Respiration Physiology 121 (2000) 257 – 276

www.elsevier.com/locate/resphysiol

Comparative human ventilatory adaptation to high altitude

Lorna G. Moore a,b,*
a
Women’s Health Research Center and the Cardio6ascular Pulmonary Research Lab (Campus Box B133),
Uni6ersity of Colorado Health Sciences Center, 4200 East Ninth A6enue, Den6er, CO 80262, USA
b
Department of Anthropology, Uni6ersity of Colorado at Den6er, Den6er, CO, USA

Accepted 3 April 2000

Abstract

Studies of ventilatory response to high altitudes have occupied an important position in respiratory physiology.
This review summarizes recent studies in Tibetan high-altitude residents that collectively challenge the prior consensus
that lifelong high-altitude residents ventilate less than acclimatized newcomers do as the result of acquired ‘blunting’
of hypoxic ventilatory responsiveness. These studies indicate that Tibetans ventilate more than Andean high-altitude
natives residing at the same or similar altitudes (PETCO2 in Tibetans = 29.69 0.8 vs. Andeans = 31.091.0, P B 0.0002
at  4200 m), a difference which approximates the change that occurs between the time of acute hypoxic exposure
to once ventilatory acclimatization has been achieved. Tibetans ventilate as much as acclimatized newcomers whereas
Andeans ventilate less. However, the extent to which differences in hypoxic ventilatory response (HVR) are
responsible is uncertain from existing data. Tibetans have an HVR as high as those of acclimatized newcomers
whereas Andeans generally do not, but HVR is not consistently greater in comparisons of Tibetan versus Andean
highland residents. Human and experimental animal studies demonstrate that inter-individual and genetic factors
affect acute HVR and likely modify acclimatization and hyperventilatory response to high altitude. But the
mechanisms responsible for ventilatory roll-off, hyperoxic hyperventilation, and acquired blunting of HVR are poorly
understood, especially as they pertain to high-altitude residents. Developmental factors affecting neonatal arterial
oxygenation are likely important and may vary between populations. Functional significance has been investigated
with respect to the occurrence of chronic mountain sickness and intrauterine growth restriction for which, in both
cases, low HVR seems disadvantageous. Additional studies are needed to address the various components of
ventilatory control in native Tibetan, Andean and other lifelong high-altitude residents to decide the factors
responsible for blunting HVR and diminishing ventilation in some native high-altitude residents. © 2000 Elsevier
Science B.V. All rights reserved.

Keywords: Adaptation, high altitude; High altitude, ventilatory acclimatization; Hypoxia, ventilatory response; Mammals, humans

1. Introduction

Studies of ventilatory adaptation to high alti-

* Tel.: +1-303-3154480; fax: + 1-303-3154871. tude occupy an important position in respiratory
E-mail address: lorna.g.moore@uchsc.edu (L.G. Moore). physiology, with much of the history and central

0034-5687/00/$ - see front matter © 2000 Elsevier Science B.V. All rights reserved.
PII: S 0 0 3 4 - 5 6 8 7 ( 0 0 ) 0 0 1 3 3 - X
258 L.G. Moore / Respiration Physiology 121 (2000) 257–276
concepts of the field having emerged in the setting
of high-altitude. Fortunately, this topic was well
reviewed in the 1980s (Dempsey and Forster,
1982; Weil, 1986). In the intervening years, several
investigative teams have undertaken studies that
address population variation in the effects of
lifelong hypoxia on ventilatory and other O2
transport responses. These collectively challenge
the prior consensus that lifelong high-altitude res-
idents ventilate less than acclimatized newcomers
do as the result of acquired ‘blunting’ of hypoxic
ventilatory response. The purpose of this review is
to summarize these recent studies in the light of
prior investigations.
Some 140 million persons live at high altitude
( \ 2500 m, 8250 ft) worldwide (Moore et al.,
1998b) but nearly all investigations have been
concentrated in three world regions — the South
American Andes, the Asian Himalayas, and the
North American Rocky Mountains. This review
will, therefore, be organized by geographic region,
distinguishing between the results of older (pre-
1980) and more recent (1980 to present) investiga-
tions. Next, the possible physiologic and genetic
mechanisms which might underlie population dif-
ferences in ventilation, hypoxic and hypercapnic
ventilatory response will be considered. Finally,
functional implications of this inter-populational
variation and areas for future investigation will be
suggested.
At the outset, some clarification of terminology
is in order. High altitude refers to altitudes above
2500 m (8250 ft) as this is where arterial O2
saturation (SaO2) falls in most persons. Ventila-
tory acclimatization is defined as a time-depen-
dent rise in ventilation which overcomes the
inhibitory effects of hypocapnic alkalosis, result-
ing in a fall in end-tidal PCO2 (PETCO2) at a given
PETO2. Ventilatory acclimatization as well as other
traits characterizing persons at high altitude are
physiological responses. Whether such physiologi-
cal responses are also adaptations depends on
whether they contribute to the ability of the or-
ganism to live and reproduce in a given environ-
ment (Dobzhansky, 1968). The distinction is
important as it is only responses with adaptive
benefit that will be preserved in a population as a
result of natural selection, assuming that there is
some degree of genetic control for the trait in
question.
2. Review by geographic region
2.1. South American Andes
More than 40 years ago, Chiodi (1957) ob-
served that high-altitude natives had lower levels
of ventilation (higher PETCO2 at a given PETO2)
than acclimatized newcomers. Subsequent An-
dean studies confirmed this impression, demon-
strating a range of PETCO2 values but ones that
were generally above that predicted by the ‘after
acclimatization’ Rahn–Otis curve (Table 1, Fig.
1). Such observations were consistent with those
in persons with cyanotic congenital heart disease
(Lahiri, 1968), supporting exaggerated hypoxia as
the likely cause of the relative hypoventilation.
These observations were followed quickly by
studies of ventilatory control. Several different
measures of hypoxic response were employed;
namely, relief of hypoxia with acute hyperoxia,
effect of acute hypoxia on the hypercapnic hyper-
ventilatory response, and the effect of acute hy-
poxia alone. The results showed uniformly low
ventilatory response. For example, relief of hy-
poxia with acute hyperoxia lowered ventilation
one-third as much in male lifelong residents of
4300 m (Cerro de Pasco, Peru) as in acclimatized
newcomers (Severinghaus et al., 1966; Sørensen,
and Severinghaus, 1968a). Essentially similar ob-
servations were made in Bolivian female high-alti-
tude natives (Cudkowicz et al., 1972). Likewise,
the ventilatory response to acute hypoxia and the
effect of hypoxia on the hypercapnic response
were diminished in Peruvian natives of 4540 m
when compared with acclimatized newcomers
(Lahiri et al., 1969a). A blunted response was
specific for hypoxia since the hyperventilatory re-
sponse to hypercapnia was similar in high-altitude
natives and acclimatized newcomers. LeFrançois
et al. (1968) aptly described the state-of-knowl-
edge when he wrote: ‘‘the points for the alveolar
values of natives are located on a line between the
acute and acclimatized Rahn and Otis curves…the
relative decrease in alveolar ventilation of natives
 L.G. Moore / Respiration Physiology 121 (2000) 257–276 259

can be explained by a diminution of ventilatory recent reports, the PETCO2 is about 3 mmHg
O2 drive’’. higher than acclimatized persons’ at a given
Recent studies by Santaloya, Beall, and our PETCO2 (Fig. 1). Recent studies also support a low
group support the earlier assertion that Andean chemosensory response. Using a progressive, iso-
natives hypoventilate relative to acclimatized new- capnic hypoxic ventilatory response (HVR) test,
comers. Averaging data from the earlier and more we found low but variable HVR in lifelong young
Table 1
Ventilatory values for Tibetans, Andean and Colorado high-altitude nativesa

