CHAPTER IINTRODUCTION

1.1 BackgroundMore 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, 2The 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. 1,2All 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 environtment-mitochondria 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. 3The 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 IdentificationBased 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 ObjectiveBased 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 BenefitSome 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 IILITERATUR REVIEW

2.1 Oxygen Cascade transfer of oxygenAerobic 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.3To 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), whichThus 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 person2.2.2 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 oxygenhas 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 systemThe 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.42.2.1 CirculationThe 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).2Several 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.2Permanent 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.62.2.2.2 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 PressureBlood 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.1,4,5At 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 acutealtitudeexposure. 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 afteraltitudeacclimatization 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 IIISUMMARY

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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