Vol.1, No.1, 4-10 (2013) Occupational Diseases and Environmental Medicine
http://dx.doi.org/10.4236/odem.2013.11002
Relationship between acute high altitude
response, cardiac function injury, and
high altitude de-adaptation response
after returning to lower altitude*
Shengyue Yang1, Qiquan Zhou2,3#, Zifu Shi4, Enzhi Feng1, Ziqiang Yan1,
Zhongxin Tian1, He Yin1, Yong Fan2,3
1Center of Respiratory Medicine, The 4th Hospital, Lanzhou Command, PLA, Xining, China
2Department of High Altitude Diseases, College of High Altitude Military Medicine, Third Military Medical University, Chongqing,
China; #Corresponding Author:
3Key Laboratory of High Altitude Medicine of Ministry of Education and Key Laboratory of High Altitude Medicine of PLA,
Chongqing, China
4The 68303 Troop Hospital of People’s Liberation Army, Wuwei, China
Received 20 September 2013; revised 25 October 2013; accepted 8 November 2013
Copyright © 2013 Shengyue Yang et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In accor-
dance of the Creative Commons Attribution License all Copyrights © 2013 are reserved for SCIRP and the owner of the intellectual
property Shengyue Yang et al. All Copyright © 2013 are guarded by law and by SCIRP as a guardian.
ABSTRACT
The relationship between acute high altitude
response (AHAR), cardiac function injury, and
high altitude de-adaptation response (HADAR)
was assessed. Cardiac function indicators were
assessed for 96 men (18 - 35 years old) dep-
loyed into a high altitude (3700 - 4800 m) envi-
ronment requiring intense physical activity. The
subjects were divided into 3 groups based on
AHAR at high altitude: severe AHAR (n = 24),
mild to moderate AHAR (Group B, n = 47) and
non-AHAR (Group C, 25); and based on HADAR:
severe HADAR (Group E, n = 19), mild to mod-
erate HADAR (Group F, n = 40) and non-HADAR
(Group G, n = 37) after return to lower altitude
(1,500 m). Cardiac function indicators were
measured after 50 days at high altitude and at 12
h, 15 days, and 30 days after return to lower al-
titude. Controls were 50 healthy volunteers
(Group D, n = 50) at 1500 m. Significant differ-
ences were observed in cardiac function indi-
cators among groups A, B, C, and D. AHAR
score was positively correlated with HADAR
score (r = 0.863, P < 0.001). Significant differ-
ences were also observed in cardiac function
indicators among groups D, E, F, and G, 12 h and
15 days after return to lower altitude. There were
no significant differences in cardiac function
indicators among the groups, 30 days after re-
turn to lower altitude, compared to group D. The
results indicated that the severity of HADAR is
associated with the severity of AHAR and car-
diac injury, and prolonged recovery.
Keywords: Acute High Altitude Response; Ca rdiac
Function; Cardiac Structure; Myocardial Enzyme;
Return to Lower Altitude; High Altitude
De-Adaptation
1. INTRODUCTION
People sometimes live in high-altitude, hypoxic envi-
ronments and this requires the body to make a complex
series of compensatory changes in neurohumoral regula-
tion, involving physiological, biochemical, and morpho-
logical changes to achieve a balance between the internal
and external environment. When an individual returns to
the normal oxygen environment, the body undergoes a
series of corresponding changes resulting in the gradual
elimination of the adaptive changes previously made.
Many people undergoing this process experience symp-
toms such as dizziness, palpitations, chest tightness,
drowsiness, precordial region pain, general fatigue, and
weakness. This response is termed a high altitude
*The authors declare that no conflicts of interest exist.

S. Y. Yang et al. / Occupational Diseases and Environmental Medicine 1 (2013) 4- 10 5
de-adaptation the response, HADAR [1-5]. In severe
cases, these symptoms can seriously affect the individ-
ual’s work and life; due to the severity, some people
have had to return to the high-altitude environment.
HADAR is a problem of great concern and research.
