HIGH ALTITUDE MEDICINE & BIOLOGY

Volume 00, Number 00, 2020

ª Mary Ann Liebert, Inc.
DOI: 10.1089/ham.2019.0101

Blood Pressure in Andean Adults Living Permanently

at Different Altitudes

Andrés Fernando Vinueza Veloz,1,2,* Aymaru Kailli Yaulema Riss,1,2,* Chris I. De Zeeuw,3,4
Tannia Valeria Carpio Arias,5 and Marı́a Fernanda Vinueza Veloz3,6
Downloaded by Cornell University package NERL from www.liebertpub.com at 08/27/20. For personal use only.

Abstract

Vinueza Veloz, Andrés Fernando, Aymaru Kailli Yaulema Riss, Chris I. De Zeeuw, Tannia Valeria Carpio
Arias, and Marı́a Fernanda Vinueza Veloz. Blood pressure in Andean adults living permanently at different
altitudes. High Alt Med Biol. 00:000–000, 2020.
Aims: To estimate the association between blood pressure (BP) and chronic exposure to altitude in non-
hypertensive Andean adults, while taking ethnicity into consideration.
Materials and Methods: Sample included 10,041 nonhypertensive adults with indigenous or mixed ethnic
background (the latter also referred to as mestizos), who permanently lived at different altitudes. BP was measured
following international recommendations. Altitude was measured in meters above the sea level (masl) using a
global positioning system. Data were analyzed through linear regression models with restricted cubic splines.
Results: A significant nonlinear relation between altitude and systolic blood pressure (SBP) as well as diastolic
blood pressure (DBP) was found (both p < 0.001). BP described a j-shaped curve, where the minimum was
observed between 750 and 1250 masl, from where both SBP and DBP rose as altitude increased. These associations
were independent from sex, age, index of economic wellbeing, body mass index, and years of education. Inter-
estingly, at all altitudes indigenous people had lower SBP and DBP in comparison to mestizos (both p < 0.001).
Conclusions: Living permanently at altitudes ‡750 masl is associated with higher SBP and DBP in Andean
dwellers and this association is modulated by their ethnic background.

Keywords: altitude; blood pressure; Ecuador; ethnic group; indigenous people; mestizos

Introduction (Bärtsch and Saltin, 2008). The initial cardiovascular re-

sponse is characterized by an increase in cardiac output,

R egulation of blood pressure (BP) depends on the

complex interactions between genetic and environ-
mental factors (Ashraf, 2015). Among environmental factors
are those associated with lifestyle and others such as tem-
perature, noise, pollution, and altitude (Brook et al., 2011;
Bruno et al., 2017). Altitude can affect BP due to its influence
on the availability of O2 for the organism. Acute exposure to
moderate/high altitudes (‡2000 masl), as is the case for
nonacclimated visitors of highlands, triggers activation of
hypoxia-induced chemoreflexes that activate the sympathetic
nervous system with a subsequent release of catecholamines
tachycardia, and peripheral vasoconstriction, which eventu-
ally result in elevated BP levels (Kanstrup et al., 1999;
Bärtsch and Gibbs, 2007; Naeije, 2010).
With progressive acclimatization, BP gradually reduces
until basal levels are reached, a process that can last weeks or
even months (Niu et al., 1995; Kanstrup et al., 1999; Bärtsch
and Gibbs, 2007). Moreover, since acclimatization results
from adaptations at the genetic and the epigenetic level, it is
necessary to analyze populations with different ethnic back-
grounds (Childebayeva et al., 2019). So far, only few studies
have investigated the effects of chronic exposure to altitude on

1
Chapintza Health Center, Ministerio de Salud Pública del Ecuador, Chapintza, Ecuador.
2
Abteilung Gastroenterologie und Diabetologie, Gemeinschaftskrankenhaus Havelhöhe, Berlin, Germany.
3
Department of Neuroscience, Erasmus MC, Rotterdam, The Netherlands.
4
Netherlands Institute for Neuroscience, Royal Academy of Arts and Sciences, Amsterdam, The Netherlands.
5
Research Group GIANH, School of Nutrition and Dietetics, Faculty of Public Health, Escuela Superior Politécnica de Chimborazo,
Riobamba, Ecuador.
6
School of Medicine, Faculty of Public Health, Escuela Superior Politécnica de Chimborazo, Riobamba, Ecuador.
*These two authors contributed equally to this work.

1
 2 VINUEZA VELOZ ET AL.