Alt Sex n PETO2 PETCO2 SaO2 HVR A HCVR S

Tibetans
Ge et al., 1994 2500 M 25b – – – 142 925 –
Hackett et al., 1980 2800 M 25 – 29 90.9 – 65 912 –
Lahiri, 1968 3350 M 3 58.6 32.1 – – –
Zhuang et al., 1993 3658 M 27 66 9 0 32 91 89.3 9 0.3 121 917 1.44 90.12
Beall et al., 1997 3800 M 88 – 29.7 9 0.5 88.5 9 0.4c 165 915 –
Huang et al., 1984b 3890 M 20 49.9 30.7 9 1.9 83.1 91.6 – –
Lahiri, 1968 3960 M 3 55.9 29.6 – – –
Hackett et al., 1980 4243 M 8 – – 8890.7 – –
Ge et al., 1994 4350 M 25b – – – 82 9 5 –
Curran et al., 1995 4400 M 20 69 91 33 9 1 88 90.5c 67 9 17 0.63 9 0.12
Lahiri, 1968 4880 M 4 48.7 28 9 0.6 – – –
Huang et al., 1981 5000 M 91 49.9 9 0.4 25.2 9 0.3 – – –
Moore et al., in press 3658 F 13 69 9 1 31 91 88.8 90.5 39 98 0.96 90.1
Beall et al., 1997 3800 F 122 – 29.2 9 0.5 89.3 9 0.3c 125 910 –
Mean (n) 4203 – (478) 55.9 90.5 29.690.8 87.8 90.6 101 9 14 1.0 9 0.1

Andeans
Cudkowicz et al., 1972 3600 M 14 59.9 90.5 33.2 90.6 – – –
LeFrançois et al., 1968 3660 M 46 56 90.5 31 9 0.5 – – –
Beall et al., 1997 3800 M 232 – 33.8 90.3 92.2 90.2c 80 9 5 –
Chiodi, 1957 3990 M 5 48.1 91.7 34.7 90.9 86.9 90.3 – –
Moore( unpublised results) 4300 M 10 60 9 1 31 9 1 86.4 9 0.6 98 926 1.06 9 0.28
Severinghaus et al., 1966 4330 M 5 49.7 91.4 31.9 90.7 81.2 91.4 – –
Banchero et al., 1966 4540 M 35 42 90.7 30 90.4 – – –
Hurtado, 1964 4540 M 40 50.5 90.7 29.1 90.5 81 90.5 – –
Lahiri, 1968 4545 M 6 49.8 90.8 31.9 90.5 – – –
Cudkowicz et al., 1972 3600 F 10 57.1 90.8 36.3 90.9 – – –
Beall et al., 1997 3800 F 212 – 34 9 0.3 91.2 9 0.2c 68 935 –
Moore (unpublished results) 4300 F 21 58 91 31 91 82.9 9 1.2 23 98 1.12 90.17
Mean (n) 4216 – (636) 53.1 9 0.9 32.3 90.6 86.0 9 0.6 67 918 1.1 90.2

Colorado
Weil et al., 1971 3100 M 8 – – – 25 9 5.6 1.53 9 0.19
Moore (unpublished results) 3100 F 9 669 2 309 1 91.4 90.6 236 9 21 2.16 9 0.18
Mean (n) 3100 – (17) – – – 130 9 13 1.8 9 0.2

a
Abbreviations (units): alt, altitude (meters); sex, M (male) and F (female); n, sample size; PETO2, end-tidal PO2 (mmHg); PETCO2,
end-tidal PCO2 (mmHg); SaO2, arterial O2 saturation (%); HVR A, hypoxic ventilatory response A value (units); HCVR S,
hypercapnic ventilatory response, DV: E/DSaO2 (LBTPS/min/mmHg).
b
Estimated since no sample size was given.
c
Converted from DV: E/DSaO2 values using the relationship between DV: E/DSaO2 and HVR A observed in more than 100 persons
in our previous studies (Moore et al., 1984; Zhuang et al., 1993).
260 L.G. Moore / Respiration Physiology 121 (2000) 257–276

Fig. 1. Rahn – Otis diagram for regional comparisons of Andean and Tibetan alveolar ventilation, expressed as the PETCO2 at a given
PETO2. Values are averaged from those provided in Table 1. Andean and Tibetan average values, weighted by sample size and taking
the variation within each sample into account, differed significantly (P B0.0002, one-way ANOVA).

male and female adult residents of 4300 m in Cerro
de Pasco, Peru (Table 1). A problem for our and
virtually all other Andean studies is that samples
were drawn from communities which were easily
accessed by road, railroad or airplane and in which
there had been interbreeding (genetic admixture)
with Europeans or other groups. As will be re-
turned to below, if HVR differences between
groups are influenced by genetic factors, variable
degrees of admixture with lowland groups might be
a source of variation for HVR. In part to address
this concern, Beall et al. (1997) measured HVR in
large, essentially random samples comprising
roughly half of all persons living in indigenous,
rural communities in Bolivia where there had been
little mining or other economic activity likely to
increase admixture with lowland groups (Table 1).
Using a hypercapnic, progressive hypoxic HVR
test, they reported DV: E/DSaO2 values averaging
− 0.4590.02 and − 0.37 90.01 in adult men and
women, respectively, with remarkably little age-re-
lated variability. Thus, overall, the results from the
recent as well as the older literature demonstrate a
lack of hypoxic ventilatory sensitivity.
2.2. North American Rocky Mountains
The first systematic study of permanent residents
at high altitude was carried out by Mabel Purefoy
Fitzgerald (Fitzgerald (1913, 1914)), a member of
the 1911 Anglo–American Pikes Peak Expedition.
Her careful measurements in 174 persons from sea
level (NC, USA) to 3267 m (CO, USA) demon-
strated that high-altitude inhabitants breathed
more than low-altitude residents. Her subjects were
likely to have been migrants to high altitude and
of primarily European population ancestry, al-
though information about place of origin was not
provided. She noted that hyperventilation was
present whether persons were male or female,
young or old. It was these observations that, many
years later, prompted Herman Rahn together with
Otis to develop the Rahn–Otis diagram (Fig. 1) for
documenting the existence of ventilatory acclima-
tization (Rahn, personal communication, 1989).
Weil et al. (1971) at the University of Colorado
made the first measurements of HVR in
lifelong residents of Leadville, CO (3100 m) using
a progressive, isocapnic test. When studied within
a few days of descent to 1600 m, the lifelong male
residents had a lower HVR and lower hypercapnic
ventilatory response (HCVR) than shorter-
term residents of 3100 m or permanent residents
of lower altitude (Table 1). Women are similar
insofar as lifelong female residents of 3100 m have
lower ventilation and SaO2 than acclimatized new-
 L.G. Moore / Respiration Physiology 121 (2000) 257–276 261

