CHAPTER I

INTRODUCTION

1.1 Background
More than 140 million people worldwide live >2500 m above sea level. 80 million
of them live in Asia, and 35 million live in the Andean mountains. This latter
region has its major population density living above 3500 m. Both the high
altitude physiologist and the intensivist are challenged by the human organism in
a hypoxic environment and the true research potentials presented by high altitude,
where the body is subjected to an essentially isolated hypoxic challenge, are only
just beginning to be realised. 1, 2
The heart and pulmonary circulation in healthy highlanders have distinct features
in comparison with residents at sea level. people native to high altitude (HA)
environments live in an environment of hypobaric hypoxia with low ambient
partial pressure of oxygen. As a consequence, they develop alveolar hypoxia,
hypoxemia, and polycythemia. Despite this, healthy highlanders are able to
perform physical activities similar to and often even more strenuous than those of
people living at sea level (SL). This phenomenon has been ascribed to adaptive
mechanisms that occur at sequential steps of the oxygen transport system with the
main purpose of decreasing the total pO2 gradient from ambient hypoxic air to
mixed venous blood at the tissue level. 1,2
All of these latter consequence may happens because of the difference of the
atmospheric pressure at high altitude and sea level. Native highlanders show
larger lung capacities than do their lowland counterparts in a manner that
transcends genetic background. There are several obstacle in the environtmentmitochondria route of oxygen-called oxygen cascade-which makes the oxygen
that we inspired will not be fully administered to mitochondria. And this
phenomenon is exagerated in high altitude environtment which has

lower

atmospheric pressure than at sea level- The most graphic example of this is

ascension to altitude. At 19,000 feet (just above base camp at Mount Everest, the
barometric pressure is half that at sea level, and thus, even though the FiO2 is
21%, the PIO2 is only 70mmHg, half that at sea level. 3
The knowledge of physiology oh high altitude is important especially for they as
natives of this kind of environtment and so it is important to assess this issue.
1.2 Problem Identification
Based on the background above, the author finds several problems as follow:
1.2.1 How is the cardiovascular and respiratory system adaptation on high altitude
residents?
1.2.2 What is the effect of the adaptation on their physical fitness?
1.3 Objective
Based on problems above there are several objectives as follows:
1.3.1 To know the cardiovascular and respiratory system efficiency of people
living on high altitude environtment.
1.3.2 To know how this affect their physical performance on daily activities.
1.4 Benefit
Some of benefits in writting this synthesis are as follows:
To give information about how high altitude environtment is different with
environtment at sea level and how this affect human physiology and how they
adapt to this kind of ennvirontment, especially for people native to high altitude
environtment. This information might be useful for athletes to improve their
physical performance by considering to train in such environtment.

CHAPTER II
LITERATUR REVIEW

2.1 Oxygen Cascade transfer of oxygen

Aerobic organisms maintain O2 homeostasis by responding to changes in O2
supply and demand in both short and long time domains. The effective transfer of
O2 from the environment to mitochondria is critical for aerobic organisms. Thus,
rapid changes in O2 supply or demand, as might accompany brief exposures to
environmental hypoxia or arise from exercise, are typically met with acute
cardiorespiratory reflexes that maintain tissue O2 homeostasis.3
To know better about the respiratory adaptative response of body towards high
altitude environtment we should know how this process of oxygen intake occurs
normally.
Dry air at sea level where the barometric pressure is 1 atmosphere (101.325kPa)
contains 20.95% oxygen. Thus the partial pressure of oxygen is an estimated (0.21
x 100kPa) = 21kPa.
When air is inspired it is humidified and thus the partial pressure of oxygen is
reduced by the water vapour content (6.3kPa). Thus the inspired partial pressure
of oxygen is an estimated (0.21 x (100kPa 6.3kPa)) = 19.8kPa.
At the alveolus, the oxygen is mixed with carbon dioxide. The ratio of the amount
of carbon dioxide produced to oxygen consumed is determined by the respiratory
quotient (RQ), which
Thus the alveolar partial pressure of oxygen is an estimated (19.8 5/0.8) =
13.6kPa.
Gas exchange occurs at the alveolar-capillary interface with oxygen (and carbon
dioxide) moving across this very thin membrane (typically 0.5 micrometres thick)
by diffusion down its partial pressure gradient. The total area available for gas
exchange is a huge 50-100m2 as a result of the vast number of alveoli in the
normal lung (typically 300 million): the resistance to gas diffusion between the
gas and blood phases is consequently very low. Oxygenated blood from the

