Respiratory Physiology & Neurobiology 158 (2007) 190203

Postnatal cardiopulmonary adaptations to high altitude

Luis Huicho a,b,c,
a

Departamento Acad emico de Pediatr a, Universidad Nacional Mayor de San Marcos, Lima, Peru b Universidad Peruana Cayetano Heredia, Lima, Peru c Instituto de Salud del Ni no, Lima, Peru Accepted 1 May 2007

Abstract Postnatal cardiopulmonary adaptations to high altitude constitute a key component of any set of responses developed to face high altitude hypoxia. Such responses are required ultimately to meet the energy demands necessary for adequate functioning at cell and organism level. After a brief insight on general and cardiopulmonary comparative studies in growing and adult organisms, differences and possible explanations for varying cardiopulmonary pathology, pulmonary artery hypertension, persistent right ventricular predominance and subacute high altitude pulmonary hypertension in different populations of children living at high altitude are discussed. Potential long-term implications of early chronic hypoxic exposure on later diseases are also presented. It is hoped that this review will help the practicing physician working at high altitude to make informed decisions concerning individual pediatric patients, specically with regard to diagnosis and management of altitude-related cardiopulmonary pathology. Finally, plausibility and the knowledge-base of public health interventions to reduce the risks posed by suboptimal or inadequate postnatal cardiopulmonary responses to high altitude are discussed. 2007 Elsevier B.V. All rights reserved.
Keywords: Cardiopulmonary adaptations; High altitude; Postnatal

1. Introduction Animals living in diverse settings but facing hypoxia/anoxia as a common factor constitute ideal models for studying different response patterns (Hochachka and Lutz, 2001). In brief, one fundamental lesson learned from comparative studies in organisms naturally or experimentally exposed to low oxygen is that there are species able to withstand hypoxia (hypoxia tolerant) and species that are not equipped to face successfully the hypoxic challenge for achieving optimal functioning and survival (hypoxia sensitive). Hypoxia-tolerant and hypoxiasensitive are terms used for referring to these two categories of animal species (Hochachka and Lutz, 2001). These two categories of animals are also referred to as genetically adapted and non-genetically adapted species to high altitude hypoxia (Monge and Leon-Velarde, 1991). We will use both set of terms interchangeably throughout the review, although the genes accounting for the different strategies developed by both groups

Correspondence address: Batallon Libres de Trujillo 227, LI 33, Lima, Peru. Tel.: +51 1 93481121; fax: +51 1 3190019. E-mail address: lhuicho@gmail.com. 1569-9048/$ see front matter 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.resp.2007.05.004

of species have not been entirely demonstrated and therefore the rst classication is probably more cautious, as it may include both genetic and functional changes. The responses to hypoxia assessed in such comparative studies range from the whole organism to sub-cellular and molecular responses. They include at least the following levels, as proposed by Hochachka et al. (1998): regulation of hypoxic ventilatory response (HVR) by carotid body chemoreceptors, oxygen sensors at pulmonary vasculature that regulate the hypoxic vasoconstrictor response and the ventilation-perfusion matching, oxygen sensors in other tissues involved in the activation of the vascular endothelial growth factor and thus the angiogenesis especially in the heart and probably in the brain, and oxygen sensors in the kidney and liver involved in an enhanced erythropoietin expression. Finally, there are tissue-specic oxygen sensing and signal transduction pathways that lead to metabolic reorganization at least in part by altering the expression rates of hypoxia-sensitive genes for metabolic enzymes and metabolic transporters. At the sub-cellular and molecular level, the metabolic efciency of genetically adapted animals is higher than that of non-genetically adapted ones. There are several mechanisms by which hypoxia-tolerant animals resolve the challenges posed by hypoxic environments, but metabolic arrest and stabilized

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Fig. 1. From the cell to the organism: several fundamental features of cells tolerant to hypoxia and of cells sensitive to hypoxia-implications of programming and of modifying factors on resulting overall organism-level responses (successful adaptation or non-adaptation). Modied from Hochachka (1986). AMS: acute mountain sickness; HAPE: high altitude pulmonary edema; HACE: high altitude cerebral edema; CMS: chronic mountain sickness, CSHAPH: chronic symptomatic high altitude pulmonary hypertension.

membrane functions appear to be the most effective strategies for extending tolerance to hypoxia (Hochachka, 1986). Depending on whether the organism is tolerant or sensitive to hypoxia, early exposure to chronic hypoxia and intervention of risk factors may alter to a varying degree early programming events at the cellular level and lead to a nal successful or non-successful pattern of adaptation at the organism level (Fig. 1). A conceptual summary of the relationships between time and physiological responses to hypoxia and the ancestral physiological phenotype as a phylogenetic adaptation to hypobaric hypoxia is seen in Fig. 2. This conceptual model of responses was taken from Hochachka et al., who discussed them in detail in several reviews (Hochachka, 1986; Hochachka et al., 1998; Rupert and Hochachka, 2001a, 2001b). We added concepts most likely present in Hochachkas propositions but not explicitly included in his model, namely: (1) the determinant role of the genetic background, which leads ultimately to an adaptive or non-adaptive set of responses to hypoxia, (2) the potential role of important modifying factors (life style, environmen-

tal and indoor pollution, and chronic respiratory diseases), and (3) the notion of programming, that is, the possible long-term indirect effects that poverty, malnutrition and other environmental agents can exert on the responses to hypoxia in the fetal and early postnatal vulnerable periods of life. Programming and modifying/risk factors were incorporated in the model as important modulators of different steps from signal transduction onwards. All such modifying effects can change substantially the genetic expression of both acute and long-term responses. Acute responses to hypoxia occur instantaneously with the hypoxic exposure, whereas adjustments requiring hours to days are termed acclimatory responses or acclimation. We also included the concept of long-term responses to imply that they can take the whole life of an individual. Only acute and acclimatory responses are possible within a given generation. However, all components of the cascade of responses can change through evolutionary time (genetic adaptation), changes that involve genetic alterations. Andean, Tibetan and Ethiopian populations show three different patterns of adaptation to high altitude