comers and tend to have lower HVR (Table 2). duration of high-altitude exposure compared with
The women were studied at their altitude of resi- the male residents.
dence, unlike the men, and at a somewhat lower
PETCO2. The only borderline statistical significance 2.3. Asian Himalayas
in HVR between the native and newcomer women
was probably due to their younger age and lesser Lahiri et al. (1967) undertook a series of inves-
tigations in Sherpa lifelong high-altitude residents
in the 1960s and 1970s. While they noted a
Table 2 PETCO2 ‘‘low (28 mmHg) by standards found in
Comparison of ventilatory characteristics in native and new- Andean subjects’’ at 4880 m, they concluded in
comer female residents of Leadville, CO, USA (alt 3100 m,
mean9 S.E.M.)a
subsequent studies that Sherpas ventilated less
than acclimatized lowlanders (Table 1) and had
Native Newcomer P value an HVR that was only one-third that of acclima-
(Sample size) (9) (9) tized lowlanders (Lahiri, 1984). More recent stud-
ies find that Sherpas or Tibetans ventilate as
Age (years) 29 9 2 309 1 NS
Height (cm) 158 93 163 9 2 NS
much as acclimatized lowlanders. Ventilation in
Weight (kg) 68 96 619 2 NS Sherpas at 4243 m was as great as that observed
Cycle phase 5 4 NS in acclimatized westerners or greater when consid-
(c ered in relation to body size (Hackett et al., 1980).
follicular) Lifelong Tibetan male residents of 3658 m had
V: O2 0.212 90.020 0.21790.005 NS
(LSTPD/min)
higher minute ventilation and similar SaO2,
V: E 7.98 90.68 9.279 0.38 B0.05 PETCO2 and PETCO2 when compared with acclima-
(LBTPS/min) tized Han (ethnic Chinese) (Table 1) (Zhuang et
f (breaths/min) 11.7 9 0.6 14.191.2 B0.05 al., 1993). Female Tibetans also ventilate as much
VT (ml BTPS) 0.70 9 0.08 0.6990.05 NS as acclimatized Han newcomers at 3658 m
PETO2 (mmHg) 66.5 9 1.6 69.491.5 NS
PaO2 (mmHg) 57.8 9 1.9 62.992.0 NSb
(Moore et al., in press). Low PETCO2 values were
PETCO2 29.7 91.4 26.79 1.1 B0.05 likewise seen in large numbers of Tibetan men
(mmHg) and women lifelong residents of 3800 m (Beall et
PaCO2 (mmHg) 27.8 9 1.0 26.1 91.0 NS al., 1997). As a result, average Sherpa or Tibetan
SaO2 (%) 91.4 9 0.6 92.6 90.4 B0.05 values are closer to and, in fact, on the acclima-
Hemoglobin 15.7 9 0.6 14.69 0.6 NS
(gm/dL)
tized newcomer Rahn–Otis curve (Fig. 1) when
HVR A value 70 9 15 1099 26 NSb compared with Andean values.
(units) Consistent with the Tibetans’ maintenance of
PETCO2 30.1 9 1.3 27.79 1.1 NSb high ventilation, lifelong male Tibetans have
(mmHg) HVR A values that are at least as great as those
HCVR S value 1.57 90.16 1.92 9 0.37 NS
x-intercept 27.9 9 0.8 25.6 9 1.4 NSb
of acclimatized newcomers, greater than those of
(mmHg) child-migrants to high altitude, and within the
Gravidity (no. 3.0 90.5 3.190.7 NS range of normal sea-level values using the pro-
pregnancies) gressive isocapnic HVR test (Zhuang et al., 1993)
Parity (no. live 2.6 90.3 2.790.3 NS or a progressive hypoxia+hypercapnia test (Beall
births)
Previous infant 2839 9160 30489202 NS
et al., 1997). In this latter study, Beall reported
birth wt. (g) DV: E/DSaO2 values of −0.9390.09 and − 0.709
Gestational age 39.3 9 0.7 39.29 0.7 NS 0.05 for Tibetan men and women; for comparabil-
(weeks) ity, these have been converted to A values in
Table 1. HCVR were also greater in the Tibetans
a
Abbreviations and units: V: O2 = O2 consumption; V: E =
ventilation; f = frequency; VT = tidal volume; PaO2 = arterial
than Han (Zhuang et al., 1993). The similarity
PO2; PaCO2 =arterial PCO2; see abbreviations for Table 1. between the Tibetans’ maintenance of ventilation
b
NS, not significant; 0.05BPB0.10. and HVR is consistent with carotid body weight
262 L.G. Moore / Respiration Physiology 121 (2000) 257–276
data in small numbers of subjects. Weights more
than doubled in high-altitude compared with sea-
level Han, an increase that was similar to that
which has previously been reported in native An-
dean highlanders (Quechua) (Arias-Stella, 1969).
Tibetan carotid bodies weighed less than Han and
were within the normal sea-level range (Tu and
Wu, 1997).
2.4. Comparison of Andean and Tibetan
high-altitude nati6es
The information acquired in the last 20 years
permits comparisons to be drawn regarding the
level of resting ventilation and hypoxic ventilatory
sensitivity in substantial numbers of Andean and
Tibetan lifelong high-altitude residents. Unfortu-
nately, the lower altitudes and smaller sample
sizes of the North American studies limit the
extent to which they can be included in this
comparison.
2.4.1. Ventilation
Tibetans ventilate more than Andean lifelong
high-altitude residents, having a lower PETCO2 at a
similar PETO2 (Fig. 1). The Tibetans’ higher venti-
lation is supported by comparisons between each
group and acclimatized newcomers as well as by
direct comparisons. Whereas Andeans generally
ventilate less, Tibetans breathe as much as accli-
matized newcomers. Our studies of the two groups
at differing elevations ((Zhuang et al., 1993) and
the values in Table 1) and Beall’s studies of
Tibetans and Andeans at the same altitude also
support higher ventilation in Tibetans than An-
deans (Beall et al., 1997). Surprisingly, Beall et al.
reported lower SaO2 in the Tibetans than Andeans
at  3800 m. However, lower SaO2 is not apparent
in the results averaged across all studies (Table 1).
Considering the length of time and numbers of
investigative teams involved, the ventilatory stud-
ies in the Tibetans than Andeans are remarkably
consistent. This is likely due to the fact that
arterial or, in these healthy persons, PETCO2 can be
used to measure alveolar ventilation per unit CO2
production. Conveniently, this not only eliminates
differences due to dead space ventilation, but it
also adjusts for differences in body size.
The only substantive discrepancy is that Santo-
laya et al. (1989) concluded that Sherpa were like
Andean adult high-altitude natives insofar as both
hypoventilated relative to acclimatized newcom-
ers. The lack of PETO2 in some of these studies
prevents their inclusion in Table 1 but the PETCO2
value of 29.39 1.1 mmHg reported for Sherpas at
 3800 m and 28.390.3 for Sherpas at  4800 m
is similar to that seen in the more recent studies.
These values are also below the Andeans’ whether
studied by the same (Milledge and Lahiri, 1967;
Lahiri et al., 1967; Lahiri, 1968; Santolaya et al.,
1989) or different groups (Table 1). The kinds of
acclimatized newcomers with whom the natives
are being compared likely contributes to differ-
ences in interpretation. In the pre-1980 reports,
acclimatized newcomers were usually moun-
taineering expedition members with exposures to
very high altitudes, whereas the more recent stud-
ies and the South American reports sampled more
sedentary persons. Since ventilation varies among
acclimatized newcomers (Reeves et al., 1993) and
at least some elite mountaineers have particularly
brisk ventilatory responses (Schoene et al., 1984),
it is possible that the apparent hypoventilation
among the Sherpa was a function of being com-
pared with the mountaineers. Smaller sample sizes
in the earlier than later reports may also have
contributed to the differences in interpretation. In
any event, the data on resting ventilation taken
together (Fig. 1, Table 1) indicate that Tibetan
(including Sherpa) natives of high altitude venti-
late more than their Andean counterparts.
2.4.2. HVR
It is less clear whether Tibetans have a higher
HVR than Andeans. Comparisons of Tibetans
and Andeans at the same altitude (Beall et al.,
1997) and between each group and acclimatized
newcomers (Severinghaus et al., 1966; Hackett et
al., 1980; Zamudio et al., 1993; Zhuang et al.,
1993) suggest that Tibetans have higher values.
However, the Tibetan HVR averaged across all
studies does not differ from Andean values (Fig.
2), nor do values differ in our comparisons of the
two groups ((Zamudio et al., 1993; Zhuang et al.,
1993) and the Zhuang, Curran and Moore values
in Table 1) or in the pre-1980 reports. Likewise
 L.G. Moore / Respiration Physiology 121 (2000) 257–276 263

