related
to increased bicarbonate and sodium diuresis, and decreased
intake by hypoxia-induced adypsia but also a loss of plasma
protein.44,46 The decrease in plasma volume accounts for
weight loss, increased hematocrit, and decreased filling
pressures of the heart at high altitudes.13,23,24 However, a
closer analysis of invasively measured stroke volume and
filling pressures shows that hypovolemia-induced decrease
in preload is unlikely to account for the decreased maximal
cardiac output.24 Further evidence against this mechanism is
provided by the observations that plasma volume
expansion does not consistently increase maximal cardiac
output and VO2max20,47 and that correction of hypoxemia
by supplemental oxygen rapidly increases maximal
cardiac output.13,23,24 There is a report of a 9% increase
in VO2max with the administration of 300 mL of 6%
hydroxyethyl starch in 8 subjects at the simulated altitude
of 6000 m.44 This could not be confirmed in another study
in 8 normal subjects acclimatized at the altitude of 5260 m
and given 1 L of 6% dextran.47 The apparent contradiction
between these 2 studies is probably related to different
severities of hypovolemia, and thus, different preload-
recruitable stroke volume.
Blood viscosity
Hematocrit increases at altitude, initially because of
hemoconcentration, then because of increased erythro-
poiesis after approximately 2 weeks.28,42,43 Increased
hematocrit at high altitude increases the viscosity of the
blood. This could theoretically decrease cardiac output.48
However, isovolumic hemodilution does not increase
Fig 6. Mean values of stroke volume (SV) as a function of oxygen uptake
(VO2) at sea level (barometric pressure [PB], 760 mm Hg) and at altitude
(PB, 450 mm Hg) with supplemental carbon dioxide (CO2) in 4 healthy
subjects (left) and without supplemental CO2 in 3 healthy subjects (right).
Altitude exposure was associated with a decreased SV at rest and at
exercise and a decrease in maximal VO2. Supplemental CO2 increased
stroke volume at rest and at exercise (after Grover et al41).
460 R. Naeije / Progress in Cardiovascular Diseases 52 (2010) 456–466
49,50
VO2max and increases only slightly maximal cardiac
output and stroke volume at high altitude.50 The
observation that supplemental oxygen improves maximal
exercise capacity and cardiac output at altitude13,23,24
strongly argues against a possible limiting effect of blood
viscosity in normal subjects at a high altitude.
Pulmonary hypertension
Hypoxia induces pulmonary vasoconstriction, but the
resulting hypoxic pulmonary hypertension is usually mild,
with mean pulmonary artery pressures usually around
25 mm Hg, a bit more in acclimatized lowlanders, a bit less
in native high-altitude inhabitants.8 It is nevertheless
possible that mild hypoxic pulmonary hypertension
contributes to altitude-related limitation in exercise
capacity. Ghofrani et al9 showed that the intake of the
phosphodiesterase-5 inhibitor sildenafil to decrease pul-
monary vascular resistance in healthy subjects either
acutely exposed to normobaric hypoxia at sea level, or
acclimatized to more chronic hypobaric hypoxia at the base
camp of Mount Everest, around 5200 m, decreased systolic
pulmonary artery pressure (PAP) and increased maximal
cardiac output (measured noninvasively) and workload. In
that study, sildenafil also improved arterial oxygenation, so
that improved maximal exercise capacity could have been
accounted for, at least in part, by an increased arterial
oxygen content. This was shown in a similar design
subsequent study on healthy volunteer studies at 5000 m
on the slopes of Mount Chimborazo (Ecuador).51 Further-
more, the efficacy of sildenafil to improve hypoxic
exercise capacity appeared to decrease over time.9,51
However, repetition of these experiments in acute
normobaric hypoxia with inhibition of hypoxic pulmonary
vasoconstriction by the endothelin receptor antagonist
bosentan, consistently showed a 20% to 25% inhibition of
hypoxia-related decrease in exercise capacity as measured
by maximal workload or VO2max.52 Partial restoration of
VO2max in that study was tightly correlated to decreased
Fig 7. Relationship between bosentan-induced changes in maximal
oxygen uptake (ΔVO2max) and resting systolic pulmonary artery
pressure (ΔsPpa) in 11 volunteers breathing a fraction of inspired O2
of 0.12. Acute hypoxia had increased sPpa from 24 ± 1 to 35 ± 1 mm Hg
(mean ± SE) and decreased VO2max from 47 ± 6 to 35 ± 5 mL/kg per
minute. Bosentan intake decreased sPpa to 30 ± 2 mm Hg and restored
VO2max to 39 ± 7 mL/kg per minute.