BP while taking ethnicity into consideration (Hurtado et al., target population was selected by simple random sampling
2012; Mingji et al., 2015; Aryal et al., 2016). In this way, it was (Freire et al., 2014).
found that while in Tibetans BP varies with altitude, in non-
Tibetans (including Andean dwellers) such variation of BP Sample
related to altitude is not observed (Aryal et al., 2016).
From the 92,502 people who participated in ENSANUT-
Furthermore, whereas some studies suggest that chronic
ECU, we selected all individuals that had geographic and an-
exposure to altitude is associated with an increase in BP as well
thropometric data and were 20 years old or older (n = 29,781).
as in prevalence of hypertension, others suggest the opposite
People who did not autoidentify themselves as mestizo or in-
(Hurtado et al., 2012; Mingji et al., 2015; Aryal et al., 2016). digenous people (n = 2951), who did not always live in their
The heterogeneity of these results may be linked to different
actual place of residence (n = 10,489), pregnant women
degrees of adaptation, different duration of time of residence in
(n = 586), people who were diagnosed as hypertensive or had a
moderate/high altitudes, different periods during the life cycle BP higher than 140/90 mm Hg (n = 2280) were excluded from
of exposure to hypobaric hypoxia, different lifestyle habits,
the study sample. We only included mestizos and indigenous
different sociocultural and socioeconomic factors, and/or dif-
people, because they form the most numerous ethnic groups in
ferent genetic factors (Rothhammer, 1987; Kanstrup et al.,
Ecuador. Hypertensive individuals were excluded since the
1999; Beall, 2007; Mingji et al., 2015; Aryal et al., 2016).
main question of this article is to find out to what extent BP is
Within this context Ecuador with its various geographical
Downloaded by Cornell University package NERL from www.liebertpub.com at 08/27/20. For personal use only.

related to altitude under normal circumstances and thus con-

regions and ethnic diversity is a privileged territory for
clusions would have been confounded if these people were
studying the influence of altitude on BP. Being crossed by the included. On the other hand, because several people were
Andean Mountains at the level of the equator, Ecuador covers
living together in the same dwelling and therefore at the same
256,370 km2 in the north west region of South America and is
altitude (coinhabitants), we randomly selected one person
divided into three natural regions seated at different altitudes. from each dwelling. As a result, the final study sample in-
The country, in which nearly 16 million people reside, is
cluded 10,061 persons (Fig. 1).
populated by various ethnic groups, of which the most nu-
merous are ‘‘mestizos’’ (mix of European and Native
Americans) and ‘‘indigenous people’’ (Native Americans) Variable definition
(Knapp et al., 2018). The objective of the present study was to Altitude. Altitude of each dwelling was measured in
study the association between BP and altitude in non- meters above the sea level (masl) using a global positioning
hypertensive Andean adults, who permanently live at dif- system (Freire et al., 2014).
ferent altitudes, and find out to what extent this potential
association depends on ethnic background. Systolic and diastolic blood pressure. Systolic blood
pressure (SBP) and diastolic blood pressure (DBP) expressed
Materials and Methods in mm Hg were measured using digital sphygmomanometers
SECA, following international recommendations (Freire
Study design and setting et al., 2014). BP was measured twice, with a period of 5
The present work is a cross-sectional analytic study. The
study sample included people who participated in the
ENSANUT-ECU study, which was carried out by the Min-
isterio de Salud Pública (MSP) and the Instituto Nacional de
Estadı́sticas y Censos (INEC) in Ecuador in 2012. The ob-
jective of ENSANUT-ECU was to assess and describe in the
Ecuadorian population health outcomes, physical activity,
nutritional status, and access to health services, focusing on
specific age-target populations. ENSANUT-ECU was carried
out countrywide, covering urban and rural areas of the 24
provinces of Ecuador following Belmont Report guidelines;
informed consent was obtained from participants (Freire
et al., 2014). Data of the study are publicly available and can
be downloaded from the INEC web page from the following
link: https://www.ecuadorencifras.gob.ec/encuesta-nacional-
de-salud-salud-reproductiva-y-nutricion-ensanut-2012

Participants of ENSANUT-ECU
Participants of ENSANUT-ECU were selected by strati-
fied multistage probabilistic sampling performed by clusters
(censal sectors). Strata refer to urban and rural areas. During
the first stage, 64 censal sectors were selected with a proba-
bility proportional to the size of urban and rural areas of each
province. During the second stage, from the censal sectors, 12
dwellings were randomly selected. During the third stage,
from the 12 selected dwellings, 1 individual from each age- FIG. 1. Study sample calculation.
 BLOOD PRESSURE IN ANDEAN ADULTS LIVING AT DIFFERENT ALTITUDES 3

minutes between the recordings. In case the difference of the
two measurements were 5 mm Hg or more, a third mea-
surement was performed after another 5 minutes. For the
current study, values of SBP and DBP corresponded to the
average of the two or three measurements taken.
Ethnic group. Ethnic group was determined by asking the
participants: how do you identify yourself according to your
culture? Participants could identify themselves as ‘‘mestizo’’
(mixed ethnic ancestry), ‘‘indı́gena’’ (indigenous people), or
another ethnic group (Freire et al., 2014).
Index of economic wellbeing. The index of economic
wellbeing (Q) was calculated with the use of principal
component analysis of 42 variables related to the character-
istics of the dwelling and income (Freire et al., 2014). Q was
Downloaded by Cornell University package NERL from www.liebertpub.com at 08/27/20. For personal use only.
the function at defined knot points and restricted the splines to
linear relationships at the tail ends. Knot points were located
at percentiles 5, 27.5, 50, 72.5, and 95 of altitude, as previ-
ously recommended to avoid forcing curvature or inflections
(Harrell, 2019). All models were adjusted by the potential
confounders listed above.
We also included interaction terms for altitude*ethnicity and
altitude*age in each model to determine if the effect of altitude
on BP was different between indigenous and mestizos, and
between different age levels. There were no statistically sig-
nificant interactions for altitude*ethnicity or altitude*age nor
for SBP or DBP, and so the interaction terms were dropped
from the models. Models were adjusted for sampling weights,
which were extracted from ENSANUT-ECU. Poststratification
weighting method was applied. Goodness-of-fit plots showed
that chosen models fitted well with the data (Supplementary
Figure S1). All statistical analyses were performed using R,