Fig. 2. Average hypoxic ventilatory response (HVR) A and hypercapnic ventilatory response (HCVR) S values for Andeans and
Tibetans as summarized in Table 1. The altitudes at which the studies were performed were similar. Whether or not the comparisons
are weighted by sample size, neither the HVR A nor the HCVR S value differs between the two groups (P =0.44 and P =0.83,
respectively).

HCVR does not differ between Tibetans and An-
deans, when all data or that acquired by a single
investigative team are compared (Fig. 2).
The inconsistent nature of the comparisons of
Tibetan versus Andean HVR is likely due to the
variety of measures used for measuring HVR.
Unlike the similarity in methods for measuring
ventilation, the kinds of HVR tests differ
markedly. Pre-1980 studies in Sherpa and Andean
highlanders used the hypoxia-induced change in
the hypercapnic hyperventilatory response, the
transient N2, or transient O2 tests (Severinghaus et
al., 1966; LeFrançois et al., 1968; Lahiri, 1984).
These are tests of shorter duration than those
used after 1980. Shorter tests were used in order
to confine the stimulus to the carotid body and to
avoid the ventilatory ‘roll-off’ (see below) that
occurs with longer hypoxic exposure. More recent
studies, however, have shown that the roll-off
does not occur within the 5 – 7 min of hypoxia
required to complete the progressive hypoxic test
(Huang et al., 1984a). However, it remains possi-
ble that these shorter tests were measuring a
different phase of the acute HVR than the pro-
gressive hypoxic test. An advantage for the longer
tests is that more ventilatory measurements can be
obtained, the magnitude of hypoxic stimulus stan-
dardized among subjects, and isocapnia more
closely controlled. Since it is not possible to com-
bine summary measures from fundamentally dif-
ferent techniques, only studies in which HVR A
values could be calculated are included in Table 1.
We chose the A value because, unlike the DV: E/
DSaO2 index of HVR, the A value uses the stimu-
lus acting on the carotid body, PO2, as the
independent variable. In our experience, the A
value test also provides a more even distribution
of x-axis values. HVR A tests similar to that
introduced by Weil et al. (1971) were employed by
Hackett et al. (1980), Zhuang et al. (1993) and
Curran et al. (1995), with Zhuang and Curran
beginning with ambient air rather than a sea-level
equivalent gas mixture in order to avoid hyper-
oxic hyperventilation and consequent hypocapnia
(see below). However, the progressive hypoxic test
used by Beall et al. (1997) began with an inspired
gas concentration of 5% CO2 in room air. Because
this combines hypoxic with hypercapnic stimuli,
results are difficult to interpret (Read et al., 1977;
Robbins and Zhang, 1999). For this reason,
Mahutte and Rebuck (1978) subsequently
modified this technique by holding PETCO2 con-
stant at the hypercapnic value for 6 min to stabi-
lize the CO2 drive before initiating the hypoxia.
Of importance is the observation of Lahiri et al.
(1969b) that hypercapnia 2 mmHg above the eu-
264 L.G. Moore / Respiration Physiology 121 (2000) 257–276
capnic PETCO2 profoundly depressed HVR in
lifelong Andean high-altitude residents, whereas it
magnified HVR in acclimatized newcomers. This
likely explains why Beall found a lower HVR in
Andeans than Tibetans whereas the other studies
did not. If true, this suggests the intriguing possi-
bility that Tibetans, Andeans, and acclimatized
newcomers may differ with respect to the depres-
sant effect of PETCO2 on HVR; this is a possibility
worthy of further investigation. Differences in the
duration of hypoxic testing might also be impor-
tant. Sugimori et al. (1996) found that test dura-
tion effects HVR differently in high versus low
responders, with a fast (3 – 5 min) test underesti-
mating HVR in high responders and overestimat-
ing it in low responders.
At present, it is not possible to resolve whether
HVR is higher in Tibetan than Andean high-alti-
tude natives. Careful testing using measures with
similar specificity for hypoxic chemosensory re-
sponsiveness is needed in representative samples
of men and women living at the same or across a
similar range of elevations. As returned to below,
additional studies should be included in order to
examine the various components of the time-de-
pendent ventilatory response to hypoxia.
3. Cellular and genetic mechanisms
In recent years, evidence has accumulated from
experimental animal studies regarding the cellular
mechanisms by which hypoxia invokes a ventila-
tory response. An important question has been
the identity of the O2 sensor in the carotid body
as well as in other cells with O2 sensitivity, such as
erythropoietic and pulmonary vascular cells.
Among the candidates for the O2 sensor are a
voltage-dependent K+ channel, a protein in the
plasma membrane closely associated with a K+
channel, mitochondrial calcium loss, and/or the
mitochondrial cytochrome aa3 complex (López-
Barneo et al., 1993). Unknown is whether there is
a common mechanism for O2 sensing in each type
of cell or whether mechanisms vary by organ or
tissue. Because respiratory chain proteins are not
required for O2 sensing in the erythropoietin sys-
tem, some have argued in favor of a body-wide,
non-respiratory protein involving a flavoheme
protein in the plasma membrane which functions
like a NADPH oxidase (Zhu and Bunn, 1999).
That the Tibetans’ pattern of hypoxic responsive-
ness varies among different organ systems is of
interest in this regard. Tibetans lack a pronounced
pulmonary hypoxic vasoconstrictor response
(Groves et al., 1993) or an exaggerated erythro-
poietic response (Winslow et al., 1989; Beall et al.,
1998) such as seen in other high-altitude groups,
yet retain carotid body chemosensory response.
This heterogeneity in O2 responsiveness among
tissues does not support the idea of a body-wide
O2 sensor. However, it is also possible that this
heterogeneity results from factors other than tis-
sue-specific differences in O2 sensing (e.g. lesser
degrees of hypoxic stimulation, increased produc-
tion of pulmonary vasodilators).
Whatever mechanisms are responsible for O2
sensing, the chain of events leading to a rise in
ventilation is thought to entail an increase in
intracellular Ca2 + in the type I (glomus) cell of
the carotid body, cytosolic release of dopamine,
increased firing of afferent fibers, greater signal
transduction to the central nervous system, aug-
mented central nervous system translation of the
increased carotid body neural output into phrenic
nerve activity, and a consequent rise in ventilation
(Fig. 3). These events are influenced by the dura-
tion of hypoxia as well as by prior hypoxic expo-
sure. At least six phases of the ventilatory
response to hypoxia can be recognized: (1) the
acute HVR occurring within the first minutes of
hypoxia, (2) a ventilatory decline or ‘roll-off’ after
10 min of hypoxia, (3) a subsequent rise over
days or ‘ventilatory acclimatization’, (4) stabiliza-
tion of the longer-term response or ‘hyperventila-
tion’, (5) loss of ventilatory sensitivity with
prolonged hypoxia (‘blunting’), and (6) possible
reversal of a ‘blunted’ HVR with prolonged nor-
moxia. Because this time-dependent chain of
events has been well-reviewed elsewhere (see Pow-