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Fig. 2. Relationship between time of exposure to hypoxia and physiological responses. Acute responses are those occurring instantaneously with the hypoxic exposure. Adjustments requiring some fraction of the life of organisms are termed acclimatory responses and they were extended here to so-called long-term responses to imply that they can take the whole life of an individual. Only acute and acclimatory responses are possible within a given generation. All components of the cascade can change through evolutionary time (phylogenetic adaptation or genetic adaptation), changes that involve genetic alterations. Andean, Tibetan and Ethiopian human populations are included as examples of different patterns of adaptation to high altitude hypoxia. Besides genetic adaptation as a resulting successful set of responses, acute and long-term non-adaptive strategies resulting in several conditions are included. Programming and modifying/risk factors were incorporated as important modulators of different steps from signal transduction onwards. Modied from Hochachka et al. (1998). AMS: acute mountain sickness; HAPE: high altitude pulmonary edema; HACE: high altitude cerebral edema; CMS: chronic mountain sickness; CSHAPH: chronic symptomatic high altitude pulmonary hypertension.

hypoxia and therefore show different phenotypes of SaO2 and eryhtropoiesis. Besides genetic adaptation as a successful set of responses, we included acute and long-term non-adaptive strategies resulting in several conditions. The resulting acute non-adaptive responses include acute mountain sickness (AMS), high altitude pulmonary edema (HAPE), and high altitude cerebral edema (HACE). On the other hand, non-adaptive responses to long-term exposure may lead to chronic mountain sickness (CMS) and chronic symptomatic high altitude pulmonary hypertension (CSHAPH). Studies on Andean, Tibetan and Ethiopian high altitude populations have revealed different patterns of adaptation to hypoxia. Andean natives show erythrocytosis and hypoxemia, and may also develop pulmonary artery hypertension (Monge, 1978; Winslow and Monge, 1978). Moreover, CMS may result from an excessively enhanced erythropoietin response (Monge, 1978; Winslow and Monge, 1978). Tibetans show consistently low oxygen saturation and lack of enhanced erythropoiesis (Beall, 2000, 2006). Recently, in Ethiopia, a third successful pattern of human adaptation to high altitude hypoxia that contrasts with both the Andean and the Tibetan patterns was described (Beall et al., 2006). In Ethiopian native residents at 3530 m, 1486 years of age, without evidence of iron deciency, hemoglobinopathy,

or chronic inammatory conditions, they found that hemoglobin concentration and arterial oxygen saturation were within the ranges of sea level populations, despite the ambient hypoxia (Beall et al., 2002). The understanding of the underlying mechanisms leading to these differences is not complete. Although it is plausible that they are due to genetic differences in the strategies for facing hypoxia, the genes involved, their transmission patterns and their distribution among and within different populations are not clear (Beall et al., 2002; Brutsaert, 2001). The effect of environmental factors other than hypoxia and the interaction of hypoxia with genetic variables on the patterns of adaptation are aspects also waiting for further clarication (Moore, 2001; Rupert and Hochachka, 2001a, 2001b). In the following sections we will discuss whether there are similar population differences in developmental cardiopulmonary adaptation patterns to high altitude hypoxia. We will offer rst a brief physiological overview on cardiopulmonary responses to hypoxia, particularly on the reactivity of the pulmonary artery. We will then discuss from a comparative perspective the responses of growing and adult organisms, and follow this with a discussion of cardiopulmonary responses in human infants and children living at high altitude. In the nal sections we will comment on the possible long-term effects of early

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hypoxic exposure on the health status in later life and whether there is a sound knowledge-base for drawing clinical and health policy recommendations regarding exposure of children to life at high altitude. 2. Comparative cardiopulmonary responses to high altitude hypoxia in developing and adult organisms 2.1. Physiological signicance of cardiopulmonary responses to hypoxia A particular challenge that hypoxic exposure presents to the lungs is that they should overcome any existing limitation to gas exchange so as to ensure that blood equilibrate completely with alveolar oxygen pressure. Three physiological mechanisms that may act as limiting factors to an efcient gas exchange have been described: intrapulmonary shunts, diffusion limitations and ventilation to perfusion heterogeneity (Scheid and Piiper, 1997; Skovgaard and Wang, 2006). Pulmonary vascular reactivity is fundamental in the reduction of the ventilation to perfusion heterogeneity by means of a constrictive response that is variable from species to species. Hypoxic pulmonary vasoconstriction (HPV) is considered a widely conserved adaptive vasomotor response to alveolar hypoxia, which distributes pulmonary blood ow to optimally ventilated lung segments by a process of vasoconstriction which specically involves the small muscular pulmonary arteries (Moudgil et al., 2005). It thus mediates ventilation-perfusion matching by reducing shunt fraction optimizing in this way systemic oxygen pressure (Moudgil et al., 2005). On exposure to hypoxia, the primary site of vasoconstriction is the precapillary muscular pulmonary and low alveolar oxygen leads to constriction of the pulmonary vasculature in birds and mammals which elevates resistance to pulmonary blood ow and leads to a rise in pulmonary arterial blood pressure (Skovgaard and Wang, 2006; Moudgil et al., 2005). In the systemic vessels, in contrast, hypoxia dilates most systemic arteries in both animals and humans. These differing responses of pulmonary and systemic arteries to hypoxia indicate that HPV, although modulated by the endothelial cells, cannot be explained by endocrine or paracrine vasoconstrictors that have concordant effects on the pulmonary and systemic circulation such as endothelin and leukotrienes (Moudgil et al., 2005). It is believed that the restricted occurrence of HPV to intrapulmonary arteries reects the localization of the molecular apparatus that mediates HPV, namely the mitochondrial redox sensor and the effectors (O2 -sensitive K+ channels in pulmonary artery smooth muscle cells) to the resistance pulmonary arteries (Moudgil et al., 2005). This seductive hypothesis should be veried through the conduction of studies aimed at developing organ-specic designs for assessing in different species developmental responses to hypoxia within the framework of an overall, integrative conception of adaptation. Also, the hypothesis paves the way for focusing the study of hypoxic adaptive responses of animals and humans exposed chronically to high altitude hypoxia on the mitochondrial level in pulmonary artery smooth muscle cells, and also for understanding better the genetic aspects of such responses. Fig. 3 shows a diagrammatic summary of the cas-