calculated for each dwelling and was expressed in quintiles

from Q1 to Q5. The lower the quintile the lower the economic
condition of the dwelling.
Statistical analyses
We considered two main outcome variables (SBP and
DBP) and two secondary parameters (pulse pressure [PP] and
mean arterial pressure [MAP]), all of which are continuous
measures. To model the outcomes we considered one ex-
planatory continuous variable (altitude), one moderator var-
iable (ethnicity), and five potential confounders (sex [males
vs. female], age in years, years of education, Q, body mass
index [BMI], and area of residence [urban vs. rural]). To
investigate the association between SBP, DBP, PP, MAP, and
altitude we implemented linear regression models with re-
stricted cubic splines (RCSs).
Implemented RCS regression models determined the
shape of the relationship between altitude and outcomes
without any prior assumption. RCSs fitted a smooth contin-
uous curve of adjusted means with 95% confidence intervals
(95% CIs) across altitude levels. RCSs allowed for changes in
RStudio and related packages available in R, including MASS,
sfsmisc, and rms (Venables and Ripley, 2002; Maechler, 2017;
R Core Team, 2018; RStudio Team, 2018; Harrell, 2019).
Results
Twenty persons (0.2%) were dropped from the analysis,
because of missing values in variables’ altitude (n = 3), BMI
(n = 15), or index of economic wellbeing (n = 2). Thus, the
analyzed sample included 10,041 people, the majority of
whom reported having always lived at <1000 masl (49%) or
at 2000–3000 masl (36%) (Table 1). Mean age was similar at
different altitudes, but average years of education and BMI
was slightly lower at >3000 masl in comparison with the
other categories of altitude (Table 1). Percentage of women
was higher compared with men at all altitudes, being lower at
<1000 masl in comparison with the other altitudes (<1000
masl: 56%; 1000–2000 masl: 57%; 2000–3000 masl: 62%;
>3000 masl: 66%) (Table 1).
Percentage of indigenous people was lower compared with
mestizos at all altitudes; this percentage drastically increased
from 8% at 2000–3000 masl to 36% at >3000 masl (Table 1).

Table 1. Characteristics of the Population at Different Altitudes

<1000 masl 1000–2000 masl 2000–3000 masl >3000 masl
(n = 4880, 49%) (n = 708, 7%) (n = 3614, 36%) (n = 839, 8%)
n (%) M SD n (%) M SD n (%) M SD n (%) M SD
Age, years 32.36 9.02 33.43 9.34 33.24 9.19 33.89 9.53
Education, years 9.99 3.96 9.21 3.89 9.90 4.34 7.31 4.21
BMI, kg/m2 26.39 4.62 26.64 4.14 26.42 4.13 25.77 3.92
Gender
Male 2153 (44) 303 (43) 1376 (38) 287 (34)
Female 2727 (56) 405 (57) 2238 (62) 552 (66)
Ethnicity
Mestizo 4268 (87) 633 (89) 3326 (92) 521 (62)
Indigenous 612 (13) 75 (11) 288 (8) 318 (38)
Q
Q1 1249 (26) 252 (35) 624 (17) 414 (49)
Q2 1176 (24) 174 (25) 682 (19) 175 (21)
Q3 1031 (21) 132 (19) 650 (18) 118 (14)
Q4 875 (18) 99 (14) 728 (20) 67 (8)
Q5 549 (11) 51 (7) 930 (26) 65 (8)
In total 10,061 people were included in the study from whom 20 presented missing values: 15 regarding BMI, 2 regarding index of
economic wellbeing and 3 regarding altitude. The final sample included 10,041 people.
BMI, body mass index; M, mean; masl, meters above the sea level; n, number; Q, index of economic wellbeing; SD, standard deviation.
 4 VINUEZA VELOZ ET AL.

7.94
8.21
7.82
7.70
The distribution of mestizos and indigenous people living at

SD
different altitudes can be observed in Table 2, which also

MAP
shows that in comparison to mestizos, a higher percentage of

83.25
84.09
85.34
85.20
indigenous people reported having always lived >3000 masl

M
Table 2. Mean Values of Systolic and Diastolic Blood Pressure, Pulse Pressure, and Mean Arterial Pressure at Different Altitudes
(6% of mestizos vs. 25% of indigenous). Additionally, dis-
tribution among Q showed that, at different altitudes (except

6.89
7.68
8.13
7.62
2000–3000 masl), most people were living in poverty (Q1

SD
and Q2) (Table 2).