ell, this journal), the purpose here will be to
determine what, if any, evidence implicates one or
more of these steps in the higher ventilation and
possibly greater HVR observed in lifelong Tibetan
than Andean residents of high altitude.
 L.G. Moore / Respiration Physiology 121 (2000) 257–276
3.1. Acute HVR
Acute HVR varies broadly among healthy per-
sons, spanning a 7-fold range in A values (Hirsh-
man et al., 1975). This is largely due to inter-
rather than intrasubject variability. Twin studies
in humans and comparisons of inbred rodent
strains suggest that genetic factors are involved
(Collins et al., 1978; Kawakami et al., 1982). The
variation in magnitude and pattern of breathing
responses to hypoxia and hypercapnia among
mice strains suggests that different genetic
mechanisms affect the hypoxic and hypercapnic
drives (Tankersley et al., 1994). Consistent
with genetic factors acting at the level of the
carotid body, rat strains with diminished ventila-
tory sensitivity to hypoxia exhibit decreased
carotid sinus nerve activity during hypoxic chal-
lenge (Weil et al., 1998). Their excised superfused
carotid bodies have correspondingly low peak cy-
tosolic calcium responses to hypoxia (Weil et al.,
1998).
Inter-individual differences in HVR at sea level
influence ventilatory acclimatization to high alti-
tude in men (Reeves et al., 1993) and women
(Muza et al., in press). Specifically, HVR at sea-
level accounted for 42% of the variation in venti-
Fig. 3. Major steps in sensory transduction in the carotid body. CNS, central nervous system. Reprinted with permission from
(López-Barneo et al., 1993).
265
lation after acclimatization (Reeves et al., 1993).
While it is unknown whether variation in acclima-
tization response is genetic, Beall found that HVR
exhibited significant heritability (i.e. the propor-
tion of variance attributable to genetic factors) in
Andean and Tibetan high-altitude natives. Be-
cause heritability was greater in Tibetans than
Andeans (34 vs. 22%), the authors concluded that
there was greater opportunity for natural selection
to act in the Tibetans (Beall et al., 1997). How-
ever, the interpretation of heritability is difficult at
best. Strictly speaking, heritability should not be
compared from one population to another, since
it is a ratio that only applies to the group in which
it was calculated (Falconer, 1960). In addition,
heritability cannot be equated with genetic con-
trol. For example, if all members of a population
have the same genetic variant (e.g. blood group
O), heritability will be zero because there is no
genetic variation. Thus, the significant (but mod-
est) difference in heritability between Andeans
and Tibetans may mean that the two groups differ
in terms of the particular genes or degrees of
genetic control. But it might also mean that the
genes influencing HVR have become fixed in the
Andeans, or that environmental variance is
greater in the Andeans.
266 L.G. Moore / Respiration Physiology 121 (2000) 257–276
Curran et al. (1997) used an alternate approach
for examining the influence of genetic factors on
HVR and ventilation at high altitude;
namely comparing the offspring of Tibetan
and Han parents with each parental pop-
ulation. She found that the Tibetan-Han
were like Tibetans in terms of their ventilation
but resembled Han with respect to HVR. Not
only were the Tibetan-Han HVR A values similar
but, like the Han, their HVR decreased with
increasing duration of high-altitude residence.
This suggests that different genetic factors influ-
ence ventilation and HVR in these highland resi-
dents.
While these studies support genetic influences
for ventilation and HVR in high-altitude popula-
tions, no candidate genes have emerged. An inher-
ent difficulty is that the genes need first to be
identified before, logically, the search for poly-
morphisms (i.e. genetic variants present at a fre-
quency greater than that expected by mutation
alone) can be conducted. Experience with other
respiratory-related conditions (e.g. asthma,
Liggett, 1997) suggests that, with time and given
the variability within the human genome, poly-
morphisms will be found. Plausible genes are
those involved in regulation of the dopaminergic
or catecholaminergic pathways and/or one or
more of the many genes implicated in oxygen
sensing (Zhu and Bunn, 1999). Preliminary char-
acterization of genetic variation has begun in
various high-altitude populations (Torroni et al.,
1994; Rupert et al., 1999a,b) but has not revealed,
to date, significant associations with HVR.
In summary, genetic factors likely influence
acute HVR in high- and low-altitude residents but
the nature of the involvement is probably com-
plex. Several genes are usually implicated when
traits, such as HVR, aggregate in families but not
as simple Mendelian traits. In addition, gene by
environment interactions and developmental fac-
tors, themselves subject to genetic influences, may
be important and may act in ways that differ
between populations (Sing et al., 1996). Further,
as suggested by Curran’s studies and returned to
below, variation in HVR may not be able to
account for differences in ventilation between
groups.
3.2. Ventilatory roll-off
The acute HVR is transitory. In low-altitude
residents, a peak response occurs within 5–7 min,
after which ventilation rolls-off to levels that are
 20% above pre-hypoxic values under isocapnic
hypoxic conditions, but near normoxic values if
PETCO2 is allowed to fall (poikilocapnia) (Huang
et al., 1984a). Unknown is whether a roll-off
occurs after acclimatization and/or varies among
lifelong high-altitude residents. In anesthetized
cats, the roll-off appears due to central nervous
system influences likely involving activation of
central dopaminergic receptors, since it was abol-
ished by the central dopaminergic receptor antag-
onist haloperidol (Tatsumi et al., 1992).
3.3. Ventilatory acclimatization
As has been reviewed elsewhere, the carotid
body plays a crucial role in mediating the acclima-
tization response to hypoxia (Bisgaard, this jour-
nal). Recent studies in cats support the possibility
that decreased endogenous dopamine activity is
involved (Tatsumi et al., 1995). However, no re-
duction in endogenous dopamine activity oc-
curred after 8 h of isocapnic hypoxia in humans
(Pedersen et al., 1999) but the time period may
not have been sufficient, since longer periods are
required for acclimatization to occur.
3.4. Hyper6entilation
As described above, the extent to which high-al-
titude residents hyperventilate varies between as
well as within populations. While persons or
groups who hyperventilate generally have a higher
HVR, it is unclear whether variation in HVR can
account for interindividual variation in ventilation
and SaO2. In data which we have collected in
Tibetan or Andean men and women, variation in
HVR (or HCVR) was unrelated to PETCO2, PETO2
or SaO2 within each group or the two groups
combined, even though lower PETCO2 was associ-
ated with higher PETO2 and SaO2 as expected.
Beall et al. (1997) observed similar results in
Tibetans and Andeans. Clearly, the level of venti-
lation at high altitude is influenced by more than
the acute HVR.
 L.G. Moore / Respiration Physiology 121 (2000) 257–276
Fig. 4. Ventilatory sensitivity to acute decrease in arterial O2