cade of responses elicited at pulmonary vasculature level when organisms are challenged by hypoxia. The genetic background provides the basis of the response, although pulmonary vascular reactivity resulting from hypoxia sensing may be modied by programming during early intrauterine or extrauterine life periods. This leads to successful long-term vascular pulmonary adaptation or to non-adaptive long-term responses that can be ultimately manifested in chronic and symptomatic high altitude pulmonary hypertension. 2.2. Cardiopulmonary responses in young organisms There is a paucity of research performed on cardiopulmonary responses to high altitude hypoxia in growing animals. A comprehensive review made on physiological adaptations to high altitude in 1991 (Monge and Leon-Velarde, 1991) concluded that animals tolerant to hypoxia such as guinea-pigs, when studied during growth, show a lower degree of ventricular hypertrophy and pulmonary artery hypertension than growing rats, considered hypoxia-sensitive animals. Unfortunately, the prenatal and postnatal time-course of such responses in humans is fundamentally unknown, though there are critical periods during prenatal and early postnatal growth. If growing organisms are exposed to certain factors such as under-feeding during these critical periods, they may be programmed for later development of diseases such as ischemic heart disease, diabetes, hypertension, and stroke (Barker, 2002). As for the more general problem of early exposure to diverse agents during critical periods of lung development and the subsequent risk of developing cardiorespiratory diseases later in life, as well as the underlying molecular mechanisms, this is a largely neglected area and more uncertainties than denitive answers still prevail (Massaro and DeCarlo Masaro, 2004). Fig. 4 depicts the different stages of human lung development and shows presumably vulnerable periods that may be affected by exposure to several agents including hypoxia. There are clearly compelling examples of late consequences of early events, such as intrauterine and postnatal exposure to parental tobacco smoking and later risk in adulthood for more respiratory symptoms, poorer lung function, and increased risk for obstructive pulmonary disease (Hafstrom et al., 2005; Harding et al., 2000; Maritz et al., 2005; Svanes et al., 2004). A recent publication by Le Cras et al. (2004) synthesized divergent studies about transforming growth factor-alpha (TGF-) pointing to its overexpression in important developmental and adult pulmonary diseases and showed that brief overexpression of TGF- by the lung, if produced when the gas-exchange saccules of the architecturally immature lung are being subdivided (septated) to form alveoli, permanently disrupts septation. Their results support the existence of a critical period for septation and for the formation of the pulmonary vasculature and provide additional evidence that early events can inuence later lung anatomy, lung function, and the development of lung disease. Importantly, this work also points to the impact early events have on the subsequent development of lung disease and adds to our still poor understanding of the molecular basis of this effect (Svanes et al., 2004). Of interest, in all species studied so far septation, whether prenatal or postnatal, occurs

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Fig. 3. Pulmonary vasculature set of responses in conditions of chronic exposure to hypoxia. A hierarchical approach is proposed where the genetic endowment is determinant in the way organisms respond to hypoxia at the pulmonary vasculature level. Early exposure to chronic hypoxia and participation of modifying/risk factors may signicantly alter the responses, which may therefore lead to increased or normal pulmonary vasculature resistance and pressure, successful or inadequate blood ow redistribution to optimally ventilated lung regions, reduction or inadequately persistent shunt fractions, improvement or not in ventilation-perfusion matching, and eventually to maintenance or not of optimum systemic oxygen pressure. The global resulting responses may signify a successful long-term pulmonary adaptation or a non-adaptive set of responses leading to chronic symptomatic high altitude hypertension. NO: nitric oxide; ET-1: endothelin-1; LKs: leukotrienes; CSHAPH: chronic symptomatic high altitude pulmonary hypertension; PAP: pulmonary artery pressure.

during a period when the organisms blood concentration of its major glucocorticosteroid hormone is low; septation ends as the glucocorticosteroid concentration rises (Massaro and DeCarlo Masaro, 2004). Administration of a glucocorticosteroid to rats or mice during the period of septation, when the concentration of corticosteroids in the blood is normally low, impairs spontaneous septation and the development of the pulmonary vasculature, resulting in pulmonary hypertension (Le Cras et al., 2000). Perinatal exposure to hypoxia may also affect septation and pave the way for later development of pulmonary hypertension (Blanco et al., 1991; Massaro et al., 1990). However, most experimental evidence on vulnerable periods comes currently from animal studies, and we should therefore be cautious in extrapolating those results to human lung development, as the critical periods seem to vary from species to species and in addition there are gender differences. Moreover, the time-period of vulnera-

bility is still nebulous for several specic phases of human lung development and more research is needed before we can derive sound recommendations on early preventive interventions. We will be back with this issue later in the review describing more evidence pointing to possible associations between events occurring early in life and the risk of developing specic lung disorders. It would be particularly illuminating to have comparative studies on the ontogenetic characteristics of cardiopulmonary responses to chronic high altitude hypoxia in hypoxia-sensitive and hypoxia-tolerant species. They offer the potential to reveal possible critical periods during early phases of cardiopulmonary growth and development in conditions of hypoxia and their relationship with adult tness to hypoxia in general and with the risk of developing later persistent cardiopulmonary pathology including symptomatic high altitude pulmonary

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Fig. 4. Prenatal and postnatal periods of lung development and the notion of critical periods. Rectangles with black areas denote greater vulnerability (critical periods) whereas those with grey areas denote lower vulnerability. Programming is more likely to occur during critical periods leading thus to various diseases later during infancy, childhood or adulthood. Proposed period times of vulnerability of specic stages of lung development to diverse agents are only approximations and some of them may not be fully applicable to human beings. Gender variations also occur. Critical periods may include prenatal phase, postnatal phase or both intrauterine and extrauterine phases. Vertical and oblique arrows on different developmental lung stages indicate modulatory effects of diverse molecules, such as growth factors. AB: antibiotics; IGF: insulin-like growth factor; EGF: epidermal growth factor; TGF-: transforming growth factor .