PP
Mean SBP of the whole sample was 114.60 mm Hg

41.06
40.42
43.04
43.70
(SD = 10.22), and mean DBP was 71.45 mm Hg (SD = 7.85).

M
Indigenous (n = 1297)
Mean PP and MAP for the whole sample was 43.1
(SD = 7.67) and 85.8 (SD = 7.92), respectively. In general,

7.71
8.17
7.91
7.89
SD
mean SBP, DBP, PP, and MAP were lower among indige-
nous people in comparison to mestizos, and these values in-

DBP
creased with altitude (Table 2). To study the association of

69.58
70.62
70.92
70.66
M
BP, PP, MAP, and altitude we implemented RCSs regression
models adjusted by sex, age in years, years of education, Q,
Downloaded by Cornell University package NERL from www.liebertpub.com at 08/27/20. For personal use only.

and BMI (see Materials and Methods section).

9.61
10.08
10.39
10.07
SD
BP and altitude

SBP
Figure 2 shows multivariate adjusted predicted mean and

110.65
111.04
113.96
114.33
M
95% CIs for regression models with RCSs for SBP, DBP, PP,
and MAP. Corresponding predicted mean values and 95%
CIs of SBP, DBP, PP, and PAM for percentiles 5 (12 masl),

(47)

(22)
(25)
25 (259 masl), 50 (1068 masl), 75 (2657 masl), and 95 (3142

(6)
n (%)
masl) of altitude are shown in Supplementary Table S1.

DBP, diastolic blood pressure; MAP, mean arterial pressure; PP, pulse pressure; SBP, systolic blood pressure.
612
75
288
318
A significant nonlinear relation between altitude and SBP
was found [F(3) = 11.00, p < 0.001]. SBP in relation to alti- by the Ethnic Group

8.18
7.84
7.62
7.35
tude showed a j-shaped curve. In fact, it was higher at 0 masl

SD
than at 750 masl, where the minimum of SBP was observed
MAP
(Fig. 2a). After 750 masl, SBP was higher as altitude in-

86.05
85.69
86.08
86.42
creased. When analysis was restricted to compare SBP be-
tween the minimum point of the curve at 750 masl and M
percentile 95 of altitude (3142.15 masl), an increase of

Table also shows distribution of mestizos and indigenous people at different altitudes.
7.68
7.64
7.63
7.87
SD
2.46 mmHg (95% CI 1.66–3.27) was observed (Fig. 2a).
A significant nonlinear relation between altitude and DBP
PP

was also found [F(3) = 3.01, p = 0.029]. DBP also described a

42.80
42.94
43.72
44.69
M

j-shaped curve in relation to altitude, although it was less

pronounced. In fact, it was higher at 0 masl than at 1250 masl,
Mestizo (n = 8761)

where the minimum of DBP was observed (Fig. 2b). After

7.99
7.72
7.69
7.53
SD

1250 masl, DBP was higher as altitude increased. When

DBP

analysis was restricted to compare DBP between the minimum

Three missing values are observed in the variable altitude.

point of the curve at 1250 masl and percentile 95 of altitude

71.78
71.37
71.51
71.52
M

(3142.15 masl), a nonstatistically significant increase of

0.54 mmHg (95% CI -0.23 to 1.30) was observed (Fig. 2b).
10.60
10.21
9.73
9.50
SD

BP and ethnicity and other covariates

SBP

SBP was significantly associated with ethnicity [SBP:

114.58
114.31
115.22
116.21

F(1) = 13.34, p < 0.001]. SBP was 1.54 mm Hg (95% CI

M

--2.37 to -0.72) lower in indigenous in comparison to

mestizos (Fig. 3a). SBP was also significantly associated with
sex [F(1) = 1739.36, p < 0.001], age [F(3) = 11.16, p < 0.001],
(49)

(38)
(7)

(6)

Q [F(1) = 9.31, p = 0.002], BMI [F(3) = 40.26, p < 0.001], and

n (%)a

area of residence [F(1) = 7.65, p = 0.006], but not with years

4268
633

521
3326

of education [F(3) = 2.09, p = 0.099]. In this way, SBP was

higher in men in comparison to women (Fig. 3b), increased
with age, and BMI (Fig. 3c, e) decreased with Q (Fig. 3d), and
Altitude (masl)

was higher at rural in comparison to urban areas (Fig. 3f).

1000–2000
2000–3000

DBP was significantly associated with ethnicity [SBP:

F(1) = 9.17, p = 0.003]. DBP was 1.00 mm Hg (95% CI -1.65 to
3000+
<1000

-0.35) lower in indigenous in comparison to mestizos (Fig. 4a).

a

DBP was also significantly associated with sex [F(1) = 1026.11,

 BLOOD PRESSURE IN ANDEAN ADULTS LIVING AT DIFFERENT ALTITUDES 5
Downloaded by Cornell University package NERL from www.liebertpub.com at 08/27/20. For personal use only.