saturation in subjects of various age groups at 800 m and 3850
m in Peru. Reprinted with permission from Lahiri (1980).
It has long been recognized that sea-level equiv-
alent gas mixtures prompt an increase in ventila-
tion among Andeans, Tibetans or Sherpas,
whereas a decrease occurs in acclimatized new-
comers (Severinghaus et al., 1966; Lahiri et al.,
1969a; Hackett et al., 1980; Zhuang et al., 1993).
The magnitude of hyperoxic hyperventilation
varies among highlanders in ways not clearly re-
lated to their acute HVR (Zhuang et al., 1993;
Curran et al., 1995), although persons with
chronic mountain sickness (CMS) who have an
extremely low HVR have even greater hyperoxic
hyperventilation than normal highlanders (Sever-
inghaus et al., 1966; Sun et al., 1990). It has been
hypothesized that hyperoxic hyperventilation is
due to the central depressant effects of hypoxia
which are normally masked by peripheral stimula-
tory influences. But hyperoxia continued to stimu-
late ventilation in highland natives even after 10
months at sea level (Lahiri et al., 1969a). A de-
crease in cerebral blood flow leading to acidifica-
tion of central chemoreceptors, via the Haldane
effect, also has been hypothesized (Lahiri et al.,
1969a), but this has not, to our knowledge, been
tested.
3.5. Acquired blunting of HVR
The ventilatory response to hypoxia is develop-
mentally regulated. In 359 subjects ranging in age
267
from 8 h after birth to 50 years, Lahiri (1980)
demonstrated that hypoxic responsiveness was ab-
sent 5 days after birth but had developed by 8–10
years. This was true whether subjects lived at low
(Tacna, 800 m) or high (Puno, 3850 m) altitude in
Peru (Fig. 4). Thereafter, HVR was progressively
lost at high altitude, whereas it remained essen-
tially unchanged at low altitude. Byrne-Quinn et
al. (1972) and Weil et al. (1971) reported similar
findings at 3100 m in Colorado, demonstrating a
normal HVR in 9–10 year olds that was absent in
older, lifelong residents. In contrast, Beall et al.
(1997) found no age-associated change in HVR in
Andean highlanders from age 13 to 94. Beall and
Lahiri both studied large numbers of persons
living at essentially the same altitudes. The kinds
of tests varied, with Lahiri using the transient N2
test and Beall a 2–3 min hypercapnia+ progres-
sive hypoxia test. As mentioned above, the hyper-
capnia present in Beall’s testing conditions may
have depressed HVR to the extent that it was not
possible to detect an age-related blunting.
The question arises as to whether Tibetans also
acquire a blunted HVR. The higher HVR in
Tibetans than acclimatized newcomers, particu-
larly when duration of high-altitude residence is
taken into account (Zhuang et al., 1993), and the
higher HVR seen in Tibetans than Andeans in
some studies (Beall et al., 1997) suggest that Ti-
betans are resistant to acquired blunting. How-
ever, Hackett et al. (1980) found an association
between HVR and cumulative high-altitude expo-
sure among Sherpa, and Curran et al. (1995)
found an age-associated decline in HVR in Ti-
betans native to 4400 m. Therefore, while further
study is warranted, it appears that at least some
degree of blunting occurs among Tibetans.
An intriguing possibility is suggested by Okubo
and Mortola who showed, in rats, that neonatal
hypoxia decreased HVR at adulthood (Table 3).
Other studies have since confirmed that hypoxia
as well as hyperoxia early in infancy influence the
maturation of carotid chemoreceptor hypoxic re-
sponse (Ling et al., 1996; Matsuoka et al., 1999).
A possible mechanism might involve the reduc-
tion or loss of charybdotoxin-sensitive K+ chan-
nels. Carotid body glomus cells from rats which
had been born and raised in an hypoxic environ-
268 L.G. Moore / Respiration Physiology 121 (2000) 257–276
ment had reduced K+ (but not Ca2 + ) current
density and failed to depolarize with acute hy-
poxia or to be inhibited by charybdotoxin, unlike
cells from normoxic animals (Wyatt et al., 1995).
Further studies are required to characterize the
kinds of K+ channels involved and the factors
influencing their developmental expression. Stud-
ies are also required to address the relationship
between alterations in K+ channels and down-
stream events, such as neurotransmitter release
and firing of afferent fibers (Fig. 3). Recent work
by Tatsumi et al. (1992) has shown that peripheral
dopaminergic blockade (by domperidone) raised
carotid sinus nerve and ventilatory responses to
hypoxia, suggesting that normally, there was do-
paminergic depression of carotid body hypoxic
sensitivity. Decreased central nervous system
translation by other, non-dopaminergic mecha-
nisms also appeared involved, since domperidone
did not fully restore neural or ventilatory respon-
siveness to control levels.
Some evidence exists to support the possibility
that developmental factors may contribute to the
higher HVR seen in Tibetans than Han high-alti-
tude natives or those who migrated as children
(Zhuang et al., 1993). Niermeyer et al. (1995)
found that Tibetan babies maintained higher SaO2
during early infancy (0 – 4 months of age) and had
less variation among behavioral states (awake,
feeding, quiet sleep, active sleep) than Han babies
born at the same altitude. The SaO2 values in
Tibetans at 3658 m were stable and as high as or
higher than those of Colorado babies at 3100 m
(Niermeyer et al., 1993), whereas Han values fell
precipitously from 0 to 4 months of age. Tibetan
babies also weighed more at birth than the Han
and more, in relation to altitude, than the Colo-
Table 3
Ventilatory and cardiovascular characteristics of rats exposed to hypoxia (10% FIO2) for 6 days following birth and studied 7 weeks
later as adults (Okubo and Mortola, 1990)
Resting ventilation (ml/kg)
HVR (% D)
Mean arterial blood pressure (mmHg)
Right ventricular/total heart wt. (%)
rado newborns. Perhaps maternal ability to sus-
tain uteroplacental O2 supply and fetal growth, or
neonatal ability to maintain ventilation and SaO2
aids the Tibetans in the acquisition of a normal
HVR. More detailed studies of developmental
regulation of HVR in both the Andean and Ti-
betan high-altitude populations are clearly
required.
3.6. Re6ersal of a ‘blunted’ HVR with prolonged
normoxia
Early reports indicated that Andean high-alti-
tude natives after 2–16 years residence at sea level
had a lower HVR than controls who were born
and raised at sea level (Sørensen and Severing-
haus, 1968b). Milledge and Lahiri (1967) and
Lahiri et al. (1969a) found that a blunted HVR
was not reversed after 6 weeks of low-altitude
residence at sea level. This lack of reversibility
contrasts with the restoration of a normal HVR
that occurs in persons with cyanotic congenital
heart disease undergoing corrective surgery at an
early age (Monge, 1948). Recent studies in large
numbers of randomly-selected high-altitude na-
tives who had lived for more than 5 years at sea
level indicate no difference in HVR when com-
pared with lifetime sea-level residents of the same
population ancestry (Vargas et al., 1998). Differ-
ences in technique might be involved; the earlier
studies examined the effect of acute hypoxia on
the hypercapnic response whereas the more recent
study entailed breathing progressively hypoxic gas