Fig 8. Oxygen uptake (VO2) as a function of venous PO2 (PvO2) according
to the equations of convectional O2 transport (Fick principle, VO2 =
cardiac output × arteriovenous O2 content difference = Q × [CaO2 −
CvO2]) and diffusional O2 transport (Fick law of diffusion, VO2 = D ×
PvO2, mitochondrial PO2 around 1-2 mm Hg, neglected, and capillary PO2
assumed equal to PvO2). The coupling between the 2 O2 transport systems
can be modeled to occur at a lower Q (from A to B) because of reduction
in convectional oxygen transport in hypoxia. An adaptational increase in
the diffusional oxygen transport (increased D, or slope of VO2 vs PvO2)
could theoretically occur in hypoxia (from B to C), but this has not been
demonstrated (after study by Wagner54).
systolic PAP (echocardiography) without change in
oxygen saturation (Fig 7). Preventive intake of dexametha-
sone or tadalafil also decreased systolic PAP (echocardi-
ography) and improved VO2max in subjects with a
previous high-altitude lung edema and a strong pulmonary
vasoconstrictor response to hypoxia, who rapidly ascended
to the altitude of 4559 m in the Italian Alps.53
Decreased peripheral demand
Because most of the decrease in maximal cardiac output
at high altitude cannot be explained by changes in blood
volume, viscosity, contractility, increased pulmonary
vascular resistance, or autonomic nervous system tone,
Wagner hypothesized that hypoxic exposure would be
associated with a decreased peripheral demand resulting
from the matching between diffusive and convective
oxygen transport systems at a lower arterial oxygenation.54
This “passive hypothesis” is illustrated in Fig 8. Thus, VO2
is determined not only by the product of cardiac output (Q)
and the arteriovenous oxygen content difference (CaO2 −
CvO2) but also by the product of a diffusion constant D and
venous PO2 (an acceptable estimation of capillary PO2,
whereas mitochondrial PO2 neglected as being close to
zero). Because an increase in PvO2 increases VO2 by an
increased diffusional transport of oxygen but decreases
VO2 by a decreased convectional transport of oxygen, a
graphical analysis shows that the 2 oxygen transport
systems must be coupled at a unique value of VO2 and
PvO2. A decrease in arterial oxygen content in hypoxia is
necessarily associated with a coupling of the oxygen
transport system at a lower VO2—or a lower cardiac
output. Oxygen uptake could theoretically be at least partly
restored by a series of adaptive changes to increase the
diffusional transport of oxygen (the slope of the VO2 −
 R. Naeije / Progress in Cardiovascular Diseases 52 (2010) 456–466
PvO2 relationship). These could include a decreased
muscle fiber diameter and or an increased capillarity, to
decrease the distance of diffusion, an increase in
myoglobin content, or decreased capillary red blood cell
velocity (because of increased viscosity). None of the
adaptive changes in diffusional oxygen transport have
been demonstrated to occur with chronic hypoxic
exposure. There has been no report of any pharmacologic
intervention to increase the diffusional transport of oxygen.
Conclusion
Thus, maximal cardiac output in hypoxia is difficult
to manipulate. The only interventions reported to
increase maximal cardiac output in hypoxia are supple-
mental carbon dioxide, plasma volume expansion,
hemodilution, and a pharmacologic decrease in pulmo-
nary vascular resistance.9,41,49,51-53 The associated im-
provement in VO2max is variable. The only interventions
reported to increase both maximal cardiac output and
VO2max are plasma volume expansion (in case of severe
hypovolemia) and specific pharmacologic pulmonary
vasodilator interventions.
Cardiac function
Invasive hemodynamic studies in hypoxic healthy
volunteers have understandably been limited to right
heart catheterizations. This approach has provided valid
cardiac output and pulmonary vascular pressure mea-
surements at rest and at exercise but cannot provide a
full assessment of ventricular pump function. Further
insight has been provided by progress in echocardio-
graphic evaluations.
