HIGH ALTITUDE MEDICINE & BIOLOGY

Volume 00, Number 00, 2020

ª Mary Ann Liebert, Inc.
DOI: 10.1089/ham.2019.0110

High Altitude as a Cause of Congenital Heart Defects:

A Medical Hypothesis Rediscovered in Ecuador

Fabricio González-Andrade1,2

Abstract
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González-Andrade, Fabricio. High altitude as a cause of congenital heart defects: a medical hypothesis re-
discovered in Ecuador. High Alt Med Biol. 00:000–000, 2020.
Background: There are *83 million people living at high altitude (>2500 m) worldwide who endure chronic
hypoxia conditions. This article aims to analyze the relationship between high altitude, identified in several
cities in Ecuador, and the prevalence of congenital heart disease (CHD).
Methods: Set in Ecuador, this epidemiological observational cross-sectional study analyzes data over a range of
18 years (from 2000 to 2017), including 34,904 reported cases of CHD, with a mean of 1939 cases per year.
Results: The mean prevalence rate of CHD found is 70.6 per 10,000 live newborns. A K-means analysis
resulted in three clusters. Cluster 1 shows the lowest altitude and prevalence of CHD, with an average of 2619 m
and 63.02 cases per 10,000 live newborns. Cluster 2 presents the second highest altitude and prevalence of
CHD, with an average of 2909 m and 72.04 cases per 10,000 live newborns. Cluster 3 shows the highest values
of altitude and prevalence of CHD, with an average of 3176 m and 86.62 cases per 10,000 live newborns.
Pearson’s coefficient is 0.979, so the correlation between the variables is positive. An altitude ranging from
2500 to 2750 m relates to a prevalence of CHD of £71 cases per 10,000 live newborns. An altitude ranging from
2751 to 3000 m relates to a prevalence of CHD of >71 and <89 cases per 10,000 live newborns. An altitude
ranging between 3001 and 3264 m relates to a prevalence of CHD of ‡89 cases per 10,000 live newborns.
Conclusions: The findings show that high altitude (>2500 m), ethnicity (Native American), rural locations, and
limited access to health care are factors that influence and increase the prevalence rate of CHD. A correlation
coefficient of 0.914 shows the direct relationship between high altitude and prevalence rates of CHD. For each
year elapsed, the prevalence of CHD increased by 3.33 cases per 10,000 live newborns.

KeyWords: Andeans; heart disease; high-altitude populations; highlanders; neonatal changes

Introduction dean Altiplano), and the Ethiopian Amhara and Oromo

igh-altitude hypoxia occurs at elevations >2500 m
H above sea level because of decreased oxygen avail-
ability brought on by lowered barometric pressure at high
elevations (Azad et al., 2017). This poses a number of chal-
lenges to human health, survival, and reproduction. It is es-
timated that there are *83 million people living at high
altitude, in various locations such as the Qinghai–Tibetan
Plateau, the Andean Altiplano, and the Semien Plateau in
Ethiopia (Bigham, 2016). Populations in these areas have
lived under chronic hypoxia conditions for thousands of
years, and show chronic adaptation to altitude (Bigham and
Lee, 2014). They include the Sherpa and Ayurveda (Qinghai–
Tibetan Plateau), the Kichwa and Aymara highlanders (An-
highlanders (Semien Plateau in Ethiopia) (West, 2017).
The most important physiological adaptations include
changes in pulmonary function, arterial oxygen saturation
(SaO2), hemoglobin concentration, and maternal physi-
ology during pregnancy (Chun et al., 2019). Several studies
(Castilla et al., 1999; Luquetti et al., 2013) have associated
these changes with congenital defects, especially congen-
ital heart disease (CHD) and microtia/anotia (Gonzalez-
Andrade et al., 2010). Another study proposed that high-
altitude adaptation is one of the strongest instances of
natural selection acting on humans (Huicho and Niermeyer,
2006). Among Andean populations, phenotypes are char-
acterized by no increase in resting pulmonary ventilation, a
decrease in hypoxic ventilatory response, and an increase in

1
Unidad de Medicina Traslacional, Facultad de Ciencias Médicas, Universidad Central del Ecuador, Quito, Ecuador.
2
Colegio Ciencias de la Salud, Universidad San Francisco de Quito USFQ, Quito, Ecuador.