mixtures, each for less than 1 min duration, with
variable inspired CO2 concentrations in order to
maintain isocapnia. To our knowledge, no data
exist concerning HVR in Tibetans or Sherpa after
prolonged residence at low altitude.
Controls Neonatal hypoxia P value
738 9140 903 9223 B0.05
179 937 143 928 B0.05
106 910 114 919 B0.05
19.3 92.1 21.9 9 2.0 B0.05
 L.G. Moore / Respiration Physiology 121 (2000) 257–276
4. Functional implications
There has been considerable debate as to the
functional consequences of the low HVR charac-
teristic of at least Andean and North American
high-altitude natives. During short-term high-alti-
tude exposure, a higher HVR has been linked to
protection from high-altitude pulmonary edema
(Hackett et al., 1988) and a better chance of
summitting very high peaks (Schoene et al., 1984).
But Lahiri (1984) and others have hypothesized
that a low HVR might be beneficial for longer-
term high-altitude adaptation. The reasoning here
is that the reduced work of breathing and lesser
sensation of dyspnea in persons with a lower
HVR would represent an energy-conserving adap-
tation, if compensated for by alterations in other
steps of O2 transport and/or utilization (e.g. in-
creased lung diffusing capacity, better distribution
of blood flow, and/or improved tissue O2 utiliza-
tion). Hochachka et al. (1991) and Hochachka
(1998) have shown an increased metabolic effi-
ciency (i.e. an improved ATP yield of per mole of
carbon fuel utilized) in skeletal muscle of
Quechua and Sherpa. However, based on differ-
ences in ventilation and perhaps HVR between
these two groups, such an energy-conserving
adaptation would be anticipated in Quechua but
not Sherpa.
The probable duration of high-altitude resi-
dence for the Andean and Tibetan populations is
relevant for assessing the functional implications
of their ventilatory characteristics since longer-
resident groups would be expected to have had
more opportunity to achieve a superior level of
adaptation by natural selection. As we have ar-
gued elsewhere (Moore et al., 1998b), Tibetans are
likely to have lived at high altitude longer than
Andeans. This is based on paleontological, ar-
chaeological and historical evidence. Hominids
(i.e. the family into which Homo sapiens and
ancestral forms are placed) have lived in close
proximity to the Tibetan Plateau for more than 1
million years (Denell et al., 1988; Huang et al.,
1995). Upper Paleolithic stone tool assemblages
consistent with materials found elsewhere dated at
25 000–50 000 years old, and more recent materi-
als, support human occupation of the Tibetan
269
Plateau for at least 25 000 years (Zhimin, 1982;
Chang, 1992). More extensive archaeological in-
vestigations have been carried out in the Andes.
The oldest sites are dated at 11 000–13 000 years
ago and provide evidence of frequent contact
between highland and coastal regions (Sandweiss
et al., 1998), suggesting human occupation of the
Andes for as long as 13 000 years. Shorter periods
of high-altitude residence characterize the Eu-
ropean and Han populations. Europeans do not
reside permanently at high altitudes today, al-
though the presence of 5000 year old human
remains at 3200 m (Seidler et al., 1992) suggests
that they have been high-altitude visitors for a
long time. Europeans have lived at high altitudes
for as long as 400 years in South America and 150
years in North America. Han have lived at high
altitude for the shortest period of time, having
moved there within the past several generations.
Not only is the duration of high-altitude resi-
dence likely to differ but other evolutionary forces
are also likely to have varied among these groups.
Important in this regard is genetic drift (i.e. the
effect of small population size which limits genetic
variability) and gene flow (i.e. the effect of inter-
breeding or the movement of genes from one
population to another). Genetic drift is likely to
have limited genetic variability among the early
migrants to the Americas, given their small num-
bers and the loss of large ( 95%, Cook, 1981)
numbers of indigenous Andean residents at the
time of European Conquest. The ensuing oppor-
tunities for interbreeding could also have resulted
in the transfer of European or other genes to the
Andean population. The Andean topography also
facilitates ready access to low-altitude regions.
Compared with Andeans, the Tibetan gene pool is
less likely to have been constricted by small num-
bers of initial migrants and/or severe population
decline. Tibetans may also have been subject to
less genetic admixture with lowland groups, given
their geographically and historically more remote
location, although this is changing today with air
travel and the influx of large numbers of Han
migrants.
Two kinds of studies have been conducted
which address the functional implications of HVR
in high-altitude residents; namely, those ones con-
270 L.G. Moore / Respiration Physiology 121 (2000) 257–276
Fig. 5. Geographic variation in chronic mountain sickness (CMS) prevalence. Tibetan residents of high altitude, whether male or
female, have lower prevalence than Han or Peruvians. Reprinted with permission from (Moore et al., 1998a).
cerned with CMS and others with intrauterine
growth restriction (IUGR).
4.1. CMS
More than 30 years ago, Severinghaus et al.
(1966) remarked that ‘‘desensitization of the pe-
ripheral chemoreceptors may be etiologic in
CMS’’. Persons with CMS have lower levels of
ventilation and a greatly diminished HVR com-
pared with normal residents of high altitude.
LeFrançois et al. (1968) observed that two to
three breaths of N2 had no effect in persons with
CMS whereas it raised ventilation 33% in
healthy high-altitude natives and more than dou-
bled it in acclimatized newcomers. The hypoventi-
lation and exaggerated hypoxemia of CMS
stimulate erythropoiesis. But while a low HVR is
likely permissive, it is not a sufficient cause of
CMS since healthy persons can also have a low
HVR (Kryger et al., 1978a; Sun et al., 1996).
There are geographic differences in the preva-
lence of CMS that generally parallel the regional
differences in ventilation and perhaps HVR, as
summarized above. Tibetan compared with Han
or Andean residents of similar altitudes have a
markedly lower CMS prevalence (Fig. 5). The
same criteria for CMS were used in the Tibetan
and Han studies. Whereas slightly different, gen-
der-specific criteria were used in the Andean stud-
ies, the hemoglobin or hematocrit values used to
define CMS were in the same range. Hence, it is
likely that Tibetan prevalence is genuinely lower
and the Han values not distinguishably different
from the Peruvian values. However, more explicit
comparisons of CMS prevalence based on com-
mon criteria and longitudinal studies of
hemoglobin (or hematocrit), ventilation and HVR
are needed (Moore et al., 1998a).
The control of breathing and brain O2 delivery
during sleep likely contribute to the occurrence of
CMS. Kryger et al. (1978a) found that persons
with CMS and healthy age-matched controls had
a similarly low HVR, but CMS patients more
frequently exhibited irregular breathing and desat-
uration during sleep. Treatment with medrox-
yprogesterone acetate (MPA, a synthetic
progestin) raised daytime ventilation, decreased
nocturnal SaO2, and lowered hemoglobin, but did