Following the 2010 earthquake in Yushu, Qinghai
Province, China, 96 young soldiers were rapidly de-
ployed from a low altitude environment to a plateau area
(elevation 3700 - 4800 m) where they engaged in heavy
physical labor for 50 days, before returning to their orig-
inal station (elevation 1500 m). This study was con-
ducted to examine cardiac function, structure, and car-
diac enzyme levels as part of an investigation into acute
mountain sickness (acute high-altitude response; AHAR)
as well as their symptoms at 12 h, 15 d, and 30 d after
their return to low altitude (HADAR response symp-
toms). This report describes the observed relationship
among the severity of HADAR, AHAR, and heart dam-
age.
2. SUBJECTS AND METHODS
2.1. Subjects
Following the Yushu earthquake, 96 male soldiers (18
- 35 years old; mean age 21.8 ± 3.6 years) were deployed
to a high-altitude environment (3700 - 4800 m) to engage
in heavy, manual labor. These men were the subjects of
observations made once they reached the plateau and
began participating in rescue operations (loading and
unloading goods, cleaning up debris, etc.) involving
heavy, physical labor for 10 h per day, every day. Fol-
lowing their high-altitude stay of 50 d and at 12 h, 15 d,
and 30 d after their return to their normal altitude envi-
ronment (1500 m), their cardiac structure, function, and
cardiac drive were examined. A control group (Group D)
consisted of 50 soldiers who remained at the 1500 m
altitude and engaged in a similar intensity of work. This
control men, aged 19 - 20 years old (mean age, 22.7 ±
3.2 years) were similar in age, physical condition, work
intensity to the group deployed to the plateau.
Based on AHAR symptom scores, the high-altitude
group was divided into a severe AHAR group (Group A,
n = 24), a mild to moderate group (Group B, n = 47), and
a asymptomatic group (Group C, n = 25). Upon their
return to the lower elevation, these same individuals
were divided into another 3 groups depending on the
severity of their HADAR symptoms: severe group
(Group E, n = 19), mild to moderate group (Group F, n =
40), and asymptomatic group (Group G, n = 37). The
study was approved by the Third Military Medical Uni-
versity medical ethics committee and the 68303 forces
ethics committee; all subjects voluntarily participated in
the observational part of the study and provided signed
informed consent.
2.2. Methods
2.2.1. AHAR Determination
During the high-altitude observation, the subjects were
observed daily by a physician and received an AHAR
score, based on our AHAR symptom scoring system
[3,6]. The subjects receiving a total of 1 - 4 points were
normal, 5 - 10 points were considered mildly sympto-
matic, 11 - 15 points were moderately symptomatic, and
>16 points were considered severe. As a result of the
scoring, 96 subjects were symptomatic for AHAR; 24
subjects were classified as severe (25.0%, Group A), 47
subjects were mild to moderate (49.0%, Group B).
AHAR symptoms were not seen in 25 subjects (26.0%,
Group C). To facilitate statistical analysis, subjects with
mild or moderate AHAR symptoms were combined into
one group (Figure 1).
2.2.2. HADAR De t er mination
Upon their return to low altitude, the Health Survey
week congruent was used to score the HADAR symp-
toms among the test subjects (19). If the total number of
points was ≤5, the subjects were considered normal, 6 -
15 points were considered to be indicative of a mild re-
action, 16 - 25 points were a moderate response, and ≥26
points indicated a severe reaction. According to the
HADAR scoring results, 59 (61.5%) subjects were ob-
served to have symptoms; 19 subjects were severe (Group
E), and 40 subjects were mild to moderate (Group F).
HADAR was not observed in 37 subjects (Group G)
(Figure 1).
Figure 1. Comparisons of right cardiac structure, function, and
mean pulmonary artery pressure among individuals at 3700 m.
mPAP: mean pulmonary arterial pressure; RVID: Right ven-
tricular internal dimension; RVOT: Outflow tract of right ven-
tricle; LVID: Left ventricular internal dimension. ※※P < 0.01
vs Group D; ##P < 0.01 vs Group C; △△P < 0.01, vs Group B.