1
 2 GONZÁLEZ-ANDRADE
SaO2, hemoglobin concentration, and birth weight (Castilla
and Adams, 1996).
Chronic hypoxia under the pressure of natural selection
may be due to specific mutations that confer an evolutionary
advantage upon the population under selection, in relation to
other control populations (Ambale-Venkatesh et al., 2017).
From the point of view of the Mendelian genotype, the se-
lection would lead to a difficult sweep, or to a soft and se-
lective sweep with foot variations (Brutsaert, 2016).
Despite research undertaken to understand cardiac devel-
opment and the identification of many related genes, the
fundamental etiology for most cases of CHD remains un-
known (Lopez-Camelo and Orioli, 1996). The literature de-
scribes several risk factors, such as folic acid insufficiency,
increased nuchal translucency during the first trimester, as-
sisted reproductive technology, maternal diabetes or obesity,
maternal hypertension, and maternal antihypertensive med-
ication, among others. Genetic causes produce *45% of
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CHD cases, both isolated and in syndromes (Miao et al.,
1988; Crawford et al., 2017; Alderman et al., 1995). Low
heritability patterns suggest that environmental factors, such
as altitude, rather than genetic factors, play an essential role
in the incidence of CHD (Zheng et al., 2017). Nongenetic
causes for impairment of normal heart development include
viral infections, maternal exposure to alcohol, drugs, envi-
ronmental teratogens, metabolic disturbances, rubella, mea-
sles, exposure to chemicals, and maternal systemic lupus
erythematosus (Chen et al., 2009; Fernández et al., 2016).
The purpose of this article is to analyze the relationship
between high altitude, identified in several cities in Ecuador,
and the prevalence of CHD. Ecuador is uniquely suited for
this analysis for three reasons: first, it is demographically
multiethnic and multicultural, with 3 main ethnic groups and
13 Native Amerindian nationalities; second, 10 of its 24
provinces are located >2500 m; and third, there is a marked
inequality among its inhabitants (Santangelo et al., 2017).
Methods
Study design
This is an epidemiological, observational, and cross-
sectional study.
Setting
Ecuador. Data analyzed was from 2000 to 2017, showing
34,904 cases in 18 years. ICD-10 codes Q20 to Q28 were
analyzed to classify CHD.
Variables
The variables were number of cases of CHD, prevalence
group, province, prevalence rate, year, and high-altitude lo-
cations.
This study did not analyze the subgroups according to
gender and age groups, because the existing information is
too large and merits making a new statistical analysis and
drafting a new article. In relation to ethnicity, and age at
diagnosis, this database does not include this subdivision.
Data sources
Data regarding the prevalence of hospital discharges were
provided by the National Institute of Statistics and Census
(INEC). At present, this is the only source for this informa-
tion available in the country. Cases considered suitable for
this study included all children born in Ecuador from January
1, 2000, to December 31, 2017.
The information that exists in the INEC database includes
the final diagnoses upon discharge from the patients in each
health facility. The diagnosis in each site varies, although the
majority of patients are identified by clinical diagnosis at
birth and finally diagnosed by echocardiography. Pulse oxi-
metry is not a routine practice for diagnosing CHD in most
health facilities in Ecuador. In a previous study (González-
Andrade et al., 2018), our research team determined that
CHD can only be partially diagnosed. Identifying those with
oxygen saturation <90% after three successive measurements
or a pre- and postductal oxygen difference of >3% resulted in
successful identification of atrial septal defect (ASD) and
patent ductus arteriosus (PDA). It is necessary to implement
new cutoff points in saturation values to identify critical
cardiac anomalies in cities placed at a high altitude. Pulse
oximetry should be recommended, as a routine practice, in all
newborns. Initially all patients were diagnosed by physical
examination at birth, and after the findings were confirmed
with echocardiography. Physical examination consisted in
cardiac auscultations and clinical manifestation screening.
An echocardiography was performed to confirm and identify
the subtype of CHD.
Bias avoidance
The same person always collected the information using a
standardized data collection sheet.
Interobserver variation, defined as the amount of variation
between the results obtained by two or more observers ex-
amining the same material, could not be fully controlled
because the training of Ecuadorian doctors in this field is
heterogeneous. However, when the confirmation of diagnosis
was made with ultrasound, in most cases, it was reduced due
to the high reliability of the method itself.
Statistical analysis
The goal was to calculate the prevalence rate per 10,000
live newborns. To determine the correlation between altitude
and the prevalence of CHD, the selected cities were first
categorized by altitude to obtain homogeneous samples
without significant variations between them. This was ac-
complished by using the hierarchical cluster and the centroid-
based clustering methods. Possible cluster solutions were
determined, and after defining the number of clusters, a K-
means analysis was carried out to obtain city clusters, as well
as their centers and means, based on altitude and the preva-
lence of CHD. Subsequently, Pearson’s correlation was used
to measure the strength of the relationship and determine
whether it was linear. Finally, correspondence analysis was
used to validate the categorization, the cluster centers or
means, and the correlation. Statistical significance was de-
termined if p-value <0.05. Using the means or centers of the
altitude clusters and the prevalence of CHD, clusters were
categorized as follows: altitude from 2500 to 2750 m, from
2751 to 3000 m, and from 3001 to 3264 m; prevalence of
CHD £71 cases per 10,000 live newborns, >71 and <89 cases
per 10,000 live newborns, and ‡89 cases per 10,000 live
newborns.
 HIGH ALTITUDE AS A CAUSE OF CHD 3