Echocardiography was used in 8 volunteers progres-
sively decompressed in 40 days to the simulated altitude
of Mount Everest (Operation Everest II), for measure-
ments of LV volumes and evaluation of systolic function
by peak systolic (brachial artery sphygmomanometry) vs
end-systolic volume (echocardiography) relationships.
This is a surrogate for completely invasive end-systolic
elastance measurements as a gold standard of load-
independent contractility. The results showed a decrease
in the volumes of both the left ventricle and the right
ventricle, compatible with hypovolemia, but a normal
ejection fraction that increased adequately at exercise. As
shown in Fig 5, the ratio of peak systolic pressure to end-
systolic volume at rest and at exercise increased at all
altitudes, indicating enhanced contractility, up to the
simulated altitude of approximately 8400 m.40 Thus,
contractility appeared to be remarkably preserved in
healthy subjects at high altitudes, indicating excellent
tolerance of the normal myocardium to extremes possible
environmental oxygen deprivation.
461
Additional resting echocardiographic measurements
were reported in a similar series of experiments in
8 healthy volunteers at simulated altitudes of 5000 m to
8000 m (Operation Everest III).55 Heart rate increased at
all altitudes accompanied by a decrease in stroke volume,
and cardiac output remained unchanged. Mitral flow peak
E velocity decreased, peak A velocity increased, and the
E/A ratio decreased, suggesting an alteration in diastolic
function. The isovolumic relaxation time (IVRT) tended to
increase, but this did not achieve significance. There was
no increase in estimated LV filling pressure. Pulmonary
artery pressure increased, with a peak transtricuspid
gradient calculated from the maximum velocity of
tricuspid regurgitation to an average of 40 mm Hg at
8000 m. Assuming a right atrial pressure of 5 mm Hg, this
allows for a calculation of a systolic PAP of 45 mm Hg,
and a mean PAP of 30 mm Hg. Left ventricular end-
systolic and end-diastolic volumes decreased, and there
was also a decrease in end-diastolic right ventricular (RV)
volume. The ratio of RV to LV end-diastolic volumes
tended to increase, but this was not significant. The LV
ejection fraction and percentage of fractional shortening
tended to increase, but this was not significant. Altogether,
these measurements confirmed previously reported mild
pulmonary hypertension, preserved LV contractility, and
decreased preload of both ventricles but showed an
abnormal LV filling pattern with decreased early filling
and greater contribution of atrial contraction, without
elevation of LV end-diastolic pressure. The authors
thought that these LV diastolic changes could be explained
by the combined effects of tachycardia and reduced
preload, with possibly also effects of ventricular interde-
pendence or hypoxia.
Left ventricular diastolic function was further ex-
plored with tissue Doppler imaging (TDI) in 41 healthy
volunteers who ascended in 24 hours to the altitude of
4559 m in the Italian Alps.56 The transtricuspid gradient
increased from 16 to 44 mm Hg, allowing for the
calculation of a mean PAP of 32 mm Hg. The transmitral
E/A decreased from 1.4 to 1.1, due to a significant increase
in the A wave. The E/A ratio and the transtricuspid
gradient were inversely correlated. The diastolic mitral
annular motion pattern measured by TDI showed similar
changes. The authors speculated that the observed mitral
E/A changes would reflect an adaptive increase in atrial
contraction rather than an alteration in diastolic function.
A complete evaluation RV and LV function by Doppler
echocardiography with TDI was reported in 25 healthy
volunteers acutely breathing a fraction of inspired oxygen
of 0.12.57 For a better understanding of the contribution of
hypoxia-induced sympathetic nervous system activation,
the authors also evaluated in normoxia the effects of low-
dose dobutamine titrated to reproduce the same increase in
heart rate. Hypoxia and dobutamine increased the
462 R. Naeije / Progress in Cardiovascular Diseases 52 (2010) 456–466

transtricuspid gradient to the same extent, from 17 to,
respectively, 36 and 33 mm Hg (P nonsignificant, hypoxia
vs dobutamine), showing the flow dependency of systolic
PAP. The acceleration time of pulmonary arterial flow,
corrected for the ejection time, decreased from 0.52 to 0.37
in hypoxia and remained unchanged at 0.53 with
dobutamine, underscoring the validity of this measure-
ment as an internal control for the diagnosis of increased
PAP at increased flow. Both hypoxia and dobutamine
increased LV ejection fraction, isovolumic contraction
velocity, acceleration, and systolic wave velocity (S) at the
mitral annulus, indicating enhanced systolic function.