hypertension. Such studies may also identify potential targets for proving therapeutic options and for implementing preventive interventions. 2.3. Cardiopulmonary response in adult organisms In contrast, studies on cardiopulmonary responses to hypoxia in adult animals are numerous. For a detailed discussion of the issue we refer the reader to a comprehensive review published in 2001 (Tucker and Rhodes, 2001). In that review, the authors distinguish the ndings in animals indigenous to low altitude from those in animals native to high altitude. Two patterns of cardiopulmonary response have been consistently shown in low altitude animals. Species such as sheep and goat show a hypo-responsive pattern characterized by low thickness of the pulmonary vessels, absent or mild pulmonary artery hypertension, and mild to moderate right ventricular hypertrophy. Hyper-responder animals such as cows show comparatively higher thickness of pulmonary arteries, moderate to severe pulmonary hypertension and marked right ventricular hypertension. In addition, animals native to high altitude such as yaks, camelids (llamas, alpacas, guanacos) and rodents and lagomorphs (guinea pigs, viscachas, pikas) show consistently less variable, attenuated pulmonary hypertensive responses with little pulmonary vascular hypertrophy and right ventricular hypertrophy. This attenuated response is also apparent among human high altitude populations, particularly in Tibetan populations. In brief, it

seems that medial pulmonary artery thickness predicts the pulmonary vascular response to high altitude (Tucker and Rhodes, 2001). These ndings strongly suggest that the cardiopulmonary responses to high altitude hypoxia are genetically driven. This does not deny at all the inuence of geneenvironment interactions or the role of developmental adaptation, whose relative importance in the context of a successful adaptation as compared to the purely genetic inuence needs to be studied. 3. Humans: cardiopulmonary changes in high altitude infants and children A basic auxiologic concept universally accepted is that children need an adequate environment to reach an optimum, unrestricted growth and development. Accordingly, there is a justied concern on the potential inuence of high altitude hypoxia on growth and development of children living in such settings. Ultimately, oxygen availability to tissues should be the minimal needed for matching the metabolic demands of a growing organism. Alternatively, an increased metabolic efciency in face of limited oxygen availability is a plausible overcoming strategy. Since cardiovascular and respiratory systems constitute key steps in the oxygen cascade they deserve a particular consideration in a review on their responses in children living under hypoxic conditions. We will focus here on studies performed in children with long-term exposure to high altitude.

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From a more specic perspective, we examine how cardiopulmonary development occurs in children resident at high altitude and how this may inuence the risk of persistence of fetal circulatory patterns (patent foramen ovale and patent ductus arteriosus), as well as of symptomatic pulmonary hypertension with consequent right-heart failure. These concerns are reected in the published literature (Alzamora Castro et al., 1960; Khoury and Hawes, 1963; Hurtado Gomez and Calderon, 1965; Lin and Wu, 1974; Miao et al., 1988; Sui et al., 1988). 3.1. Cardiopulmonary transitional changes in the high altitude infant In a comprehensive review of early postnatal transitional cardiopulmonary changes in infants living at high altitude it was emphasized there that the immediate postnatal period is a dynamic one, with continuous developmental changes in virtually every aspect of the cardiopulmonary system (Niermeyer, 2003). Such changes involve alveolar structure, pulmonary blood ow, circulatory patterns, central nervous system control of breathing, regulation by peripheral chemoreceptors, inputs from metabolic rate and thermoregulation, hemoglobin synthesis, and modulators of oxyhemoglobin binding. Within seconds after birth, the lungs ll with air, pulmonary blood ow increases, and fetal shunts through the foramen ovale and ductus arteriosus close. The respiratory system is challenged by a rapid increase in metabolic rate and by the gradual resetting of the carotid chemoreceptors from fetal to postnatal PaO2 values, while the nal steps in structural maturation of the alveolar gas exchange units take place. Oxygen is crucial in modulating this series of events and, subsequently, birth into a hypoxic high altitude environment has not only short-term impact but also implications that may extend throughout the life-span. The availability of oxygen inuences profoundly the nature and intensity of the developmental cardiopulmonary changes that occur in the perinatal period from fetus to newborn infant. Such changes are clearly different at high altitude from those occurring at sea level and include differences in oxygen arterial saturation, breathing patterns and maturation of respiratory control reexes, and velocity of regression of fetal characteristics of the pulmonary vasculature. Various differences in transitional changes vary not only with postnatal age and altitude, but also among populations living in different high altitude settings, suggesting an important inuence of genetic adaptation on perinatal physiology. Exposure to chronic high altitude hypoxia during the perinatal transition also results in apparent lifelong alterations in respiratory reex responses and pulmonary vasoreactivity. Disruption of the normal process of cardiopulmonary transition can result in symptomatic high altitude pulmonary hypertension. It is also very likely that the high altitude hypoxia may interact synergistically with hypoxemia due to acute respiratory infections in young infants still undergoing transition, contributing in this way to infant mortality at high altitude (Lozano, 2001). 3.1.1. Arterial oxygen saturation Arterial oxygen saturation (SaO2 ) decreases with increasing altitude, but this decrease is not linear. The SaO2 of infants at