Results Table 3 gives the distribution of number of cases by

Table 1 shows the distribution of number of CHD cases per
year and prevalence rates from 2000 to 2017. The mean
prevalence rate of CHD found was 70.6 per 10,000 live
newborns. Table 2 gives the distribution of number of cases
in the highest cities and prevalence rates from 2008 to 2017.
Table 3 gives the distribution of number of cases by highest
prevalence rate and the average altitude of each city from
2008 to 2017.
Using K-means analysis, three clusters formed by the
following cities were identified:
Cluster 1: Latacunga, Guano, Suscal, San Fernando,
Salcedo, Déleg, Guaranda, Biblián, Bolı́var, Pelileo,
Cuenca, Otavalo, Saraguro, Azogues, Ambato, and
Sangolquı́.
Cluster 2: El Ángel, Huaca, El Tambo, Tulcán, Quero,
Pujilı́, Machachi, Saquisilı́, Cevallos, Tabacundo, San
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highest prevalence rate and average altitude of the city since
2008–2017. Table 4 gives the distribution of group parame-
ters and the correlation between variables.
Figure 1 shows the dendrogram where solutions with two or
three clusters are displayed, with three clusters being the
option that offers better discrimination between altitude and
the prevalence of CHD. Figure 2 shows the categorization
and correlation force through the correspondence analysis, for
which the variables of altitude and prevalence of CHD were
projected in the two-dimensional space. The results show that
an altitude ranging from 2500 m to 2750 m relates to the
prevalence of CHD in £71 cases per 10,000 live newborns. An
altitude ranging from 2751 to 3000 m relates to the prevalence
of CHD in >71 and <89 cases per 10,000 live newborns. An
altitude ranging from 3001 to 3264 m relates to the prevalence
of CHD in ‡89 cases per 10,000 live newborns.
In the analysis of the prevalence time series, it was ob-