Dobutamine had similar effects on RV indices of systolic
function. Hypoxia did not change RV area shortening
fraction, tricuspid annular plane systolic excursion
(TAPSE), isovolumic contraction velocity, isovolumic
contraction acceleration, and S wave at the tricuspid
annulus. Regional longitudinal wall motion analysis
revealed that S, systolic strain, and strain rate were not
affected by hypoxia and increased by dobutamine on the
RV free wall and interventricular septum but increased by
both dobutamine and hypoxia on the LV lateral wall.
Hypoxia increased IVRT corrected for the RR interval at
both annuli, delayed the onset of the E wave at the
tricuspid annulus, and decreased mitral and tricuspid
inflow and annuli E/A. Dobutamine shortened the
tricuspid annulus IVRT corrected for RR and decreased
tricuspid but not mitral E/A (Fig 9). Altogether, these
results suggested that short-term hypoxic exposure is
associated with a preserved RV systolic function, either
sympathetically mediated or homeometric adaptation to
mild pulmonary hypertension. Early RV diastolic
changes probably reflected an increased afterload.
Changes in diastolic filling patterns of both ventricles
and increased LV contractility would be essentially
explained by acute hypoxia-induced activation of the
sympathetic nervous system.
These measurements were most recently repeated in 15
healthy high-altitude inhabitants of the Bolivian altiplano,
at approximately 4000 m, as compared to age and body
surface area-matched acclimatized lowlanders.58 Acute
exposure to high altitude in lowlanders caused an increase
in mean PAP, to 20 to 25 mm Hg, decreased RV and LV
E/A with a prolonged IVRT of the RV, an increased RV
performance (Tei) index, and maintained RV systolic
function as estimated by TAPSE and tricuspid annulus S
wave. This profile was essentially unchanged after
acclimatization and ascending to 4850 m, except for a
higher PAP. The natives presented with relatively lower
PAP and higher oxygen saturation (pulse oximetry) but
more pronounced alteration in indices of diastolic function
of both ventricles, a decreased LV ejection fraction,
decreased TAPSE and tricuspid annulus S wave, and
increased RV Tei index. The estimated LV filling pressure

Fig 9. Mean pulsed-TDI isovolumic contraction velocity (ICV), systolic ejection (S), IVRT, early (E) and late (A) diastolic waves, recorded at the tricuspid
annulus in 19 subjects in normoxia, in acute hypoxia, or with a dobutamine infusion in normoxia. *P b .05 compared to normoxic baseline. The increase in
heart rate was similar during hypoxia test or dobutamine infusion. Hypoxia did not change ICV, S, and E and increased A and IVRT. Dobutamine
increased ICV, S, and A; did not change E; and decreased IVRT. Sample recordings in a 25-year-old woman (right). After study by Huez et al.57
 R. Naeije / Progress in Cardiovascular Diseases 52 (2010) 456–466 463

was somewhat lower in high-altitude natives. Thus, the
cardiac adaptation to high altitude appeared qualitatively
similar, with however slight but significant deterioration
of indices of both systolic and diastolic function in high-
altitude natives, in spite of less marked pulmonary
hypertension and better oxygenation. The authors
explained these results by combined effects of a lesser
degree of sympathetic nervous system activation, relative
hypovolemia, and may be some negative inotropic effects
of a long lasting hypoxic exposure. The Bolivian subjects
live in less favored economic conditions, and this is known
to be associated with an increased prevalence of
cardiovascular diseases. However, none of the Bolivian
subjects included in the aforementioned study was a
smoker or presented with cardiovascular risk factors such
as hypertension, diabetes, or obesity. The prevalence of
cardiovascular conditions has been reported repeatedly to
be lower in the South American altiplanos than in North
America or Western Europe.7
Echocardiographic measurements have also been
reported in a study on high-altitude Peruvian dwellers
with a diagnosis of Monge's disease.59 This form of
chronic mountain sickness, predominantly reported in
South America, is defined by the combination of excessive
polycythemia, fluid retention, and relative hypoventila-
tion, accompanied by an increase in PAP in proportion
to decreased arterial oxygenation.8 The patients with
Monge's disease presented with transtricuspid gradients at
an average of 34 mm Hg, which is in the range reported in
acclimatized lowlanders, and an RV dilatation with an
increased Tei index to an average of 0.54, higher than
reported in both acclimatized lowlanders and healthy high-
altitude inhabitants. The authors excluded the diagnosis of
heart failure clinically and on the basis of preserved
indices of RV and LV systolic function. However, a higher
RV Tei index in patients with Monge's disease may reflect
a more important alteration of RV function.