FIG. 2. Multivariate adjusted predicted mean for the regression models with RCSs for (a) SBP, (b) DBP, (c) PP, and (d)
MAP. DBP, diastolic blood pressure; MAP, mean arterial pressure; PP, pulse pressure; RCS, restricted cubic spline; SBP,
systolic blood pressure.

p < 0.001], age [F(3) = 17.192, p < 0.001], Q [F(1) = 12.05,
p = 0.001], and BMI [F(3) = 27.19, p < 0.001], but not with years
of education (F(3) = 0.66, p = 0.578) or area of residence
[F(1) = 0.07, p = 0.791]. In this way, DBP was higher in men in
comparison to women (Fig. 4b), increased with age and BMI
(Fig. 4c, e), and decreased with Q (Fig. 4d).
PP and MAP
A significant nonlinear relation between altitude and PP was
found [F(3) = 5.90, p = 0.001]. PP in relation to altitude showed
a j-shaped curve. In fact, it was higher at 0 masl than at 500 masl,
where the minimum of PP was observed (Fig. 2c). After 500
masl, PP was higher as altitude increased. When analysis was
restricted to compare PP between the minimum point of the
curve at 500 masl and percentile 95 of altitude (3142.15 masl), an
increase of 2.18 mmHg (95% CI 1.46–2.90) was observed
(Fig. 2c). PP was significantly associated with sex [F(1) = 403.99,
p < 0.001], age [F(3) = 59.99, p < 0.001], BMI [F(3) = 8.03,
p < 0.001], and area of residence [F(1) = 13.01, p < 0.001], but not
with ethnicity [F(1) = 2.40, p = 0.121], years of education
[F(3) = 0.99, p = 0.396], or with Q [F(1) = 0.16, p = 0.692].
 6 VINUEZA VELOZ ET AL.
Downloaded by Cornell University package NERL from www.liebertpub.com at 08/27/20. For personal use only.