S. Y. Yang et al. / Occupational Diseases and Environmental Medicine 1 (2013) 4- 10
6
2.2.3. Cardiac Structure and Function
Determination
Color Doppler ultrasound (LOGIQ-type, GE Health-
care, Little Chalfont, UK) was used to detect the average
pulmonary artery pressure (mPAP), right ventricular di-
ameter (RVID), right ventricular outflow tract (RVOT),
left ventricular diameter (LVID), left ventricular ejection
fraction (LVEF), and myocardial performance index (Tei
index). Inspections were made with the subject in the left
lateral position, with measurement taken over a 1-h pe-
riod with the subject in a resting state. The pulsed Dop-
pler sample volume involved the measurement of the
steady-state heart rate, the spectrum of the mitral and
aortic blood flow, and the measurement of the peak A
mitral valve flow between the end of the next cardiac
cycle E peak time period (a line), and the aortic ejection
time (b line). The Tei index is calculated according to the
formula: Tei index = (ab/b). Simpson’s method was used
to calculate each subject’s LVEF [7]. mPAP measure-
ments involved the determination of right ventricular
ejection early time (RVPEP) and pulmonary blood flow
acceleration time (AT), and was calculated according to
the equation: mPAP (mmHg) = 42.1 (RVPEP/AT) - 15.7
[8,9]. RVID, RVOT, and LVID were measured accord-
ing to established methods.
2.2.4. Determination of Cardiac Enzyme Levels
A 3 ml, early morning, fasting blood sample was ob-
tained, allowed to clot, and centrifuged at 4˚C for 10 min
(3500 rpm, centrifugal radius = 15 cm). The resulting
serum was collected and frozen at −20˚C, until analyzed.
The rate method was used to determine the concentra-
tions of serum creatine kinase isoenzyme-MB (CK-MB)
and lactate dehydrogenase isoenzyme-1 (LDH-1). Meas-
urements were made using a kit purchased from Lanzhou
Biochem Bio (lanzhou, China), in strict accordance with
the manufacturer’s instructions. An automatic biochemi-
cal analyzer (BS-400 type; Mindray Medical Instrumen-
tation, Shenzhen, China) was used to take the measure-
ments.
2.3. Statistical Analysis
SPSS 17.0 software (IBM, Armonk, NY, USA) was
used for statistical analyses. Homogeneity of variance
among the groups was determined by single factor anal-
ysis of variance and Tamhane variance analysis when
heterogeneity of variance was observed. Differ- ences
between 2 groups were compared using Student’s t-test,
and the results obtained at different times, within each
group, were compared using a paired t-test. Corre- lation
analysis was performed using the Pearson’s linear corre-
lation analysis. P < 0.05 was considered statistically sig-
nificant.
3. RESULTS
3.1. Cardiac Structure, Function, and
Myocardial Enzymes in Each Group
The mPAP, RVID, RVOT, RVID/LVID ratio, Tei in-
dex, CK-MB level, and LDH-1 level were significantly
higher in severe AHAR group than in mild to moderate
AHAR group, asymptomatic group or control group
(Figure 2). No significant differences were evident in the
LVID values (Figure 1).
LVEF was significantly lower among severe AHAR
group individuals than among those in mild to moderate
AHAR group, asymptomatic group or control group.
There was also a significant difference between mild to
moderate AHAR group and asymptomatic group and
control group; asymptomatic group was also signifi-
cantly different from control group (P < 0.01) (Figure 2).
3.2. Relationship between AHAR with
HADAR
Among the 96 subjects observed, 59 demonstrated
HADAR symptoms upon returning to the lower altitude.
Among the 24 subjects with severe AHAR, 18 experi-
enced severe HADAR (75.0%), 5 (20.8%) experienced
light to moderate HADAR, and 1 (4.2%) did not experi-
ence HADAR symptoms. Of the 47 subjects who suffer-
ing from mild to moderate AHAR, 1 (2.1%) experienced
severe HADAR symptoms, 32 (68.1%) experienced mild
to moderate HADAR, and 14 (29.8%) did not experience
HADAR. Of the 25 subjects not suffering from AHAR,
the HADAR was mild to moderate in 3 individuals and
did not occur in 22 (88.0%) subjects. A linear correlation
analysis revealed that the total AHAR points and the
Figure 2. Comparisons of Tei index, left cardiac function, and
cardiac muscle enzyme levels among groups at 3700 m. LVEF:
Left ventricular ejection fraction; Tei index: Cardiac muscle
work index; CK-MB: Creatine kinase isoenzyme-MB; LDH-
1:Lactic dehydrogenase isoenzyme-1; Group A scores ≥ 16;
Group B scores 5 - 15; Group C scores ≤ 4; Group D, normal
controls at an altitude of 1500 m. ※※P < 0.01 vs Group D; ##P
< 0.01 vs Group C; △△P < 0.01, vs Group B.