A small percentage of otherwise normal subjects
present with a constitutively increased pulmonary
vascular reactivity to hypoxia and are prone to the
development of lung edema when rapidly taken to high
altitudes.60 Recent progress in portable Doppler echocar-
diography has revealed that these subjects may present
with severe hypoxic pulmonary hypertension inducing
high-altitude acute right heart failure, characterized by a
dilatation of right heart chambers with a septal shift,
dilatation of the inferior vena cava with loss of
inspiratory collapse, indicating increased right atrial
pressure, and RV TDI disclosing an apically prominent
“postsystolic shortening” wave (Fig 10). This specific
TDI aspect of RV postsystolic shortening reflects
asynchronic contraction the RV, much like recently
reported by magnetic resonance imaging studies in severe
pulmonary arterial hypertension.61

Fig 10. High-altitude right heart failure in previously healthy subject after arrival in La Paz, 3600 m, and touring on the Bolivian altiplano at altitudes
around 4000 m. Maximum velocity of tricuspid regurgitation (A) is suggestive of severe pulmonary hypertension, with pressures around 40 mm Hg; there
is dilation of the right ventricle with abnormal eccentricity index (B); RV apex postsystolic shortening; and dilatation of the inferior vena cava with loss of
inspiratory collapsibility. These aspects indicate right heart failure on hypoxic pulmonary hypertension (after study by Heath and Williams7).
464 R. Naeije / Progress in Cardiovascular Diseases 52 (2010) 456–466
In summary, acute hypoxic exposure is generally
associated with mild pulmonary hypertension, increased
heart rate, decreased stroke volume, increased indices of
LV systolic function, maintained indices of RV systolic
function, and altered diastolic filling patterns of both
ventricles without increased filling pressures. These
changes are explained by the combined effects of
increased PAP, sympathetic nervous system activation,
and homeometric adaptation of RV function to afterload
and hypovolemia. Cardiac function adaptation to even
milder pulmonary hypertension in high-altitude natives is
qualitatively similar, even though indices of both systolic
and diastolic function of both ventricles appear to be
somewhat depressed. These differences are explained by a
different level of sympathetic nervous tone, decreased
preload, and possibly direct cardiac effects of lifelong
oxygen deprivation.
The coronary circulation
The coronary oxygen extraction is normally very high,
with resulting coronary sinus venous PO2 being one of the
lowest in the body. Thus, the hypoxic myocardium must
rely on an increased oxygen delivery, as extraction cannot
much increase. Accordingly, acute hypoxic exposure has
long ago been shown to be associated with an increased
coronary blood flow.62 This observation has been recently
confirmed.63 Acute low oxygen breathing to simulate an
altitude of 4500 m in healthy subjects increased coronary
blood flow so that coronary oxygen delivery was
maintained. In these same experiments, there was an
exercise-induced hyperemia by approximately 40%, sug-
gesting preserved coronary flow reserve. However, more
prolonged stays at altitude have been shown to decrease
coronary blood flow, in high-altitude inhabitants as well as
in recently acclimatized lowlanders.64,65 Corresponding
coronary flow reserve measurements have not yet been
reported. However, epidemiologic data and clinical
experience on the South American altiplanos indirectly
suggest that coronary flow reserve would be maintained in
more chronic hypoxic conditions as well, even though
oxygen delivery becomes probably more dependent on
arterial oxygen content, which is increased with polycy-
themia, than on coronary flow. These observations are in
keeping with preserved contractility40,57-59 and absence of
symptoms or electrocardiographic changes suggestive of
myocardial ischemia in healthy volunteers exposed to
simulated high altitudes.66,67 Altogether, the data support
the notion that the tolerance of the normal myocardium to
hypoxic exposure is generally excellent.