FIG. 3. Multivariate adjusted predicted means for DBP are shown by (a) ethnicity, (b) sex, (c) age groups, (d) Q, (e) BMI
groups, and (f) area. BMI, body mass index.
A significant nonlinear relation between altitude and MAP
was found [F(3) = 6.76, p = 0.001]. MAP in relation to altitude
showed a j-shaped curve. In fact, it was higher at 0 masl than at
750 masl, where the minimum of MAP was observed (Fig. 2c).
After 750 masl MAP was higher as altitude increased. When
analysis was restricted to compare MAP between the mini-
mum point of the curve at 750 masl and percentile 95 of
altitude (3142.15 masl), an increase of 1.07 mm Hg (95%
CI 0.45–1.69) was observed (Fig. 2d). MAP was signifi-
cantly associated with ethnicity [F(1) = 13.24, p < 0.001], sex
[F(1) = 1585.38, p < 0.001], age [F(3) = 4.60, p = 0.003], BMI
[F(3) = 39.41, p < 0.001], and Q [F(1) = 13.53, p < 0.001], but
not with years of education [F(3) = 1.38, p = 0.247] or with area
of residence [F(1) = 1.03, p = 0.309].
Discussion
The present study investigated the association between BP
and altitude in nonhypertensive Andean adults belonging to
two of the major ethnic groups in Ecuador, indigenous people
 BLOOD PRESSURE IN ANDEAN ADULTS LIVING AT DIFFERENT ALTITUDES
Downloaded by Cornell University package NERL from www.liebertpub.com at 08/27/20. For personal use only.
FIG. 4. Multivariate adjusted predicted means for DBP are shown by (a) ethnicity, (b) sex, (c) age groups, (d) Q, (e) BMI
groups, and (f) area.
and mestizos, who permanently live at different altitudes.
Our main finding was that there is a significant association
between altitude and BP; this increment was independent of
sex, age, years of education, Q, BMI, and area of residence.
Furthermore, a close examination of both ethnic groups al-
lowed us to identify an interesting difference: SBP and DBP
of indigenous people were lower than those of mestizos.
Other studies have also reported a positive effect of chronic
exposure to altitude on BP. Most of them have been performed
7
in human communities permanently living in geographical
regions located at moderate/high altitudes (‡1500 masl), in-
cluding people from Tibet and Ethiopia. Such studies have
shown that in Tibetan and Ethiopian dwellers, BP rises as
altitude increases (Clegg et al., 1976; Aryal et al., 2016).
Furthermore, two systematic reviews have reported that in
dwellers of Tibet the prevalence of hypertension increases
with altitude (Mingji et al., 2015; Aryal et al., 2016). Even so,
the effect of altitude on BP is modified by genetic, cultural, and
 8 VINUEZA VELOZ ET AL.
lifestyle factors, among others (Baker, 1969; Makela et al.,
1978), which may well explain why debates about the relation
between altitude and BP in Andean indigenous communities
are still ongoing (Baker, 1969; Makela et al., 1978; Lindgärde
et al., 2004; Aryal et al., 2016). Furthermore, such factors may
also explain the j-shaped curve described by BP in relation to
the increase of altitude.
Why is the response of BP to the increase of altitude
different between indigenous people and mestizos?
Our findings showed differences between indigenous
people and mestizos regarding the effect of altitude on BP.
For example, BP of indigenous people was lower compared
with mestizos. To our knowledge, this is the first study that
reports such differences in BP between nonhypertensive
Downloaded by Cornell University package NERL from www.liebertpub.com at 08/27/20. For personal use only.
mestizos and indigenous people in Ecuador. A possible ex-
planation is that indigenous people have indeed developed
specific physiological adaptations in response to hypoxia that
are likely inherited from generation to generation. Such
specific physiological adaptations probably depend on ge-
netic variations, the identification and nature of which have
recently begun to be investigated. For example, Hyndman
et al. (2002) and Kumar et al. (2015) reported that a point
genetic variation (Thymine 786—Cytosine) in the En-
dothelial Nitric Oxide Synthase 3 gene (eNOS3) is associated
with a higher SBP, but not DBP (Hyndman et al., 2002;
Kumar et al., 2015). eNOS3 is involved in the synthesis and
release of nitric oxide (NO) from the vascular endothelium,
where it plays an important role in regulating the vascular
tone and thereby BP. This genetic variation has recently been
identified in Tibetans and could explain why their BP in-
creases as altitude increases. However, it is not known
whether similar genetic variations are also present in Andean
dwellers, and it will have to be investigated to what extent
such potential variations may also contribute to the difference
in the BP among indigenous people and mestizos.
Clinical implications
Genetic variations such as those involved in O2 regulation,
erythropoietic response, or NO production and their subse-
quent effects on BP, could endow indigenous people with
flexible physiological mechanisms to adapt to altitude
(Winslow et al., 1989; Bigham et al., 2009; Yi et al., 2010;
Moore, 2017). Although hypoxic and hypobaric conditions
are known to lead to functional adaptations of the organism
that optimize O2 transport with a secondary effect on BP,
their specific implications for susceptibility to suffer from
cardiovascular diseases are still debated.
For example, whereas some studies suggest that hypoxia
may directly reduce the prevalence of hypertension in An-
deans, others indicate the opposite (Ruiz and Peñaloza,
1977; Baker, 1969; Mingji et al., 2015; Aryal et al., 2016).
Culturally driven dietary or lifestyle habits plus genetic
susceptibility may be the main reason behind this contro-
versy. Such factors may also explain why the prevalence of
hypertension is lower in Tibetan monks, who generally have