S. Y. Yang et al. / Occupational Diseases and Environmental Medicine 1 (2013) 4- 10 7
total HADAR points exhibited a significant positive cor-
relation (r = 0.863, P < 0.001).
3.3. Relationship between HADAR Severity
and Cardiac Structure, Function, and
Cardiac Enzyme Levels after Returning
to a Lower Altitude
Upon returning to a lower altitude for 12 h, Group E
individuals demonstrated mPAP, RVID, RVOT, RVID/
LVID ratio, Tei index, CK-MB levels, and LDH-1 levels
that were significantly higher than those for subjects in
mild to moderate Group, asymptomatic group, and con-
trol group. LVEF was significantly lower in severe
HADAR Group individuals than in individuals from mild
to moderate HADAR Group, asymptomatic group, and
control group; mild to moderate Group, asymptomatic
group, and control group also demonstrated significant
differences (P < 0.01). There were no significant differ-
ences in LVID between the groups (Figure 3).
After 15 d at low altitude, severe HADAR Group
mPAP, RVID, RVOT, and RVID/LVID ratios were sig-
nificantly higher than in mild to moderate HADAR
Group, asymp- tomatic group, and control group (P <
0.05); there was also a significant difference between
mild to moderate HADAR Group individuals and those
in asymptomatic group and control group (P < 0.05), but
not between as- ymptomatic group and control group.
The LVEF, Tei index, CK-MB levels, and LDH-1 levels
in each group did not demonstrate a significant differ-
ence (P > 0.05). All data are shown in Figure 4.
After returning to a lower altitude for 30 days, there
were no significant differences among the indicators for
Figure 3. Relationship between HADAR, cardiac structure,
function, and mean pulmonary artery pressures 12 h after re-
turning to 1500 m. mPAP: Mean pulmonary arterial pressure;
RVID: Right ventricular internal dimension; RVOT: Outflow
tract of right ventricle; LVID: Left ventricular internal dimen-
sion; LVEF: Left ventricular ejection fraction; Tei index: Car-
diac muscle work index; CK-MB: Creatine kinase isoenzyme-
MB; LDH-1: Lactic dehydrogenase isoenzyme-1; Group E
scores ≥ 26; Group F scores 6 - 25; Group G scores ≤ 5; Group
D, normal controls at an altitude of 1500 m. ※※P < 0.01 vs
Group D; ##P < 0.01 vs Group G; △△P < 0.01, vs Group F.
any of the groups (Figure 5).
The diameter of pulmonary artery and the right ven-
tricular outflow tract in the plateau at fiftieth days was
significantly larger than the diameter of pulmonary artery
and the right ventricular outflow tract in 30 days after
returned to lower altitude, furthermore, compared with
50 days the exposure to high altitude, the diameter of
right ventricular outflow tract was significantly larger
than the diameter of pulmonary artery in 30 days after
returned to lower altitude, suggesting that the right ven-
tricular recovery than pulmonary artery slower recovery
(Figure 6).
4. DISCUSSION
The results of this study showed that the right ven-
tricular function, structure, myocardial enzyme level
were significantly increased in the subjects with severe
AHAR. In contrast, the left ventricular function was sig-
nificantly lower. The responses of the human body to the
high-altitude hypoxic environment and heavy physical
work included more severe AHAR, pulmonary hyperten-
sion, changes in the right ventricle, reduced cardiac func-
tion and myocardial damage; but the changes in the left
ventricular structure were less obvious. The reason may
be that people engaged in heavy labor, in high-altitude,
hypoxic environments, require a substantial increase in
oxygen consumption. Therefore, when the body is ex-
posed to a hypoxic environment, the hypoxia causes
pulmonary vasoconstriction, pulmonary hypertension,
and right ventricular load increase, leading to right ven-
tricular enlargement. The AHAR severity, mPAP level,
Figure 4. Relationship between HADAR, cardiac structure,
function, and mean pulmonary artery pressure 15 d after re-
turning to 1500 m. mPAP: Mean pulmonary arterial pressure;
RVID: Right ventricular internal dimension; RVOT: Outflow
tract of right ventricle; LVID: Left ventricular internal dimen-
sion. LVEF: Left ventricular ejection fraction; Tei index: Car-
diac muscle work index; CK-MB: Creatine kinase isoenzyme-
MB; LDH-1: Lactic dehydrogenase isoenzyme-1; Group E
scores ≥ 26; Group F scores 6 - 25; Group G scores ≤ 5; Group
D, normal controls at an altitude of 1500 m. ※※P < 0.01 vs
Group D; ##P < 0.01 vs Group G; △△P < 0.01, vs Group F.