high altitude depends on several variables, including the ambient oxygen pressure, age of infants, state of awakening, feeding, respiratory rate and pattern, oxygen hemoglobin afnity, and reactivity of the pulmonary vessels. In addition, SaO2 shows population variations that may be reecting differing genetic adaptation to high altitude. At 3100 m, saturation in awakening infants is signicantly higher than those in active or quiet sleep. It is variable with feeding, tending to be intermediate between wakefulness and sleep. This pattern is similar with further altitude increase, and at 3658 m in Lhasa, the highest saturations occur in the rst 2 days after birth, followed by a decline in the rst week (Niermeyer et al., 1995). Tibetan newborn infants show consistently higher oxygen saturations than Han infants, although they reside at the same altitude in Lhasa. In the rst 2 days after birth, SaO2 averages 90% to 94% in the Tibetans and 86% to 92% in the Han. During infancy, Tibetan infants maintain fairly constant values in all states, while Han infants show a progressive decline during sleep through 4 months (Niermeyer et al., 1995). Andean infants between 2 and 5 months show at a similar altitude (3750 m) values roughly lower than Tibetan infants, with averages of 88 3% (Reuland et al., 1991). In El Alto, Bolivia (4018 m) infants have a mean SaO2 of 86.9% overall and a mean of 87.8% during the awake state (Gamponia et al., 1998). At 4540 m in Peru, SaO2 values range from 57% to 75% in infants from 30 min to 72 h of age (Gamboa and Marticorena, 1971) and from 74% to 81% during infancy and childhood (Sime et al., 1963). These values show a wide range, and thus some caution is warranted before deriving conclusions on normal values in different high altitude settings. As remarked previously, in addition to altitude and postnatal age, SaO2 variations are related to other factors such as behavioral state or activity and population group. Moreover, oxygen hemoglobin afnity also inuences SaO2 values, and oxygen hemoglobin afnity in turn depends on proportion of fetal hemoglobin, 2,3 DPG, PCO2 , pH and temperature. It has been reported that the proportion of fetal hemoglobin (HbF) in high altitude newborn infants is higher than that of their sea level counterparts (Ballew and Haas, 1986). When differences were assessed between different populations living at high altitude on the Andean plateau, lower proportions of HbF were demonstrated among high altitude residents of native Aymara and Quechua versus mestizo background, and over 25% of native infants showed a predominance of adult hemoglobin (HgbA) in cord blood (Galarza Guzman, 1988). The advantage of HbF in high altitude newborns may depend on how adequate is the delivery of oxygen to the tissues during fetal life. Differences in adult SaO2 values found among different adult populations native to high altitude have also been shown among Tibetan and Han neonates born to women resident at high altitude. Tibetan infants displayed higher SaO2 and birth weight and lower hemoglobin concentration than Han newborns (Niermeyer et al., 1995). These ndings reect likely genetic differences in the degree of adaptation to high altitude hypoxia of Tibetan and Han populations. Hypoxia may have operated distinctly in these populations through genetic modication of regulators of pulmonary vascular reactivity and blood ow such as

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nitric oxide production, which is known to be under genetic control (Marsden et al., 1993; Pearson et al., 2001). Pulmonary vascular reactivity may in turn modify the SaO2 . Alternatively, direct effects on genes accounting for oxygen saturation may have operated distinctly in different populations (Beall, 2006). It seems that oxygen saturation has no heritability in the Andean natives, but does among Tibetans where an autosomal dominant major gene for higher oxygen saturation has been detected (Weiss, 1993). Women estimated with high probability to have high oxygen saturation genotypes have more surviving children than those estimated with high probability to have the low oxygen saturation genotype. These ndings suggest that ongoing natural selection favoring greater reproductive success is increasing the frequency of the high saturation allele at this major gene locus (Beall et al., 1994, 1997, 2004). This is interesting given the amount of mobility and cross-breeding that occurs nowadays. 3.1.2. Ventilation and pulmonary function For a detailed discussion on the development of ventilatory control in infants, the reader is referred to a recently published review (Cohen and Katz-Salamon, 2005). The ventilation control is related to the function of the peripheral chemoreceptors, which are the bodys principle O2 (hypoxia) sensors. The HVR of newborn infants is well known. It consists of an initial and transient peripherally mediated increase in ventilation, which quickly returns to baseline or even below (Cohen et al., 1997). The fall in ventilation during sustained hypoxia, is due to hypoxic depression of chemoreception, which has peripheral and central components. With advancing age, the initial transient increase in ventilation becomes sustained for longer and the hypoxic depression becomes less dramatic, although development is slow and the biphasic response persists in some form into adulthood (Easton et al., 1988; Cohen et al., 1997). Of note, hypometabolism is known to occur on exposure to hypoxia in newborns, but infants at high altitude maintain metabolic rate with no major alterations in ventilation (Mortola et al., 1992). Neonates gestated and born at high altitude (3850 m) show a similar biphasic HVR as neonates born at a lower altitude (800 m), that is, initial increase in ventilation, followed by a sustained decrease that may persist beyond the termination of the hypoxic stimulus (Lahiri et al., 1978). Of note, when infants born at high altitude experienced a prolonged exposure to 3850 m, resting ventilation did not increase or decrease as compared with sea level infants. Developmental control of ventilation is also inuenced by early exposure to hypoxia. Thus it has been shown that the mature hyperbolic curve of the HVR is delayed in rats raised at high altitude as compared with rats growing at sea level (Joseph et al., 2000). Interestingly, infants native to La Paz (4000 m), showed deeper and slower respiratory pattern and greater oxygen extraction than infants native to Santa Cruz (500 m) (Mortola et al., 1992). However, in this study, there were no differences in pulmonary ventilation, oxygen consumption, or carbon dioxide production between the two groups. Pulmonary development at the level of gas exchange units is also inuenced by perinatal exposure to hypoxia. In rat models, the velocity of lung volume increase is slower, there is a delayed