not raise HVR during wakefulness (Kryger et al.,
1978b). It is likely that progestin acts as a ventila-
tory stimulant during sleep. In surgically post-
menopausal women, progestin and estrogen
decreased the frequency of sleep-disordered
breathing (Pickett et al., 1989). Hormonal changes
associated with the menopause increase the occur-
rence of CMS, as judged by hemoglobin levels
and symptomatology (Leon-Velarde et al., 1997).
Other determinants of tissue O2 delivery, namely
brain blood flow and glucose metabolism, may
also influence susceptibility to CMS. We found
that CMS patients in Tibet had more frequent
episodes of sleep-disordered breathing and hy-
poventilation than controls and, as a result, had
much lower levels arterial O2 content during the
night (Sun et al., 1996). In addition to their lower
 L.G. Moore / Respiration Physiology 121 (2000) 257–276
HVR, the CMS patients had a diminished internal
carotid artery blood flow response to the hypoxia
and hypercapnia occurring during episodes of
sleep-disordered breathing. This suggested that
brain O2 delivery was compromised, not only as a
result of poor oxygenation but also because of
poor cerebral blood flow. Differences in brain
glucose metabolism may also be present. Using
positron emission tomography, Hochachka et al.
(1996) have shown that Andean natives
(Quechua) have modest hypometabolism in most
brain regions whereas Sherpa had levels which
were essentially the same as those of low-altitude
residents. Acclimatized European or North Amer-
ican newcomers exposed to much higher altitudes
and intensive exercise had a third pattern, charac-
terized by hypometabolism in some regions and
hypermetabolism in others (Hochachka et al.,
1999). Better maintenance of cerebral blood flow
and/or conserved brain glucose metabolism could
be protective against CMS in Tibetan highlanders.
Further assessment of the determinants of brain
O2 delivery will be important for determining
factors increasing susceptibility to CMS, a serious
health problem likely affecting 6 million persons
worldwide (Moore et al., 1998a).
Fig. 6. In native residents of Leadville, CO (3100 m), resting
ventilation measured 1 – 2 years postpartum, correlates closely
with birth weight of the infant born previously to the women
while living at that altitude.
271
4.2. IUGR
IUGR has been well-described at high altitude,
resulting in lower birth weights for infants of the
same gestational age when compared with low-al-
titude newborns. Some years ago, we asked if a
woman’s ventilatory response to pregnancy influ-
enced her infant’s birth weight. We found that
pregnant women residing at high altitude in Colo-
rado and Peru increased their ventilation, like
women at low altitude, but the increase raised
SaO2 at higher elevations (Moore et al., 1982). The
rise in ventilation was due largely to increases in
HVR (Moore et al., 1986) due, in turn, to the
stimulatory effects of progestin, estrogen and
higher metabolic rate (Regensteiner et al., 1989).
The hormones acted peripherally as well as cen-
trally to raise carotid body neural output response
to hypoxia and its central translation, thereby
increasing ventilation (Hannhart et al., 1989,
1990). The women with the greatest increase in
ventilation and HVR gave birth to heavier birth
weight babies.
More recently, we have observed that not only
did ventilation during pregnancy relate to infant
birth weight but also the mother’s resting ventila-
tion correlated closely with the birth weight of her
infant born  2 years previously (Fig. 6). Thus
constitutional factors influencing ventilation in
highland residents as well as the ventilatory re-
sponse to pregnancy may influence IUGR. Since
IUGR increases mortality risk during early in-
fancy, factors that raise ventilation and HVR
appear to have adaptive value in high-altitude
residents.
5. Conclusions and future directions
In summary, recent as well as older studies of
lifelong high-altitude residents demonstrate that
Tibetans ventilate more than Andean high-alti-
tude natives at the same or similar altitudes.
Tibetans ventilate like acclimatized newcomers
whereas Andeans generally breathe less than accli-
matized newcomers. Existing data are unclear as
to whether HVR differs between these groups.
Tibetans have an HVR as high as that of acclima-
272 L.G. Moore / Respiration Physiology 121 (2000) 257–276
tized newcomers whereas Andeans do not, but
HVR is not consistently greater in Tibetan than
Andean residents. Inter-individual and popula-
tion-specific genetic factors affect acute HVR and
likely modify acclimatization and the hyperventi-
latory response to high altitude. But other factors
contribute importantly to the level of ventilation
attained after prolonged high-altitude residence.
Factors such as the ventilatory roll-off following
the acute HVR and the stimulatory effect of
hyperoxia require further study. Blunting or loss
of HVR with prolonged high-altitude residence
has been demonstrated in Andean as well as
Tibetan high-altitude residents, although its mech-
anisms remain poorly understood. Developmental
factors, particularly those effecting neonatal arte-
rial oxygenation are likely important. Existing
data suggest that a low HVR is permissive for the
development of CMS and serves to augment the
degree of IUGR among high-altitude residents.
Future studies are needed to test explicit hy-
potheses concerning each of the several compo-
nents of the ventilatory response to hypoxia in
high-altitude populations. For example, it is not
known whether the ventilatory roll-off with pro-
longed hypoxia is diminished in Tibetans com-
pared with Andeans. Longitudinal studies of
ventilatory control in humans or experimental
animals that were hypoxic as neonates will also be
useful, particularly in relation to maladaptive syn-
dromes such as CMS. Systematic sampling, rather
than simply convenience samples, is required to
permit meaningful population comparisons. In
conjunction with such physiological studies, more
molecular approaches are required for determina-
tion of the source(s) of populational differences
and the processes by which natural selection and
other evolutionary forces may be involved. Exper-
imental animal studies using, for example rodent
strains with genetic differences in ventilatory re-
sponse, and techniques such as subtractive hy-
bridization, differential display or gene chip
technology will aid in identifying candidate gene
regions. Comparison of carotid body ultrastruc-
ture and gene expression in species with and
without blunted HVR (e.g. yaks and llamas, see
Kobayashi et al. (1998) and Wu et al. (1998)) may
also prove useful.
Acknowledgements
Many persons helped in the conduct of our
studies, including Tarshi Droma, Robert F.
Grover, Shao-Yung Huang, Robert E. and
Rosann G. McCullough, Carlos Monge, Susan
Niermeyer, John T. Reeves, Shinfu Sun, John V.
Weil, Stacy Zamudio, and Jianguo Zhuang.
Koichiro Tatsumi generously provided advice
during the preparation of this article. Studies by
our group were supported, in part by NIH
HL14985, HD000681, HL 60131; NSF BNS-
8903554; and US Army contract DAMD 17-87-C-
7202. David Young generously conducted the
statistical test in Fig. 1.
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