However, altitude exposure may be an unwelcome
stress in patients with preexisting cardiac conditions.
Exposure to moderate hypoxia to simulate an altitude of
2500 m has been shown to be associated with a decrease in
coronary flow reserve by 18% in patients with coronary
heart disease as compared to an increase of 10% in healthy
controls.63 Altitude exposes the coronary circulation to the
combined effects of ambient hypoxia, exercise, cold,
hypocapnia because of hyperventilation, and increased
sympathetic nervous system tone as possible causes of
myocardial ischemia.60 Therefore, patients with coronary
artery disease are advised to avoid physical exercise or
uncomfortable traveling at altitude and to avoid rapid
ascents to altitudes higher than 2000 to 2500 m.
Coronary artery disease appears to be less common in
high-altitude inhabitants as compared to sea level
controls, but this may be related to a lower prevalence
of cardiovascular risk factors.7 Epidemiologic studies in
New Mexico at altitudes ranging from 900 to 2100 m
indicate an altitude-related decreased mortality rate for
coronary heart disease, which the authors attributed to
healthier lifestyle with relatively more physical exercise
at altitude.68
Blood pressure
Blood pressure either does not change or increases slightly
in response a short-term hypoxic exposure.10,30,51-53,55-57,69
Increased blood pressure during altitude acclimatization
is entirely explained by sympathetic nervous system
activation.69 Permanent residence at high altitudes is
associated with a decrease in both systolic and diastolic
blood pressures.70,71
There is some evidence that mild systemic hypertension
improves with prolonged altitude stays and that the
prevalence of hypertension is lower in high-altitude
inhabitants as compared to sea level controls.71
Syncope occasionally occurs at high altitudes in
otherwise healthy individuals.72 This has been reported
in young adults, often within 24 hours of arrival at altitude,
and tentatively explained by a sympathetic-parasympa-
thetic imbalance. High altitude-induced syncope tends to
recur, and in the author's experience, may be prevented by
drugs effective in the treatment of acute mountain sickness
such as acetazolamide or corticosteroids.
The electrocardiogram
The electrocardiogram at altitude shows variably
increased amplitude of P wave, right QRS axis deviation,
and signs of RV overload and hypertrophy.65,66 Some-
times, an electrocardiogram may remain unchanged up to
extreme altitudes, as illustrated by the normal tracing
taken on Mrs Phantog, the deputy leader of the successful
1975 Chinese ascent of Mount Everest.73 Altitude and
exercise may be associated with supraventricular and
ventricular premature beats, but the limited data available
 R. Naeije / Progress in Cardiovascular Diseases 52 (2010) 456–466
do not show evidence of an increased incidence of life-
threatening arrhythmias in either normal subjects or
patients with heart disease.60
Conclusions
The adaptation of the cardiovascular system to altitude
is variable, depending on individual predisposition and
rate of ascent, but follows a rather reproducible pattern,
characterized by a normal cardiac output at rest but a
decreased maximal cardiac output, and a decreased stroke
volume in all circumstances. Much of the individual
variability is dependent upon the severity of associated
pulmonary hypertension, which is most often mild but
may be severe in a proportion of cases. Maximal aerobic
exercise capacity is essentially explained by the adaptive
matching of convectional and diffusional oxygen transport
systems but may be modulated by pulmonary vascular
resistance. Attempts at disturbing any of the determinants
of the cardiovascular adaptation to altitude is met by little
success, which shows, as Jack Reeves liked to say, how
difficult it is to fool Mother Nature.74
Acknowledgments
Pascale Jespers and Amira Khouiled helped in the
preparation of this report.
Massimiliano Mulè translated Angelo Mosso's work on
the cardiac adaptation to altitude.
Critical comments of Peter Wagner were greatly
appreciated.
Statement of Conflict of Interest
The author declares that there no conflicts of interest.
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