septation of gas exchange saccules, the gas exchange surface area is blunted, and there is an accelerated thinning of the alveolar walls (Massaro et al., 1989). These changes may constitute the underlying mechanisms of pulmonary anatomic and functional changes observed in infants and children living at high altitude and exposed to hypoxia in early periods of development. 3.1.3. Pulmonary artery pressure Infants born at high altitude display in general a constrictive arterial pulmonary response to ambient hypoxia which is related to an increased thickness of the muscular layer in the pulmonary vessels. This vasoconstriction leads in turn to right ventricular hypertrophy. These characteristics have been studied through electrocardiographic, echocardiographic, hemodynamic and histopathologic studies in children gestated, born and resident at high altitude settings. How long the increased pulmonary artery and the right ventricular pattern predominate has been shown to vary at different altitudes. Infants studied in Mexico (2240 m) through echocardiography showed slightly elevated pulmonary artery pressures at 1530 days (Victoria-Oliva et al., 1996). In Leadville, Colorado (3100 m), echocardiography showed that pulmonary artery pressure showed normal to moderately elevated values during the neonatal period that normalized completely by 24 months of age (Niermeyer et al., 1993). All these infants had received supplementary oxygen immediately after birth that may have modied the pulmonary artery pressure response veried later in infancy. Healthy infants in La Paz (37004000 m) showed a gradual decrease of pulmonary artery pressure as determined by echocardiography (Niermeyer et al., 2002). An echocardiographic comparative study revealed that right ventricular anterior wall of infants native to La Paz (3600 m) was greater than that of infants native to Santa Cruz (300 m), difference that persisted through the rst year of extrauterine life; by contrast, low altitude infants showed a signicant decrease of wall thickness by the end of the rst month of life (Aparicio et al., 1991). Heart catheterization has also been performed for assessing the pulmonary artery pressure response. Neonates born in Morococha, Peru (4540 m), showed pulmonary artery pressure values close to systemic blood pressures when alveolar PO2 was about 50 mm Hg, values that persisted for 72 h after birth. Interestingly, the pulmonary artery pressure showed an inverse correlation with SaO2 and administration of 100% oxygen to some infants led to a fall of pressure to values near normal for sea level (Gamboa and Marticorena, 1971). The electrocardiographic ndings also point to similar patterns of persistence of increased pulmonary artery pressure and right ventricular preponderance, again being the time-course of such changes dependent on the age of infants and on the altitude of residence (Marticorena, 1983). Another avenue of evidence for developmental artery pulmonary pressure response came from histopathologic studies performed in Peruvian infants. The histologic pattern of the pulmonary artery trunk at various altitudes ranging from sea level to 4540 m showed a delayed changed from the aortic to adult structure. Infants born at sea level display a transitional

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pattern by 6 months and an adult pattern by 2 years of age, whereas residents above 3440 m may show persistence of an aortic (high-pressure) pattern into the preschool years (Salda na and Arias-Stella, 1963a, 1963b). As for high altitude-related structural heart abnormalities, echocardiography measurements performed in infants aged from 2 weeks to 6 months in La Paz (37004000 m) revealed persistence of an anatomically patent foramen ovale in 75% through 3 months and 44% through 6 months (Niermeyer et al., 2002). None of these infants showed a clinically signicant shunting. However, other studies in school-age children in Tibet (Miao et al., 1988) and Peru (Alzamora Castro et al., 1960) have identied an increased prevalence of symptomatic patent ductus arteriosus and patent foramen ovale with increasing altitude of residence. Finally, there is evidence that high altitude interacts with acute respiratory infections, particularly in young infants and children, aggravating the hypoxemia and increasing thus the risk of death (Reuland et al., 1991; Onyango et al., 1993; Lozano et al., 1994; Dyke et al., 1995; Duke et al., 2001; Lozano, 2001). Consequently, it has been proposed that SaO2 monitoring through an extensive use of pulse oximetry should be investigated and implemented for avoiding severe hypoxemia and death in high altitude infants and children with acute respiratory infections (Duke et al., 2002; Huicho, 2003). The use of pulse oximetry monitoring would also be a more efcient strategy for detecting hypoxemia and risk of death at high altitude than clinical signs (Reuland et al., 1991; Duke et al., 2002). In summary, increased pulmonary arterial pressure and right ventricular preponderance persist at altitudes above 4000 m well beyond infancy in Andean populations. Because these ndings have not been related to clinical signs, they have been considered as adaptive responses to high altitude hypoxia. However, these changes have also been described in infants in La Paz, Leadville and Lhasa who developed symptomatic acute or subacute pulmonary hypertension (Khoury and Hawes, 1963; Hurtado Gomez and Calderon, 1965; Sui et al., 1988; Niermeyer et al., 1998). Thus, caution should be exercised before considering asymptomatic pulmonary hypertension as a universal adaptive response. 3.2. Later cardiopulmonary changes in high altitude children and adolescents In Peruvian children living at the same altitude in Tintaya, Marquiri, and Nu noa (4100 m), but having different degrees of genetic admixture and different nutritional and socioeconomic conditions, we showed substantially higher height and weight in those with better nutrition and socioeconomic condition (Pawson et al., 2001). This nding is suggestive of a relatively minor inuence of high altitude hypoxia on physical growth in face of relatively advantageous socioeconomic conditions (Pawson et al., 2001). Interestingly, Nu noa children, with predominant Quechua ancestry, showed higher arterial oxygen saturation values and lower heart rate than the other two groups, predominantly mestizo, ndings suggestive of a better degree of adaptation in Nu noa children (Huicho et al., 2001). Fur-