Gabriel, Quito, Cayambe, Pı́llaro, and Riobamba. served that during the period from 2000 to 2017, the linear
Cluster 3: Mocha, Tisaleo, Cajabamba, Pucará, Cañar, relationship in the prevalence of CHD shows a p-value of
and Guamote. 0.000, where the correlation coefficient 0.914 shows that the
Cluster 1 was characterized by the lowest altitude and relationship has been direct. This means that the prevalence
prevalence of CHD; the average was 2619 m and 63.02 cases of CHD shows a tendency toward growth. In the linear re-
per 10,000 live newborns. Cluster 2 showed the second gression model, it was observed that, for each year elapsed,
highest altitude and prevalence of CHD, with an average of the prevalence of CHD increased by 3.33 cases per 10,000
2909 m and 72.04 cases per 10,000 live newborns. Cluster 3 live newborns, as shown in Figure 3. Figure 4 shows the
showed the highest values of altitude and prevalence of CHD, distribution map by provinces of CHD by diagnostic group.
with an average of 3176 m and 86.62 cases per 10,000 live Apparently, the prevalence of CHD in this study of 70.6
newborns (Tables 1 and 2). per 10,000 live births is lower than that of the general pop-
This categorization of cities based on altitude and the ulation, which is 80 per 10,000 live births. This could be
prevalence of CHD revealed a strong correlation between confusing. However, Table 3 gives 10 cities in which the
both variables. Pearson’s coefficient was 0.979, so the cor- prevalence is higher than the highest prevalence reported
relation between them is positive, meaning that as altitude worldwide, in Asia. You can also see five cities in which the
increased, so did the prevalence of CHD. This correlation was prevalence is higher than the average prevalence in the world.
not linear since the p-value was >0.05. This explains that the high altitude is significant in the ap-
pearance of CHD. Of course, more thorough studies are
Table 1. Distribution of Number of Cases needed to ratify this assertion.
of Congenital Heart Disease by Year It is not possible that some cases might have been missed,
and Prevalence Rate Since 2000–2017 leading to lower average prevalence because the database
collects all existing information. Ecuador is a relatively small
Year Cases LNB Rate · 10,000 country that facilitates the capture of information.
2000 1288 296,149 43.5
2001 1273 238,170 53.4 Discussion
2002 1534 275,300 55.7
2003 1281 262,004 48.9 The mean prevalence rate of CHD found was 70.6 per
2004 1251 254,362 49.2 10,000 live newborns. This value is similar to those of most
2005 1189 252,725 47.0 countries in the world. However, if a comparison is made
2006 1501 278,591 53.9 between the clusters previously described, as given in
2007 1559 283,984 54.9 Table 3, a strong correlation between altitude and prevalence
2008 1799 211,055 85.3 can be identified. Pearson’s coefficient was 0.979, so the
2009 1929 298,337 64.7 correlation between variables is positive. This means that as
2010 2311 292,375 79.1 altitude increases, so does the prevalence of CHD. This
2011 2502 301,106 83.2
2012 2453 297,309 82.5 correlation was not linear since the p-value was >0.05.
2013 2698 277,620 97.5 High altitude >2500 m, ethnicity (Native American), and
2014 2500 278,460 89.9 rural locations are factors that influence and increase the
2015 2677 283,313 94.5 prevalence rate of CHD. It is a fact that the highest prevalence
2016 2529 272,090 92.9 rate reported in developed countries is 125 per 10,000 live
2017 2611 288,123 90.6 newborns. In contrast, Ecuador reports higher prevalence
Total 34,885 4,941,073 70.6 rates between 128.5 and 497.9 cases per 10,000 live new-
borns. This is a significant difference that coincides with the
Rate calculated by 10,000 newborns.
LNB, live newborns. hypothesis that high altitudes could increase the prevalence
Data source: Institute of Statistics and Census (INEC). of CHD. Another important factor is that higher prevalence
Elaboration and analysis: author. rates are most frequent in rural areas. One can observe that
 4 GONZÁLEZ-ANDRADE

Table 2. Distribution of Number of Cases by Highest Cities and Prevalence Rate

of Congenital Heart Disease Since 2008–2017
Average altitude in masl City Canton Province Cases LNB Rate · 10,000
3264 Mocha Mocha Tungurahua 12 552 217.4
3245 Tisaleo Tisaleo Tungurahua 5 940 53.2
3200 Cajabamba Colta Chimborazo 4 2918 13.7
3160 Pucará Pucará Azuay 11 856 128.5
3125 Cañar Cañar Cañar 60 5830 102.9
3060 Guamote Guamote Chimborazo 14 6363 22.0
3007 El Ángel Espejo Carchi 5 1148 43.6
3000 Huaca San Pedro Carchi 1 746 13.4
2990 El Tambo Catamayo Cañar 7 1370 51.1
2980 Tulcán Tulcán Carchi 90 11,747 76.6
2960 Quero Quero Tungurahua 22 2078 105.9
2947 Pujilı́ Pujilı́ Cotopaxi 61 8991 67.8
2945 Machachi Mejia Pichincha 71 10,804 65.7
2920 Saquisilı́ Saquisilı́ Cotopaxi 11 4492 24.5
2892 Cevallos Cevallos Tungurahua 7 774 90.4
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2877 Tabacundo Pedro Moncayo Pichincha 39 4432 88.0