pulmonary circulation is mixed with a small amount of blood in the arterial

system that will have bypassed oxygenated alveoli. This is known as venous
admixture or physiological shunt and consists of blood from the bronchial
circulation, Thebesian vessels (cardiac veins draining directly into the cardiac
cavities) and blood that has passed areas of poor ventilation.
The reference value for the partial pressure of oxygen in arterial blood (PaO2) is
10.3kPa to 13.3kPa. Beyond childhood, there is a progressive reduction with
increasing age [4]. At tissue level oxygen diffuses from capillary blood and
ultimately reaches the mitochondria within the cells where cellular respiration
occurs. At this point the partial pressure of oxygen is 1 5kPa. The mitochondrion
will continue to respire aerobically until the partial pressure of oxygen falls below
the Pasteur Point. This is thought to be 0.15-0.3kPa [5]. Inspired air is then
warmed and saturated with water vapour in the upper airways
Figure 1 illustrates the cascading partial pressure of oxygen through the
respiratory system. The ranges for partial pressures are shown for arterial blood
and the mitochondrion. Artery on Everest shows the average value for the partial
pressure of oxygen in the arterial blood of 4 climbers at 8,400m on their descent
from the summit of Mt. Everest. An oxygen partial pressure of < 8kPa is accepted
as the threshold for respiratory failure.4

Figure 1. Oxygen cascade on normal person

2.2.2 Peripheral tissue changes

Despite the importance of this final step in the delivery ofoxygen to the
mitochondria, relatively little is knownabout the adaptive changes which take
place in the peripheral tissues at altitude. Capillary density in muscle is
unchanged, although the average diameter of muscle fibres appears to be
reduced.2 Possible advantage of this change would be to reduce the distance that
oxygen
has to diffuse from the capillaries to the mitochondria. Muscle myoglobin appears
to be increased at altitude improving oxygen diffusion through muscle cells. 2 This,
perhaps, acting as an oxygen reservoir during periods of profound cellular
hypoxia.

2.2 Effect of high altitude exposure to normal cardiovascular system

The role of the cardiovascular system is simple; to drive the delivery of oxygen to
the tissues need it and carry away the metabolic effluent. It needs to respond to the
changing metabolic needs of the tissues in such a way that oxygen delivery meets
demand. How it does this is complex, even more so at altitude, where the reduced
barometric pressure-compared with one at the sea level- and therefore partial
pressure of oxygen, cause further stress on the body.4
2.2.1 Circulation
The major effects of acute hypoxia on the heart and lung are shown in Figure 3.
Hypoxia directly affects the vascular tone of the pulmonary and systemic
resistance vessels and increases ventilation and sympathetic activity via
stimulation of the peripheral chemoreceptors. Interactions occur between the
direct effects of hypoxia on blood vessels and the chemoreceptor-mediated
responses in the systemic and pulmonary circulation.5

Figure 2. Effect of hypoxia towards the cardio-pulmonary system

The heart and pulmonary circulation in healthy people living at HA exhibit
important physiological and anatomic characteristics, which resemble those that
occur in chronic clinical conditions associated with alveolar hypoxia, hypoxemia,
and polycythemia. Healthy HA natives have pulmonary hypertension (PH), right
ventricular hypertrophy (RVH) and increased amount of smooth muscle cells
(SMCs) in the distal pulmonary arterial branches. All these findings become
exaggerated when healthy highlanders lose their capacity for adaptation and
develop chronic mountain sickness (CMS).2
Several mechanisms appear to regulate local oxygen delivery according to the
needs of the tissues; for instance, the release of ATP from red blood cells and the
generation of NO by various ways appear to regulate local oxygen delivery
according to the needs of the tissue. These mechanisms may decrease with
prolonged stay at high altitude when oxygen content of the blood increases
because of ventilatory acclimatization, an increase in hematocrit associated with
plasma volume reduction, and an increase in red blood cell mass due to
erythropoiesis.5