ther studies are needed that compare SaO2 in Andean, Tibetan and Ethiopian children. They should carefully assess potential modifying factors such as migration patterns to lower altitudes, frequency of early respiratory conditions, indoor pollution, and nutritional and socioeconomic status. Physical growth and functional development of the respiratory system seem to follow a pattern different from that in sea level children and adolescents. Anatomic and functional studies showed that the thorax and respiratory system display an accelerated growth and maturation in high-altitude children (Frisancho, 1976; Frisancho, 1969; Mueller et al., 1978). Also, children with a genetic ancestry suggestive of long-term exposure to high altitude seem to have higher chest dimensions relative to stature and higher respiratory functional measurements than children of European ancestry living at high altitude (Greksa, 1986, 1988; Greksa et al., 1987, 1988; Stinson, 1985). As it has been shown in infants, several electrocardiographic, vectorcardiographic, hemodynamic and histopathologic studies in children and adolescents living at high altitude have shown persistent hypertrophy of the pulmonary artery muscular layer, asymptomatic pulmonary artery hypertension and a related right ventricular hypertrophy. As we already mentioned above, these characteristics persist well beyond infancy and extend into late childhood, particularly in children living at extreme altitudes (Marticorena, 1983; Pe naloza et al., 1960, 1961, 1964). A recent study in healthy Tibetan and Han children aged 712 years also showed a high prevalence of ECG abnormalities consistent with right heart strain in both groups, with no difference between the two ethnic groups or sexes. Children were studied at two altitudes at 3500 and 4500 m. These results contrast with other reports showing higher rates of chronic altitude sickness in Han Chinese children. The authors conclude that other studies showing higher observed rates of symptomatic chronic altitude sickness in Han Chinese children suggest that extracardiologic factors play a role in the pathogenesis of the disease. They nevertheless acknowledge limitations of their study, including small sample size and the low sensitivity of the electrocardiogram in the detection of right ventricular strain (Hulme et al., 2003). Overall, all the above research on developmental cardiopulmonary responses in children living at high altitude show consistently a prolonged right ventricular predominance beyond infancy and a concomitant persistence of asymptomatic pulmonary artery hypertension, characteristics that seem to reect an adaptive set of strategies in Andean and Tibetan children living at high altitude. However, the description of symptomatic high altitude pulmonary hypertension and of altitude-related structural heart abnormalities in different populations of children living in Bolivia, Leadville and Lhasa (Hurtado Gomez and Calderon, 1965; Khoury and Hawes, 1963; Niermeyer et al., 1998; Sui et al., 1988; Niermeyer et al., 2002; Miao et al., 1988; Alzamora Castro et al., 1960) strongly suggest the existence of differing pulmonary artery pressure response patterns to high altitude hypoxia among different populations. This is similar to the erythropoietic and SaO2 responses, which show different patterns in Andean, Tibetan and Ethiopian populations. In some populations the absence of a delayed regression of an increased pulmonary artery pressure and right ventricular

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preponderance may be indicating a better adaptation to high altitude, whereas in those populations with a slower change to adult patterns or even absence of such transition, the responses may be indicating a lower degree of adaptation. We can advance the hypothesis that, similarly to what has been described in adult populations, different patterns of adaptation to high altitude are probably present in relation to the pulmonary artery response in Andean, Tibetan and Ethiopian children. We need further research to conrm this hypothesis and also to identify the time-period of the occurring changes. Furthermore, factors such as genetic admixture, patterns of migration to lower altitudes, outdoor and indoor pollution, nutritional and socioeconomic conditions were not adequately addressed or they were completely absent in most of the above cited studies. Thus there is a legitimate concern on whether the pattern of cardiopulmonary responses is consistently similar when such factors differ among different study populations of children. These factors may act to modify the pulmonary artery pressure response to hypoxia. Further studies aimed at assessing the possible inuence of these conditions on developmental cardiopulmonary responses of different high altitude children populations are warranted. In this regard, we recently studied preschool and schoolaged children resident at 4100 m in Tintaya, Peru (Huicho et al., 2005; Huicho and Niermeyer, 2006, 2007). Our broad objective was to correlate clinical assessments with anatomic and physiologic cardiovascular ndings. Other specic objectives included the determination of prevalence of pathologic cardiopulmonary ndings and of prevalence of symptomatic high altitude pulmonary hypertension. We took advantage of an existing mining settlement that comprised 150 families, with 336 children. The study population also facilitated exploration of genetic and environmental factors such as admixture, patterns of exposure to altitude, and duration of residence at high altitude. We administered a structured questionnaire to every selected family for obtaining information on surnames of children, parents, and grandparents and on language(s) spoken in the household as indicators of ethnic origin. Questions also covered the altitude of birth for each child and altitude of residence prior to arrival at Tintaya, duration of residence in Tintaya, and typical annual pattern of movement. Problems during the perinatal period were sought, as were childhood health problems, with particular emphasis on cardiorespiratory ailments and chronic conditions. The responses to altitude change, level of activity at high altitude, and environmental smoke exposure were also assessed. Subsequently, all children underwent a complete physical examination, anthropometry, oxygen saturation measurements, hemoglobin determination, electrocardiography and echocardiography. We found that most children showed at least some degree of high altitude ancestry, based on analysis of maternal and paternal surnames and the surnames of maternal and paternal grandparents. Our schoolchildren showed also a high mobility pattern to lower altitudes, most of them traveled to lower altitude during summer vacation and winter break each year. They enjoyed furthermore a good nutritional status and lived in favorable housing conditions. In those children, we did not nd evidence of pulmonary artery hypertension out of the

context of heart structural abnormalities. The prevalence of such abnormalities was also similar to that of sea level. Controlling for potential confounding factors that may inuence echocardiographic and electrocardiographic measurements including sex, nutritional status, chest dimensions, pulse oximetry, hemoglobin concentration, ethnicity, length of residence at high altitude, or parental history of exposure to high altitude, did not reveal a consistent inuence of such variables. Our ndings clearly differ from previous studies. Several explanations may be offered for these discrepant results. Most children showed at least some degree of high altitude genetic pattern through patronymic evaluation. This trait may have conferred them a genetic adaptive advantage, although this cannot explain completely the absence of pulmonary hypertension. In addition, other factors such as the frequent descent to lower altitudes may have attenuated the effects of hypoxia on the development of cardiopulmonary system. Although we were not able to assess completely whether the outdoor and indoor pollution inuences developmental pattern, it is plausible that pollution can affect important periods of the cardiopulmonary development process. It is known that indoor pollution is a risk factor for respiratory infections, and thus we can speculate that frequent presentation of such illnesses may impair the setting of adaptive cardiopulmonary responses in early life. Our study population enjoyed unusually good outdoor and indoor conditions for a high altitude mining settlement. Finally, we acknowledge the need to perform studies that adequately assess the real role of pollution and of the prevalence of respiratory infections on the patterns of cardiopulmonary development through comparative observation of high altitude children living under different degrees of exposure to pollutants. 4. Symptomatic high altitude pulmonary hypertension The previous ndings on cardiopulmonary responses to high altitude in infants and children are clearly relevant to the risk of development of high altitude-related cardiopulmonary pathology in general and more specically of a clinical condition called high altitude pulmonary hypertension. There are several reports of the latter in the literature and all have been described in infants, children and adults resident at altitude (Grover et al., 1966; Hurtado Gomez and Calderon, 1965; Khoury and Hawes, 1963; Lin and Wu, 1974; Sui et al., 1988; Wu et al., 1998; Wu and Miao, 2002; Wu et al., 2003). The hallmark of the condition is the presence of pulmonary artery hypertension and it is associated with several clinical features. A recent consensus statement on high altitude diseases denes high altitude pulmonary hypertension as a clinical condition occurring in children and adults resident above 2500 m and characterized by a mean pulmonary artery pressure above 30 mm Hg or a systolic pulmonary artery pressure above 50 mm Hg, right ventricular hypertrophy, heart failure, moderate hypoxemia and the absence of excessive erythrocytosis (Leon-Velarde et al., 2005). There has been some confusion in the literature and several terms have been historically used, including chronic mountain sickness of the vascular type, high altitude heart disease, hypoxic cor pulmonale, infant subacute mountain sickness, pediatric high altitude heart dis-

