Respiratory Physiology & Neurobiology 158 (2007) 224236

Cardiac adaptation to chronic high-altitude hypoxia: Benecial and adverse effects

B. Ostadal , F. Kolar
Centre for Cardiovascular Research, Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic Accepted 6 March 2007

Abstract This review deals with the capability of the heart to adapt to chronic hypoxia in animals exposed to either natural or simulated high altitude. From the broad spectrum of related issues, we focused on the development and reversibility of both benecial and adverse adaptive myocardial changes. Particular attention was paid to cardioprotective effects of adaptation to chronic high-altitude hypoxia and their molecular mechanisms. Moreover, interspecies and age differences in the cardiac sensitivity to hypoxia-induced effects in various experimental models were emphasized. 2007 Elsevier B.V. All rights reserved.
Keywords: High-altitude hypoxia; Permanent; Intermittent; Adaptation; Age; Reversibility; Heart; Protection; Molecular mechanisms; Hypertrophy

1. Introduction Chronic myocardial hypoxia as the result of disproportion between oxygen supply and demand at the tissue level may be induced by several mechanisms. The most common causes are undoubtedly (i) ischemic hypoxia (often described as cardiac ischemia), induced by the reduction or interruption of the coronary blood ow, and (ii) systemic (hypoxic) hypoxia, characterized by a drop in PO2 in the arterial blood but adequate perfusion. For the sake of completeness we could add (iii) anemic hypoxia, in which the arterial PO2 is normal but the oxygen transport capacity of the blood is decreased. In terms of relevant chronic clinical syndromes, ischemic hypoxia is manifested primarily in chronic ischemic heart disease whereas systemic hypoxia is associated with chronic cor pulmonale of varying origin, sleep apnea, cyanosis due to a hypoxemic congenital heart disease, and changes in the cardiopulmonary system induced by a decrease in barometric pressure at high altitude (Table 1). In two cases, however, systemic hypoxia can be considered as physiological: (i) the fetal myocardium adapted to hypoxia corresponding to an altitude of 8000 m and (ii) the myocardium of subjects living permanently at high altitudes. In both situations the myocardium is signicantly more resistant to acute

oxygen deciency but in populations in lowlands this property is lost soon after birth (Moret, 1980; Heath and Williams, 1995). Although the heart obviously has the capability to adapt to various forms of hypoxia, this review relates only to effects of chronic high-altitude hypoxia (HAH). From the broad spectrum of related problems we have concentrated on the development and regression of adaptive responses of the myocardium as they were described in experimental studies. Since most of the recent papers published on the different aspects of myocardial adaptation to HAH refer almost exclusively to studies published in the last few years, particular attention was paid to original reports on the discussed questions.

2. Denition, experimental model It should be pointed out that the term adaptation has been described in different ways, which occasionally leads to semantic problems in biology. According to the glossary edited by the International Union of Physiological Sciences (Bligh and Johnson, 1973), adaptation is change which reduces the physiological strain produced by a stressful component of the total environment. In contrast, the denition by Adolph (1956) discards the notion of benet: adaptations are modications of organisms that occur in the presence of particular environments and circumstances . . . not limited, as is often done, to

Corresponding author. Tel.: +420 296 442 553; fax: +420 296 442 125. E-mail address: ostadal@biomed.cas.cz (B. Ostadal).

1569-9048/$ see front matter 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.resp.2007.03.005

B. Ostadal, F. Kolar / Respiratory Physiology & Neurobiology 158 (2007) 224236 Table 1 Experimental models of chronic hypoxia Model Hypobaric hypoxia Permanent Intermittent Normobaric hypoxia Permanent Human relevance Life at high altitude Repeated ascents in mountains (mountaineering, tourism, pilgrims), high-altitude training Hypoxemic congenital heart disease, severe chronic obstructive lung disease, severe chronic ischemic heart disease Exacerbations of chronic obstructive lung disease, ischemic heart disease (acute coronary syndrome, exercise), sleep apnea

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Intermittent

modications that seem favorable to the individual. In fact, adaptation to chronic HAH is an adjustment that does not imply, in an obligatory sense, that it is benecial. Functional adaptive changes require time to materialize; they occur through (i) genotypic adaptations, which result from genetically xed attributes to those species that have lived for generations in their environment, and (ii) phenotypic adaptations (including accommodation, acclimation, and acclimatization) which are labile processes occurring within the lifetime of an organism, and decay when these circumstances no longer exist (Bouverot, 1985). The term adaptation as used in this review, refers to changes in cardiac structure and function that result from chronic exposure to natural or simulated HAH. The most frequently used experimental model in research on HAH is either the natural mountain environment or hypoxia simulated under laboratory conditions in a normobaric or hypobaric chamber (Table 1). This model permits the study of the time-course of development of benecial and adverse adaptive changes, the possibility of their spontaneous reversibility when the animals are removed from the hypoxic atmosphere, and/or the pharmacological protection against unwanted manifestations. As compared to simulated high altitude, other factors such as cold or physical activity have to be taken into account in a natural mountain environment, though hypoxia remains the main stimulus. Chronic hypoxia is, however, not always permanent; it is often of intermittent nature, e.g. in repeated ascents in mountains, in exacerbations of chronic obstructive lung disease during an acute respiratory infection, or in sleep apnea. Likewise, hypoxia is not continual in myocardial ischemia, when it depends on the actual regional coronary blood ow (Ostadal and Widimsky, 1985; Ostadal et al., 1994). Experimental data comparing the effects of permanent and intermittent HAH on the myocardium are, however, very sporadic. In addition, current experimental protocols of intermittent hypoxia vary greatly in cycle length, severity and number of hypoxic episodes per day and number of exposure days. It is evident that these factors are critical in determining whether intermittent hypoxia is benecial or harmful (B eguin et al., 2005). Another interesting methodological problem is the difference between effects of normobaric and hypobaric hypoxic exposures. Similarly as in the previous case, the available literature is not conclusive. Whereas Sheedy et al. (1996) have found that both hypobaric and normo-