2870 San Gabriel Montúfar Carchi 11 3421 32.2
2864 Nabón Nabón Azuay 85 1707 497.9
2850 Quito Quito Pichincha 5628 330,896 170.1
2830 Cayambe Cayambe Pichincha 116 12,611 92.0
2800 Pı́llaro Santiago Tungurahua 35 4631 75.6
2764 Riobamba Riobamba Chimborazo 355 42,369 83.8
2750 Latacunga Latacunga Cotopaxi 297 27,077 109.7
2740 Guano Guano Chimborazo 14 5256 26.6
2720 Suscal Suscal Cañar 4 752 53.2
2690 San Fernando San Fernando Azuay 0 394 0.0
2683 Salcedo Salcedo Cotopaxi 36 8139 44.2
2675 Déleg Déleg Cañar 2 454 44.1
2668 Guaranda Guaranda Bolı́var 101 14,791 68.3
2620 Biblián Biblián Cañar 20 3201 62.5
2605 Bolı́var Bolı́var Carchi 8 24,488 3.3
2600 Pelileo San Pedro de Pelileo Tungurahua 30 8484 35.4
2550 Cuenca Cuenca Azuay 1063 85,671 124.1
2550 Otavalo Otavalo Imbabura 133 19,142 69.5
2530 Saraguro Sarguro Loja 26 4020 64.7
2518 Azogues Azogues Cañar 122 12,008 101.6
2500 Ambato Ambato Tungurahua 462 51,579 89.6
2500 Sangolquı́ Rumuñahui Pichincha 127 11,371 111.7
Rate calculated by 10,000 newborns.
masl, meters above sea level.
Data source: Institute of Statistics and Census (INEC).
Elaboration and analysis: author.

the prevalence rates are heterogeneous; the distribution by
altitude clusters shows the differences.
Although these findings remain a hypothesis, it is evident
that there is causality between CHD and high altitude. In
addition, access to health services is also heterogeneous, so
there would be a bias in larger cities where higher prevalence
rates are present due to the national health care referral sys-
tem. Despite this, the town of Nabón in the province of Azuay,
located at 2864 m, shows a prevalence of 497.9 per 10,000
live newborns. This rate is extremely high and could be ex-
plained by the fact that the local population has limited access
to health services and, therefore, the prevalence of CHD could
be due to lack of adequate prenatal control. However, high
altitude could also be the direct cause of this high prevalence.
This study includes all Ecuadorian cities >2500 m. The
towns of Nabón (15,121 inhabitants), Mocha (1209), Pucará
(1200), and Quero (11,544), which are small in terms of
number of inhabitants, show the highest prevalence of CHD.
They are semirural villages with the majority of the popula-
tion being Native American. This could also explain the
presence of an ancestral ethnic component as a causal factor.
It found increased prevalence of CHD in recent years com-
pared with early 2000s. This is explained by three reasons: (1)
increased access to health facilities, (2) increase in the number
of doctors specializing in pediatrics and pediatric cardiology,
(3) improvement of clinical diagnostic and ultrasound methods.
Unique environments characterize the places located at
high altitude; one such characteristic is low air compress-
ibility. Although the amount of oxygen remains constant,
20.93%, at both high and low altitudes, the number of gaseous
molecules per unit volume is greater at lower altitudes than at
higher altitudes. Therefore, barometric pressure, which de-
pends on the concentration of molecular air, has an inversely
proportional relationship with the altitude at which it is
measured. This particular pressure follows a nonlinear trend.
It is worth noting that adaptation to chronic hypoxia is
polygenic and implies the presence of several biological
pathways. In addition, geographically isolated populations
 HIGH ALTITUDE AS A CAUSE OF CHD 5