a healthy lifestyle (Li et al., 2015). Thus, habits related to
education, healthy diet, and lifestyle, may all contribute to
BP and interact with factors that are triggered by changes in
altitude.
Implications for public health
While the prevalence and absolute burden of hypertension
is increasing globally, the awareness of hypertension and the
relevance of its treatment and control are unacceptably low
(Mills and Stefanescu, 2020). This may be particularly rel-
evant for countries with low and medium income, such as
Ecuador, where the increase in the prevalence of this disease
is even greater with respect to high-income countries (Mills
and Stefanescu, 2020). Therefore, our findings suggest that
health policies in countries like Ecuador should be applied
with great attention and even be reformulated to be sensitive
to ethnic variations.
Limitations and methodological considerations
There may be several aspects that could interfere with our
findings, such as health status and salt consumption of in-
terviewed people. For instance, our models were adjusted by
sex, age in years, years of education, index of economic
wellbeing and BMI, but not by biochemical indicators of
cardiovascular risk or salt consumption. We did not include
such variables, because information on this regard was
available only for half of the sample. Another limitation of
the present study concerns the method that was used to cat-
egorize people as mestizo or indigenous in the ENSANUT-
ECU study. Belonging to a particular ethnic group was
determined by asking each individual how he/she identifies
his/herself according to his/her culture and not by performing
a genetic analysis. So our study could suffer from information
bias. People may autoidentify themselves as mestizo instead
of indigenous to prevent ‘‘social stigma.’’
Further research and recommendations
More studies should be performed to help to better under-
stand our findings. Further research should focus on investi-
gating the influence of genetic, physiological, environmental,
and lifestyle factors on BP and cardiovascular susceptibility
taking ethnicity into consideration.
Conclusions
Our main finding was that SBP, DBP, PP, and MAP in-
creased with altitude in Andean dwellers in a nonlinear
fashion, and that such increment was independent from from
sex, age, years of education, Q, BMI, and area of residence.
Furthermore, a close examination of ethnic groups allowed us
to identify one interesting difference: SBP and DBP of in-
digenous people were lower than those of mestizos.
Author Contributions
The main author of this work declares that all authors
have contributed and work on the development of it as
follows: Andrés Fernando Vinueza Veloz, MD: Conception
and design, analysis and interpretation of data, drafting of
the article, and final approval of the version to be published.
Dr. Aymaru Kailli Yaulema Riss: Conception and design,
analysis and interpretation of data, drafting of the article,
and final approval of the version to be published. Prof. Dr.
Chris I. de Zeeuw: Critical revision for important intellec-
tual content, and writing and final approval of the version to
be published. Dr. Tannia Valeria Carpio Arias: Critical re-
vision for important intellectual content, and final approval
 BLOOD PRESSURE IN ANDEAN ADULTS LIVING AT DIFFERENT ALTITUDES
of the version to be published. Marı́a Fernanda Vinueza
Veloz: Conception and design, analysis and interpretation
of data, drafting of the article, critical revision for important
intellectual content, and final approval of the version to be
published.
Acknowledgments
The authors would like to thank the School of Medicine
and the Faculty of Public Health of the Escuela Superior
Politécnica de Chimborazo (ESPOCH) and the Secretarı́a
Nacional de Educación Superior e Investigación (SE-
NESCYT) for their support. Special thanks are given to Dra.
Silvia Proaño Lucero and Dra. Paulina Robalino Valdivieso
for their professional feedback and support. C.I.D.Z. is sup-
ported by the Dutch Organization for Medical Sciences
(ZonMw), Life Sciences, and Social and Behavioral Sci-
Downloaded by Cornell University package NERL from www.liebertpub.com at 08/27/20. For personal use only.
ences, NeuroBasic, Medical NeuroDelta, INTENSE as well
as ERC-adv and ERC-POC of the EU. The authors also thank
Carlos Martin Román, Silvia Gonzales, and Marco Gonzales
for their technical support.
Author Disclosure Statement
No competing financial interests exist.
Funding Information
The authors received no financial support for the research,
authorship, and/or publication of this article.
Supplementary Material
Supplementary Figure S1
Supplementary Table S1
References
Aryal N, Weatherall M, Bhatta YKD, and Mann S. (2016).
Blood pressure and hypertension in adults permanently living
at high altitude: A systematic review and meta-analysis. High
Alt Med Biol 17:185–193.
Ashraf M. (2015). Hypertension at High Altitude: The Interplay
Between Genetic and Biochemical Factors in the Setting of
Oxidative Stress Hypertension Research. The Japanese So-
ciety of Hypertension, Tokyo: Japan, pp. 1–2.
Baker PT. (1969). Human adaptation to high altitude. Science
163:1149–1156.
Bärtsch P, and Gibbs JSR. (2007). Effect of altitude on the heart
and the lungs. Circulation 116:2191–2202.
Bärtsch P, and Saltin B. (2008). General introduction to altitude
adaptation and mountain sickness. Scand J Med Sci Sports
18:1–10.
Beall CM. (2007). Two routes to functional adaptation: Tibetan
and Andean high-altitude. Proc Natl Acad Sci U S A
104(Suppl 1):8655–8660.
Bigham AW, Mao X, Mei R, Brutsaert T, Wilson MJ, Julian
CG, Parra EJ, Akey JM, Moore LG, and Shriver MD.
(2009). Identifying positive selection candidate loci for