2.2.2 Heart

The consequences of acute hypoxia are an increase in heart rate (both at rest and
on exercise), myocardial contractility, and cardiac output for the first few days.
The higher the altitude, then the greater the increase in heart rate. With
acclimatization, cardiac output falls at rest and on exercise in association with a
decrease in left ventricular work but an increase in right ventricular work. On
exercise however, even in acclimatised subjects, heart rate for a given work load
is greater than at sea level except at maximal exercise where maximal heart rate is
reduced compared to sea level values.5,6 This may be due to decreasing maximal
oxygen (VO2max) consumption we can get at high altitude environtment.
2.2.2.1 Myocardial Contractility and Coronary Circulation
The findings suggest that in spite of the severe hypoxaemia, pulmonary
hypertension and reduction in preload, cardiac contractility is maintained even at a
simulated altitude of 8000m.2
Permanent residents at high altitude have a reduced coronary blood flow
compared to sea level residents because of the increased oxygen of arterial content
after by a process of acclimatization. And yet there appears to be no increase in
incidence of myocardial ischaemia. One explanation is that there is a greater
density of coronary artery terminal branches in these residents compared to sea
level control.6
2.2.2.2 Stroke Volume

Both cardiac output and heart rate rise acutely with exposure to hypoxia and there
is no consistent change to stroke volume. Once acclimatized a subjects cardiac
output during exercise returns towards sea level values whereas heart rate
continues to be elevated. Thus stroke volume must be reduced and this has been
confirmed in several studies.1 This is not due to a loss of myocardial contractility
but perhaps due to a reduction in plasma volume and therefore preload or a
reduction in cardiac filling time secondary to the increased heart rate.

2.2.2.3 Blood Pressure

Blood pressure changes little with acute exposure to altitude; however there is
usually an increase for the first few weeks when lowlanders travel to altitude. This
is probably due to an increase in the sympathetic drive and vascular tone.6

2.3 Respiratory Acclimatization

The changes in respiratory physiology that occur with increasing altitude are
driven by the fall in the partial pressure of oxygen that occurs with decreasing
barometric pressure. The effective transfer of O2 from the environment to
mitochondria is critical for aerobic organisms. Thus, rapid changes in O2 supply
or demand, as might accompany brief exposures to environmental hypoxia or
arise from exercise, are typically met with acute cardiorespiratory reflexes that
maintain tissue O2 homeostasis.3,4This process of respiratory adaptation to the
harsh environment of the high altitude is called respiratory acclimatization.
Figure 2 illustrates the oxygen cascade at sea level and at 5800 m (where the
barometric pressure is around one half of the sea level value) both at rest and
during maximal exercise. The slopes of the altitude curves are less steep than the
sea level curves and one can consider the adaptive processes of acclimatization as
working to reduce, as much as possible, the size of each step in the cascade
between ambient air and mixed venous blood (representative of tissue
oxygenation) resulting in a final partial pressure at high altitude that is not greatly
different from the sea level value.2

Figure 3. Respiratory Acclimatization of people on high altitudes

This process shows us how our body compensate themself after being exposed to
the environtment of high altitude.
2.3.1 Ventilation
Ventilation is regulated by three stimuli; carbon dioxide (CO2), oxygen and pH.
These

stimuli are

sensed and

transduced by peripheral

and central

chemoreceptors.2 The efferent response is co-ordinated by the medullary

respiratory centres. Changes within this system must occur at altitude to facilitate
survival in the hypobaric hypoxic environment. At oxygen partial pressures above
13.3kPa the receptors produce very little output; however, as the partial pressure
falls below 8kPa output increases rapidly. This makes good protective,
physiological sense when one considers that the oxygen dissociation curve
steepens acutely at an oxygen partial pressure below 8kPa. This acute and
reversible increase in ventilation induced by hypoxia is the key respiratory change
associated with environmental hypoxia, and is termed the hypoxic ventilatory
response (HVR). HVR stimulates an increase in ventilation on acute exposure to a
hypoxic environment. This is necessary for survival and is mediated in the most
part by the response of the carotid body. The resultant hypocapnia blunts the
ventilatory response as dictated by the HCVR. HVD occurs, its aetiology is