Table 3. Distribution of Number of Cases by Highest Prevalence Rate and Average Altitude
of the City Since 2008–2017
Average altitude in masl City Canton Province Cases LNB Rate · 10,000
2864 Nabón Nabón Azuay 85 1707 497.9
3264 Mocha Mocha Tungurahua 12 552 217.4
2850 Quito Quito Pichincha 5628 330,896 170.1
3160 Pucará Pucará Azuay 11 856 128.5
2550 Cuenca Cuenca Azuay 1063 85,671 124.1
2750 Latacunga Latacunga Cotopaxi 297 27,077 109.7
2500 Sangolquı́ Rumuñahui Pichincha 127 11,371 111.7
2960 Quero Quero Tungurahua 22 2078 105.9
3125 Cañar Cañar Cañar 60 5830 102.9
2518 Azogues Azogues Cañar 122 12,008 101.6
Highest prevalence reported worldwide (in Asia) 93.0
2830 Cayambe Cayambe Pichincha 116 12,611 92.0
2892 Cevallos Cevallos Tungurahua 7 774 90.4
2500 Ambato Ambato Tungurahua 462 51,579 89.6
2877 Tabacundo Pedro Moncayo Pichincha 39 4432 88.0
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2764 Riobamba Riobamba Chimborazo 355 42,369 83.8

2980 Tulcán Tulcán Carchi 90 11,747 76.6
2800 Pı́llaro Santiago Tungurahua 35 4631 75.6
Mean prevalence rate in Ecuador 34,885 4,941,073 70.6
2550 Otavalo Otavalo Imbabura 133 19,142 69.5
2668 Guaranda Guaranda Bolı́var 101 14,791 68.3
2947 Pujilı́ Pujilı́ Cotopaxi 61 8991 67.8
2945 Machachi Mejia Pichincha 71 10,804 65.7
2530 Saraguro Sarguro Loja 26 4020 64.7
2620 Biblián Biblián Cañar 20 3201 62.5
3245 Tisaleo Tisaleo Tungurahua 5 940 53.2
2720 Suscal Suscal Cañar 4 752 53.2
2990 El Tambo Catamayo Cañar 7 1370 51.1
2683 Salcedo Salcedo Cotopaxi 36 8139 44.2
2675 Déleg Déleg Cañar 2 454 44.1
3007 El Ángel Espejo Carchi 5 1148 43.6
2600 Pelileo San Pedro Tungurahua 30 8484 35.4
2870 San Gabriel Montúfar Carchi 11 3421 32.2
2740 Guano Guano Chimborazo 14 5256 26.6
2920 Saquisilı́ Saquisilı́ Cotopaxi 11 4492 24.5
3060 Guamote Guamote Chimborazo 14 6363 22.0
3200 Cajabamba Colta Chimborazo 4 2918 13.7
3000 Huaca San Pedro Carchi 1 746 13.4
2605 Bolı́var Bolı́var Carchi 8 24,488 3.3
2690 San Fernando San Fernando Azuay 0 394 0.0
Rate calculated by 10,000 newborns.
Data source: Institute of Statistics and Census (INEC).
Elaboration and analysis: author.

could have developed different physiological and genetic
adaptation mechanisms. An alternative strategy explores the
fact that adaptation to hypoxia in humans is relatively recent
(<1000 generations), with a strong natural selection, which
coincides with the arrival of populations to the South
American continent *14,000 years ago. The polymorphic
regions under selection have long haplotypes with low ge-
netic diversity. It has been described that >1000 genes are
potentially involved in chronic hypoxia due to high altitude.
The results show that an altitude ranging from 2500 to
2750 m relates to the prevalence of CHD in £71 cases per
10,000 live newborns. An altitude from 2751 to 3000 m is

Table 4. Distribution of the Parameters of the Groups and Correlation Between the Variables
Cluster
1 2 3
Variables Mean (SD) Mean (SD) Mean (SD) Pearson coefficient (r) p
a
Altitude (masl) 2619 (87) 2909 (87) 3176 (77) 0.979 0.132
Prevalence by 10,000 LNB 63.02 (37.40) 72.04 (38.28) 8962 (77.04)
a
Important Pearson correlation force.
SD, standard deviation.
Source: author.
 6 GONZÁLEZ-ANDRADE
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FIG. 1. Dendogram based on altitude and prevalence of CHD. Note: based on hierarchical cluster. CHD, congenital heart
disease. Source: author.