S. Y. Yang et al. / Occupational Diseases and Environmental Medicine 1 (2013) 4- 10
8
Figure 5. Relationship between HADAR and right cardiac
structure, function, and mean pulmonary artery pressure 30 d
after returning to 1500 m. mPAP: Mean pulmonary arterial
pressure; RVID: Right ventricular internal dimension; RVOT:
Outflow tract of right ventricle; LVID: Left ventricular internal
di- mension; Group E scores ≥ 26; Group F scores 6 - 25;
Group G scores ≤ 5; Group D, normal controls at an altitude of
1500 m.
and right ventricular size may be related to differences in
individual tolerances and responses to hypoxia. In people
with poor hypoxia tolerance, hypoxic mitochondrial ATP
synthesis impairment in myocardial cells may result in a
reduced myocardial energy supply, leading to obvious,
severe symptoms. When hypoxia tolerance is relatively
good, the inhibition of mitochondrial ATP synthesis is
relatively mild, resulting in relatively mild heart damage
and other symptoms [10-13]. For individuals who do not
demonstrate AHAR, only sub-clinical effects on cardiac
structure and function may occur.
The results of this study also show that the total
AHAR and HADAR points showed a significant positive
correlation. Upon returning to the lower altitude, subjects
in the severe HADAR group demonstrated mPAP, RVID,
RVOT, RVID/LVID ratio, Tei index, CK-MB level, and
LDH-1 level results that were significantly higher than
among those in the other groups; LVEF was significantly
lower than in the other groups. Among subjects in the
mild to moderate HADAR group there were also similar
differences between these individuals and those in the
asymptomatic and control groups. After returning to a
lower elevation for 15 d, individuals in the severe HA-
DAR group continued to demonstrate mPAP, RVID,
RVOT, and RVID/LVID ratio results that were signifi-
cantly higher than those in the mild to moderate HADAR
group, the asymptomatic HADAR group, or the control
group. Subjects in the mild to moderate HADAR group
also demonstrated significant differences in these pa-
rameters as compared with subjects in the asymptomatic
HADAR group or in the control group. However, there
were no differences between the HADAR group and the
control group. The LVEF, Tei index, CK-MB level, and
LDH-1 level values were restored to the values observed
(a) (b)
(c) (d)
Figure 6. Pulmonary artery diameter and right ventricular out-
flow tract diameter return to lower altitude 30 days. (a)
Pulmonary artery diameter up to 34 mm expsure 50 days under
high altitude expansion environment; (b) Pulmonary artery
diameter is 19 mm return to lower altitude 30 days; (c) Right
ventricular outflow tract diameter up to 40 mm exposure 50
days under high altitude environment; (d) Right ventricular
outflow tract diameter is 40 mm return to lower altitude 30
days.