unclear. With ongoing exposure to hypoxia, ventilation remains augmented and

the HVR is sensitized. Individuals who are acclimatized in this way will increase
ventilation even with a modest increase in altitude. The mechanism for this is
likely to be multifactorial. In contrast, those who are not acclimatised may have
no increase in ventilation up to altitudes of 3500m. 3,4
2.3.2 Diffusion
At altitude there is diffusion limitation. Diffusion of oxygen into the capillary
occurs along the entire length of its communication with the alveoli. Despite this,
there is a failure to reach equilibrium between alveolar and capillary PO2 at the
end pulmonary capillary. This is exacerbated by exercise at altitude as cardiac
output increases and the time that the red blood cell spends adjacent to the alveoli
in the pulmonary circulation is shortened. In the case of diffusion limitation,
increasing the partial pressure of oxygen within the alveolus will increase gas
exchange.4 This diffusion limitation is one responsible for the reduced cardiac
output even further when induced by exercise at high altitude.
2.3.3 Physiology development of HA natives
Healthy HA natives have pulmonary hypertension (PH), right ventricular
hypertrophy (RVH) and increased amount of smooth muscle cells (SMCs) in the
distal pulmonary arterial branches. PH with a mean value of PAP (PPA) of _60
mm Hg was found in HA newborns, a finding similar to that described at SL.
After birth, however, the changes in PAP were very different. In contrast to the
fast decline at SL, PPA at HA decreased slowly, and a mild or moderate degree of
PH remained until adult age. The calculated pulmonary vascular resistance (PVR)
was 5 times greater at HA than at SL. The postnatal persistence of PH at HA
implies a delayed closure of ductus arteriosus and, as a consequence, an increased
prevalence of patent ductus arteriosus at HA. The evidence indicates that the main
factor responsible for PH in healthy highlanders is the increased amount of SMCs
in the distal pulmonary arteries and arterioles, which increases the PVR.15,16

Vasoconstriction is a secondary factor because the administration of oxygen

decreases the PAP only by 15% to 20%. Hypervolemia, polycythemia, and
increased blood viscosity, although considered causal factors in earlier studies,17
are now considered secondary factors. The main role of the structural changes in
the pulmonary vasculature is confirmed by the slow decline of PAP, which
becomes normal after 2 years of residence at SL.1,2,5 These development process of
adaptation is what makes them differs from those who live at sea level.
2.3.4 Pulmonary Circulation

Pulmonary vascular resistance (PVR) increases in response to low alveolar partial

pressures of oxygen. This occurs on acute exposure to hypoxia, in the
acclimatized and in those living at altitude. This is hypoxic pulmonary
vasoconstriction.
The hypoxia of altitude causes a global pulmonary constriction. This is not known
to contribute positively to the acclimatization process and is considered the core
aetiological factor in high altitude pulmonary oedema.4
2.4 Haemodynamics
2.4.1 Plasma Volume
At altitude there is generally a reduction in plasma volume as a result of diuresis.
This is likely to be caused by changes in the feedback loops as a result of hypoxia.
Hypoxic stimulation of the carotid bodies reduces sodium reabsorption in the
kidneys via neural pathways leading to both a natriuresis and diuresis. ANP (and
BNP) is produced in the right atrium and is normally released as a result of atrial
stretch but more recently has also been shown to be released in the presence of
hypoxia. The rapid reduction in plasma volume on exposure to high altitude
results in an increase in haemoglobin concentration. At the same time as the
reduction in plasma volume, hypoxia stimulates renal and hepatic erythropoietin
production stimulating erythropoiesis. 6 Thus, this change in plasma volume also

has correlation with the regulation of the erithropoiesis process occuring on high
altitude environtment.
2.4.2 Regulation of Hemoglobin Concentration
The EPO gene is induced by hypoxia inducible factor-1 (HIF-1). Interestingly
this nuclear factor, which is rapidly broken down in normoxia, but accumulates in
hypoxia, is responsible for inducing multiple other genes that may well play a part
in acclimatisation and adaptation to altitude; products include lactate
dehydrogenase, nitric oxide synthase and vascular endothelial growth factor.
There is an elevation in EPO production within the first 2 hours of hypoxia,
peaking at 24-48 hours and declining to normal The EPO gene is induced by
hypoxia inducible factor-1 (HIF-1). Interestingly this nuclear factor, which is
rapidly broken down in normoxia, but accumulates in hypoxia, is responsible for
inducing multiple other genes that may well play a part in acclimatisation and
adaptation to altitude; products include lactate dehydrogenase, nitric oxide
synthase and vascular endothelial growth factor.
There is an elevation in EPO production within the first 2 hours of hypoxia,
peaking at 24-48 hours and declining to normal. However, the benefit of an
increase in haemoglobin on the oxygen content of the blood is offset by the fact
that it increases viscosity; there is an exponential increase when levels rise above
18g/dl. Blood flow is inversely proportional to viscosity and at high levels the
increase in resistance of flow through the pulmonary and systemic circulation is
sufficient to reduce cardiac output. Hence although oxygen content may be
increased, oxygen delivery to the tissues may be reduced. 1,5,6
2.5 Physical fitness of high altitude natives
Natives of high altitude (HA) may have enhanced physical work capacity in
hypoxia due to growth and development at altitude or, in the case of indigenous
Andean and Himalayan residents, due to population genetic factors that determine
higher limits to exercise performance. There is a growing scientific literature in
support of both hypotheses, although the specific developmental vs. genetic