high-altitude adaptation in Andean populations. Hum
Genomics 4:79–90.
Brook RD, Weder AB, and Rajagopalan S. (2011). ‘Environ-
mental Hypertensionology’ the effects of environmental
factors on blood pressure in clinical practice and research.
J Clin Hypertens 13:836–842.
9
Bruno RM, Di Pilla M, Ancona C, Sorensen M, Gesi M, Taddei
S, Munzel T, and Virdis A. (2017). Environmental factors and
hypertension. Curr Pharm Des 23:3239–3246.
Childebayeva A, Harman T, Weinstein J, Goodrich JM, Doli-
noy DC, Day TA, Bigham AW, and Brutsaert TD. (2019).
DNA methylation changes are associated with an incremental
ascent to high altitude. Front Genet 10:1062.
Clegg EJ, Jeffries DJ, and Harrison GA. (1976). Determinants
of blood pressure at high and low altitudes in Ethiopia. Proc R
Soc London Ser B Biol Sci 194:63–82.
Freire WB, Ramı́rez-Luzuriaga MJ, Belmont P, Mendieta MJ,
Silva-Jaramillo MK, Romero N, Sáenz K, Piñeiros P, Gómez
LF, and Monge R. (2014). Volume I: National Survey of
Health and Nutrition of the Ecuadorian population from zero
to 59 years old. ENSANUT-ECU 2012. Ministry of Public
Health/National Institute of Statistics and Censuses, Quito,
Ecuador.
Harrell FE. (2019). rms: Regression Modeling Strategies. R pack-
age version 5.1-4. https://CRAN.R-project.org/package=rms
(accessed June 11, 2020).
Hurtado A, Escudero E, Pando J, Sharma S, and Johnson RJ.
(2012). Cardiovascular and renal effects of chronic exposure
to high altitude. Nephrol Dial Transplant 27(Suppl 4):iv11–
iv16.
Hyndman ME, Parsons HG, Verma S, Bridge PJ, Edworthy S,
Jones C, Lonn E, Charbonneau F, and Anderson TJ. (2002).
The T-786/C mutation in endothelial nitric oxide synthase
is associated with hypertension. Hypertension 2002;39:919–
922.
Kanstrup I-L, Poulsen TD, Hansen JM, Andersen LJ, Bestle
MH, Christensen NJ, and Olsen NV. (1999). Blood pressure
and plasma catecholamines in acute and prolonged hypoxia:
Effects of local hypothermia. J Appl Physiol 87:2053–2058.
Knapp GW, MacLeod MJ, and Pozo Velez H. (2018). Ecuador j
History, Geography, & Culture j Britannica.com. Encicl.
Britanica. https://www.britannica.com/place/Ecuador (ac-
cessed September 20, 2019).
Kumar R, Kohli S, Mishra A, Garg R, Alam P, Stobdan T,
Nejatizadeh A, Gupta M, Tyagi S, and Qadar Pasha MA.
(2015). Interactions between the genes of vasodilatation
pathways influence blood pressure and nitric oxide level in
hypertension. Am J Hypertens 28:239–247.
Li X, Cai H, He J, Ramachandran D, Xie P, Huang Y, Wang H,
Liu Y, Qiao Y, and Zhang Q. (2015). Prevalence, awareness,
treatment and control of hypertension in Tibetan monks from
Gansu Province, Northwest China. Clin Exp Hypertens 37:
536–541.
Lindgärde F, Ercilla MB, Correa LR, and Ahrén B. (2004).
Body adiposity, insulin, and leptin in subgroups of Peruvian
Amerindians. High Alt Med Biol 5:27–31.
Maechler M. (2017). sfsmisc: Utilities from ‘Seminar fuer
Statistik’ ETH Zurich. https://cran.r-project.org/package=
sfsmisc (accessed June 11, 2020).
Makela M, Barton SA, Schull WJ, Weidman W, and Roth-
hammer F. (1978). The multinational andean genetic and
health program—IV. Altitude and the blood pressure of the
aymara. J Chronic Dis 31:587–603.
Mingji C, Onakpoya IJ, Perera R, Ward AM, and Heneghan CJ.
(2015). Relationship between altitude and the prevalence of
hypertension in Tibet: A systematic review. Heart 101:1054–
1060.
Moore LG. (2017). Measuring high-altitude adaptation. J Appl
Physiol 123:1371–1385.
Mills KT, Stefanescu A, and He J. (2020). The global epide-
miology of hypertension. Nat Rev Nephrol 16:223–237.
 10
Naeije R. (2010). Physiological adaptation of the cardiovascular
system to high altitude. Prog Cardiovasc Dis 52:456–466.
Niu W, Wu Y, Li B, Chen N, and Song S. (1995). Effects of
long-term acclimatization in lowlanders migrating to high
altitude: Comparison with high altitude residents. Eur J Appl
Physiol Occup Physiol 71:543–548.
R Core Team. (2018). R: A Language and Environment for
Statistical Computing. https://www.r-project.org (accessed
June 11, 2020).
Rothhammer F. (1987). Determinantes de la presión arterial en
una población andina nativa Blood pressure determinant
factors in a native (Blood pressure determinant factors in a
native Andean population). Arch Biol Med Exp 20:394.
RStudio Team. (2018). RStudio: Integrated Development En-
vironment for R. www.rstudio.com (accessed June 11, 2020).
Ruiz L, and Peñaloza D. (1977). Altitude and hypertension.
Mayo Clin Proc 52:442–445.
Downloaded by Cornell University package NERL from www.liebertpub.com at 08/27/20. For personal use only.
Venables WN, and Ripley BD. (2002). Modern Applied Sta-
tistics with S. Fourth. New York: Springer.
Winslow RM, Chapman KW, and Gibson CC. (1989). Different
hematologic responses to hypoxia in Sherpas and Quechua
Indians. J Appl Physiol 66:1561–1569.
Yi X, Liang Y, Huerta-Sanchez E, Jin X, Cuo ZX, Pool JE, Xu
X, Jiang H, Vinckenbosch N, Korneliussen TS, Zheng H, Liu
VINUEZA VELOZ ET AL.
T, He W, Li K, Luo R, Nie X, Wu H, Zhao M, Cao H, Zou J,
Shan Y, Li S, Yang Q, Asan, Ni P, Tian G, Xu J, Liu X, Jiang
T, Wu R, Zhou G, Tang M, Qin J, Wang T, Feng S, Li G,
Huasang, Luosang J, Wang W, Chen F, Wang Y, Zheng X, Li
Z, Bianba Z, Yang G, Wang X, Tang S, Gao G, Chen Y, Luo
Z, Gusang L, Cao Z, Zhang Q, Ouyang W, Ren X, Liang H,
Zheng H, Huang Y, Li J, Bolund L, Kristiansen K, Li Y,
Zhang Y, Zhang X, Li R, Li S, Yang H, Nielsen R, Wang J,
and Wang J. (2010). Sequencing of 50 human exomes reveals
adaptation to high altitude. Science 329:75–78.
Address correspondence to:
Marı́a Fernanda Vinueza Veloz
School of Medicine
Faculty of Public Health
Escuela Superior Politécnica de Chimborazo
Riobamba EC060155
Ecuador
E-mail: maria.vinueza@espoch.edu.ec
Received January 17, 2020;
accepted in final form July 6, 2020.