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ease, and adult subacute mountain sickness (Leon-Velarde et al., 2005). The consensus statement did not provide information on the prevalence of high altitude disease and listed some risk factors, including previous pulmonary arterial hypertension, history of persistent excessive pulmonary vasoconstriction in response to hypoxia, and hypoxemia during sleep (Leon-Velarde et al., 2005). An adequate assessment of prevalence requires the study of samples with known denominator. Unfortunately, most studies referring to high altitude disease in children did not provide this substantial information. Similarly, the determination of risk factors ideally needs cohort studies or casecontrol studies adequately controlled for bias, and we have not found such studies in the reviewed literature. It seems from the above discussed studies that symptomatic high altitude pulmonary hypertension is (1) a potentially lifethreatening condition presenting in infants, children and even adults with risk factors and (2) that subjects without high altitude genetic ancestry may be more susceptible. Among populations with some degree of genetic admixture, the pre-existence of pulmonary artery hypertension may be an important risk factor. The role of other factors such as indoor pollution, pre-existing respiratory conditions such as asthma, particularly if not controlled, and migration patterns to low altitudes, requires further study. 5. Possible long-term implications of early cardiopulmonary patterns of growth and development at high altitude A series of papers on the pediatric origins of adult lung diseases has recently been published that include general developmental issues and specic lung problems arising in infancy, childhood and adulthood, which are associated with early prenatal or postnatal exposure to different agents (Eber and Zach, 2000; Holt and Sly, 2000; Le Sou ef, 2000; Robinson, 2000; Sly, 2000; Stick, 2000; von Mutius, 2000). Additional epidemiological studies showed that exposure to factors that restrict fetal growth, lead to low birth weight, or interfere with early postnatal growth, can alter lung development and have later adverse effects on lung function and respiratory health. Major causal factors include reduced nutrient and oxygen availability, nicotine exposure via maternal tobacco smoking and preterm birth, each of which can affect critical stages of lung development (Hafstrom et al., 2005; Harding et al., 2000; Maritz et al., 2005; Svanes et al., 2004). Similarly, experimental studies have demonstrated that these environmental insults can permanently alter lung structure and hence lung functions, increasing the risk of respiratory illness and accelerating the rate of lung aging (Harding et al., 2000; Maritz et al., 2005). A fetus is able to mount a proliferative response to a common allergic trigger (beta-lactoglobulin, house dust mite, etc.) as early as 22 weeks of pregnancy (Fig. 4). Maternal exposure to allergens inuences self-IgG production which modulates the allergen exposure of the fetus resulting in either primary sensitization of T cells or tolerance to the allergen. Atopic mothers create a more Th2-orientated environment for

the developing fetus than non-atopic mothers (Warner, 1999). Thus early manipulation of the maternal immune response during pregnancy, either by reducing self-exposure to environmental allergens or controlling her allergic reactions, may be a method of preventing later development of allergic disease in infants (Warner, 1999) (Fig. 4). Early postnatal antibiotic use in the rst 6 months of life preceded the manifestation of wheeze but not eczema or allergic sensitization during the rst 2 years of life (Kummeling et al., 2007) (Fig. 4). However, there is still incomplete understanding of the molecular and cellular mechanisms by which these factors adversely affect lung development and whether such effects can be blocked or reversed (Maritz et al., 2005). The role of early postnatal respiratory infections such as bronchiolitis and pneumonia in the later development of chronic respiratory diseases including asthma and chronic obstructive pulmonary disease is somewhat contradictory and needs further investigation (Stick, 2000). Chronic hypoxia is an attractive model that can be used in animals for performing comparative studies on whether hypoxia modies the programming events in the fetus and the newborn and whether it inuences on the risk of developing cardiopulmonary conditions in later periods of life. In fact, cohort and/or casecontrol studies in humans may also reveal the ways by which chronic hypoxia operates on early periods of life for determining later cardiopulmonary clinical conditions in human high altitude populations, as well as the underlying molecular mechanisms. Demonstration of critical periods of cardiopulmonary growth and development that are vulnerable to chronic hypoxia may lay the basis for developing early preventive interventions related to lifelong permanence at high altitude.

6. Clinical and public health implications: is the evidence strong enough? The strength of the available evidence is currently not enough for implementing sound clinical and health policy recommendations for preventing and managing high altitude-related conditions in children going to or already living at high altitude. However, the implication is that newcomers, particularly those of non-high altitude ancestry, may be at more risk of developing symptomatic high altitude pulmonary hypertension. Also, it seems that those infants and children with pre-existing pulmonary artery hypertension and those with an acute respiratory infection should be cautioned against traveling to high altitude, particularly against a rapid ascent. In addition, it seems advisable to recommend supplementary oxygen to infants and children living at high altitude and suffering from an acute respiratory infection, particularly pneumonia, when values of SaO2 are lower than those considered normal for the altitude of residence. Pneumonia is known to lead to hypoxemia and it very likely aggravates any pre-existing high altitude hypoxia. Normal SaO2 values published for infants and children living at sea level are clearly not applicable to children living at different altitudes and thus further investigation is warranted for identifying cutoff SaO2 values below which supplementary oxygen should be mandatory (Duke et al., 2002; Huicho, 2003).

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