origins of putative population trait differences remain obscure. Considering

whole-body measures of exercise performance, a review of the literature suggests
that indigenous HA natives have higher mean maximal oxygen consumption
(VO(2) (max)) in hypoxia and smaller VO(2) (max) decrement with increasing
hypoxia. At present, there is insufficient information to conclude that HA natives
have enhanced work economy or greater endurance capacity, although for the
former a number of studies indicate that this may be the case for Tibetans. At the
physiological level, supporting the hypothesis of enhanced pulmonary gas
exchange efficiency, HA natives have smaller alveolar-arterial oxygen partial
pressure difference ((A-a)DO(2)), lower pulmonary ventilation (VE), and likely
higher arterial O(2) saturation (SaO(2)) during exercise. At the muscle level, a
handful of studies show no differences in fiber-type distributions, capillarity,
oxidative enzymes, or the muscle response to training.1,4,5
At the metabolic level, a few studies suggest differences in lactate
production/removal and/or lactate buffering capacity, but more work is needed in
this area. There are two striking features of the lactate paradox at very high
altitudes. The first is that maximal blood lactate concentrations, that is, those
concentrations associated with the highest level of exercise, fall in a roughly linear
fashion as altitude increases. During hypoxia, at a given O2 consumption the
venous and arterial lactate concentrations, the venous and arterial concentration
differences, and the net lactate release were lower after acclimatization than
during

acute altitude exposure.

While

breathing

O2-enriched

air

after

acclimatization at a given O2 consumption the venous and arterial lactate

concentrations and the venous and arterial concentration differences were
significantly lower, and the net lactate release tended to be lower than while
breathing ambient air at sea level before acclimatization. We conclude that the
lower lactate concentration in venous and arterial blood during exercise
after altitude acclimatization reflected less net release of lactate by the exercising
muscles, and that this likely resulted from the acclimatization process itself rather
than the hypoxia.7
2.5.1 Physical fitness of HA natives at sea level

High altitudes natives transferred to sea level showed both high aerobic capacity
and very high maximal heart rate. Corresponding maximal heart rates detected
during exercise test are similar to those reached by them during maximal effort
level when climbing at high altitude. In addition to the aerobic power and cardiac
chronotropic reserve shown by the HA natives, their high performance on the
mountain could be due to the greater utilization of glucose rather than fatty acids
as energetic substrate, the higher ventilatory efficiency particulary at high altitude,
and the existence of a higher anaerobic threshold compared to the sea altitude
natives, although they generally exercise at relatively at low work intensity, they
do so in a hypoxic environtment.8,9

CHAPTER III

SUMMARY
3.1 Adaptation on high altitude environtment
High altitude environtment has distinct characteristic than what on sea level has. It
is the atmospheric pressure on high altitude, which is lower than on the sea level.
This, will further affect the total amount of oxygen intake that we can inspired and
our cardiovascular and respiratory system as our body intend to adapt to the
environment to maintain the oxygen supply throughout our bodywhich is called
acclimatization. It consist on several things such as cardiac output, which is higher
at high altitude, heart beat which is high but reduce as the process of
acclimatization starts, increasing-or decreasing in some of people-blood pressure,
and there is distinct feature of the population of high altitude heart compared to
those who born and live for a long time at sea level-HA Natives has persistent
RVH which is not seen on sea level resident.
The pulmonary system of people natives to high altitude also has distinct feature
from they who live at sea level. It can be seen as the develop a higher ventilation
and diffusion limitation. There also PH and HRV develop in this habitant.
3.2 Effect of high altitude adaptation towards physical fitness
Natives of high altitude (HA) may have enhanced physical work capacity in
hypoxia due to growth and development at altitude or due to population genetic
factors that determine higher limits to exercise performance. At the metabolic
level, a few studies suggest differences in lactate production/removal and or
lactate buffering capacity. Their venous and arterial lactate concentrations, the
venous and arterial concentration differences, and the net lactate release were
lower after acclimatization.

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