in the control group level after being at the low altitude
for 30 days,
The HADAR and AHAR severities were correlated
with the degree of heart damage in these subjects. Those
experiencing more severe AHAR while at the elevated
elevation and having more significant HADAR symptoms
upon their return to the low altitude experienced more
severe structural damage to the right side of their hearts
and a slower recovery time. After a period of adaptation
to high-altitude, hypoxic environments, the return to low-
altitude environments results in hypoxia-reoxygenation
injuries. The mechanism may involve the following
components. 1) Energy metabolism: enhanced myocar-
dial tissue hypoxia results in anaerobic glycolysis and
decreased ATP generation, resulting in a decrease in
cellular energy supply. Hypoxic damage to the mito-
chondria may result in the mitochondria not being effec-
tive when aerobic conditions are restored to the myocar-
dial cells [9]. 2) Reactive oxygen species generation:
oxygen free radicals (OFR) involved in clearing tissue
hypoxia may result in the generation of reactive oxygen
species; restoration of oxygen may result in the genera-
tion of a large number of OFR in the membranes of
myocardial cells, resulting in the formation of lipid per-
oxides that react with intracellular proteins and nucleic
acids. These peroxides may cause structural and func-

S. Y. Yang et al. / Occupational Diseases and Environmental Medicine 1 (2013) 4- 10 9
tional changes to cells, leading to myocardial cell dam-
age [14]. Zhang K, et al. [15] study confirmed, with en-
hanced of myocardial injuries, the increased levels of
Malondialdehyde (MDA), lactate dehydrogenase (LDH)
and interleukin 6 (IL-6), the LOB (Chrysoeriol7-O-
[-D-glucuronopyran-osyl-(1 → 2)-O–D-glucuronopy-
ranoside]) can decreased plasma levels of MDA, LDH,
IL-6, suggesting that the LOB could be a potential the-
rapeutic agent for myocardial ischemia/reperfusion (I/R)
injury and hypoxia/reoxygenation (H/R) injury. 3) Cal-
cium overload: anaerobic glycolysis may enhance myo-
cardial hypoxia, causing intracellular acidosis. As the
extracellular pH gradually returns to normal after the
restoration of normal oxygenation, intracellular and ex-
tracellular formation of transmembrane pH gradients
may result in enhanced sodium and hydrogen exchange,
increasing the intracellular Na concentration. Since the
cells generate less ATP after reoxygenation, the cell
membrane and sarcoplasmic reticulum calcium and so-
dium pump functions may be reduced, leading to intra-
cellular calcium overload. The increase in the intracellu-
lar calcium concentration can further activate endothelial
cells, promoting OFR generation, and leading to further
damage [16,17]. But Li Q [18] study shows that endocan-
nabinoids can suppresses calcium overload through inhi-
bition of INCX during perfusion with simulated ischemic
solution; the effects may be mediated by CB2 receptor
via PTX-sensitive Gi/o proteins. 4) High altitude hypoxia
stress induced myocardial injury, restore oxygen after
myocardial injury has not been fully restored, or restore
later than other functions. Hu J, et al. [19] study show
that simple plateau hypoxia exposure endothelin (ET)-1
α concentrations gradually increased whereas HIF-1 ex-
pression in myocardial cells was significantly higher (P <
0.01). There was low pressure hypoxia exposure after
myocardial mitochondria numbers were reduced during
the initial phase of acute stress response to hypoxia and
cellular injury but, later, mitochondrial numbers were
restored to normal values. Plasma VEGF concentrations
increased under exposure group hypoxia in low pressure
hypoxia exposure, which were significantly higher than
those of control group. Therefore Hu concluded that
high-altitude hypoxia exposure: a) induced HIF-1 α ex-
pression; b) prompted adaptation/acclimatization after
initial stress and cellular injury; and c) enhanced VEGF
expression. The mechanism of HADAR and hypoxia-
reoxygenation injury on the body is extremely complex
and requires further in-depth studies in order to more
fully elucidate them.
5. ACKNOWLEDGEMENTS
The authors thank the personnel from the 68303 Infantry brigade and
68303 Troop Hospital of the People’s Liberation Army for their assis-
tance in this study. This work was funded by the National Science and
Technology Ministry (Grant#2009BAI85B03) and Army Health Sub-
ject (Grant# 2013BJZ032).
6. AUTHOR CONTRIBUTIONS
Conceived and designed the experiments: Shengyue
Yang, Qiquan Zhou; Performed the experiments: Enzhi
Feng, Ziqiang Yan, Zhongxin Tian, He Yin, Zifu Shi;
Analyzed the data: Shengyue Yang; Contributed reagents/
materials/analysis tools: Zifu Shi; Wrote the manuscript:
Shengyue Yang, Qiquan Zhou; English translation: Yong
Fan.
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