related to the prevalence of CHD in >71 and <89 cases per
10,000 live newborns, whereas an altitude from 3001 to
3264 m was related to the prevalence of CHD in ‡89 cases per
10,000 live newborns. In summary, the higher the altitude,
the higher the prevalence.
In the analysis of the prevalence time series, it is observed
that during the period from 2000 to 2017, the linear relation-
ship in the prevalence of CHD has a p-value of 0.000, wherein
the correlation coefficient 0.914 shows that the relationship
has been direct. This means that the prevalence of CHD has a
tendency toward growth. In the linear regression model, it is
observed that for each year elapsed, the prevalence of CHD
increased by 3.33 cases per 10,000 live newborns.
The most important and largest study performed in
Tibet populations >3000 m has shown that high altitude is a
significant environmental risk factor for CHD, especially
patent ductus arteriosus. Women showed high prevalence
in comparison with men. They found a prevalence of 52.1 per
10.000 in children students of both genders (Chun et al.,
2019). Another study showed a wide variation in CHD
 HIGH ALTITUDE AS A CAUSE OF CHD 7
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FIG. 2. Correspondence analysis based on altitude and prevalence of CHD. PCC, prevalence of CHD. Elaboration:
author.

prevalence and composition existed in Tibetan children
among different altitudes with no clear differences (Zheng
et al., 2013). However, the CHD prevalence and composition
differed significantly between populations of school children
living above and below 4200 m (Zheng et al., 2017). At al-
titudes of 3500–4100 m and 4548, children from 4200 to
4900 m were compared for CHD prevalence (120.9 vs. 43.2
per 10,000, p < 0.001), patent ductus arteriosus and atrial
septal defect were most frequent. The differences were more
remarkable in women, who had slightly and insignificantly
greater prevalence of total CHD, PDA, and ASD than men. In
summary, in Tibet a direct relationship between high altitude
>3000 m and CHD has been demonstrated, mostly in women,
the PDA being the most frequent pathology.
Functional experimentation is needed to answer chronic
adaptation questions associated with high-altitude exposure.
Greater knowledge regarding the identification of epige-
netic modifications is necessary to gain further insight into
the molecular mechanisms of adaptive changes in Andean
populations. Such knowledge is important to understand
biological traits and their genetic control on human patterns,
origins, and the evolutionary forces that maintain them.

FIG. 3. Time series of the prevalence of CHD during 2000–2017. *Significant correlation, based on the regression model.
Source: author.
 8 GONZÁLEZ-ANDRADE
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FIG. 4. Distribution map of the number of cases by highest cities and prevalence rate since 2008–2017.

Results specificities, it has national coverage. Targeted and well-

Limitations of the study
designed studies are required to confirm these results.

Unfortunately, the only existing database is the one

maintained by the INEC. This database only reports hospital
discharges from all over the country, which means that there
is a tendency toward patient selection. However, the database
is quite complete and, although it does not reflect some
Conclusions
High altitude >2500 m, ethnicity (Native American), rural
locations, and limited access to health care are factors
that influence and increase the prevalence rate of CHD.
 HIGH ALTITUDE AS A CAUSE OF CHD
A correlation coefficient of 0.914 shows the direct relation-
ship between high altitude and CHD prevalence rates. For
each year elapsed, the prevalence of CHD increased by 3.33
cases per 10,000 live newborns.
Availability of Data and Materials
The data supporting this article is available upon request to
the corresponding author.
Consent for Publication
Data from the INEC are available to the public. No consent
is required for its use.
Acknowledgments
The author thanks all the medical colleagues and hospital
professionals who in some way facilitated the development of
Downloaded by East Carolina University from www.liebertpub.com at 01/26/20. For personal use only.
this research.
Authors’ Contributions
The research protocol and its design, data collection, sta-
tistical analysis, evaluation and interpretation of the data,
critical analysis, discussion, writing, and approval of the final
article were all carried out by the author.
Author Disclosure Statement
The author reports no conflict of interest.
Funding Information
The author declares that the financial resources for the
elaboration of this investigation do not come from any ex-
ternal funds. This research was self-funded.
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Address correspondence to:
Fabricio González-Andrade, MD, PhD
Unidad de Medicina Traslacional
Facultad de Ciencias Médicas
Universidad Central del Ecuador
Iquique N14-121 y Sodiro-Itchimbı́a, Sector El Dorado
170403 Quito
Ecuador
E-mail: fabriciogonzaleza@gmail.com
Received October 2, 2019;
accepted in final form December 2, 2019.