baric hypoxia induced the same degree of right ventricular (RV) hypertrophy, remodeling of pulmonary arterioles, and increases in hematocrit, Savourey et al. (2003) have demonstrated that, compared to normobaric hypoxia, hypobaric hypoxia led to a greater hypoxemia, hypocapnia and lower arterial oxygen saturation (myocardial parameters were not investigated). Sensitivity to hypoxia is characterized by marked interspecies differences; this raises the question of suitable experimental animals. Cattle and pigs are among the most sensitive animals, sheep and dogs seem less liable to develop hypoxic pulmonary hypertension and RV hypertrophy, while rats and rabbits fall between these two groups (Tucker et al., 1975; Herget and Palecek, 1978; Reeves et al., 1979; Wauthy et al., 2004). The signicance of experimental results for clinical practice depends on the extent to which observed changes are comparable to ndings in humans. Pulmonary hypertension, RV hypertrophy, muscularization of the pulmonary arterioles and the enlargement of the carotid body occur in both rats and humans; the development of their ventilatory adaptation to chronic hypoxia is comparable (Heath and Williams, 1995; Ostadal et al., 1998). It is obvious, that the attempt to summarize the existing data on the effects of chronic HAH on the myocardium is complicated by different experimental models, duration and degree of hypoxic stimulus as well as by the selected experimental animals. Adaptation to HAH is characterized by a variety of functional changes to maintain homeostasis with minimum expenditure of energy (Durand, 1982). Such adjustments may protect the heart under conditions that require enhanced work and consequently increased metabolism. Adaptation thus increases cardiac tolerance to all major deleterious consequences of acute oxygen deprivation. Furthermore, chronic permanent hypoxia may have a signicant antihypertensive effect, due to decreased peripheral resistance in the systemic circulation (Henley et al., 1992). In addition to protective effects, adaptation to chronic hypoxia (as also with other types of adaptation) also induces other adaptive responses including hypoxic pulmonary hypertension and RV hypertrophy, which may under excessive hypoxia result in congestive heart failure. We shall, therefore, deal with the development of both benecial and adverse effects of myocardial adaptation to chronic HAH. 3. Cardioprotective effects 3.1. Adult heart In chronic HAH, the myocardium must preserve adequate contractile function in spite of lowered oxygen tension in the coronary circulation. Such an environment requires genotypical adaptation or acclimatization (in lowlanders after prolonged residence at high altitude), which may have cardioprotective effects. It was reported already in the late 1950s (Hurtado, 1960) that the incidence of myocardial infarction is lower in people who live at high altitude (Peru, 4000 m). An epidemiological survey from New Mexico (Mortimer et al., 1977) gave some evidence that even living at moderate elevations (2100 m) could result in protection against death from ischemic heart disease. In addition to chronic hypoxia, however, other factors such as

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Fig. 1. Typical examples of cardioprotective effects of adaptation to chronic intermittent HAH in rats. Reduction of infarct size, normalized to the area at risk (IS/AR, Neckar et al., 2002a,b), decreased number of premature ventricular complexes during ischemia (PVCs, Asemu et al., 1999) and improved recovery of postischemic contractile function (Widimsky et al., 1973).

relatively increased physical activity and reduced obesity have to be taken into consideration while explaining the protective effects of living at high altitude. Epidemiological observations on the protective effect of high altitude were conrmed in experimental studies using a model of HAH simulated in a hypobaric chamber. In this connection, it should be pointed out that the rst experiments were carried out in Prague in 1958 by Kopecky and Daum. They found that cardiac muscle isolated from rats exposed every other day for 6 weeks to an altitude of 7000 m recovered its contractile function during reoxygenation following a period of acute anoxia to a higher level than that of control animals. These results were later conrmed by Poupa et al. (1966, acute anoxia in vitro, isoproterenol-induced cardiac necrosis) and McGrath and Bullard (1968, acute anoxia in vitro). Furthermore, it has been reported (Widimsky et al., 1973; McGrath et al., 1973) that a similar protective effect can be induced by a relatively short intermittent exposure of rats to simulated high altitude (4 h/day, a total of 24 exposures up to 7000 m). Moreover, a signicant sex difference was demonstrated in the resistance of isolated cardiac muscle to oxygen deciency; the myocardium of female control rats proved to be more tolerant to hypoxia. Chronic HAH resulted in enhanced resistance in both sexes, yet the sex difference was maintained (Ostadal et al., 1984b). These ndings were later repeatedly conrmed in studies using various experimental models, adaptation protocols, and different end points of injury. It has been found that the heart of animals adapted to HAH develop smaller myocardial infarction (Meerson et al., 1973; Turek et al., 1980; Neckar et al., 2002a), exhibit better functional recovery following ischemia (Tajima et al., 1994), and had a lower number of ventricular arrhythmias (Meerson et al., 1987, 1989; Asemu et al., 2000). Examples of these cardioprotective effects are shown in Fig. 1. The antiarrhythmic protection was critically dependent on the experimental model and the degree and duration of hypoxic exposure (Asemu et al., 2000). Moreover, Henley et al. (1992) observed that adaptation to HAH attenuated the development of systemic hypertension and left ventricular (LV) hypertrophy in spontaneously hypertensive rats. In this connection it is inter-

esting to mention the study of Milano et al. (2002), comparing the cardioprotective effect of permanent (5500 m, 2 weeks) and intermittent (1 h/day exposure to normoxia) normobaric hypoxia in rats; they have found signicantly better protection upon reoxygenation in rats exposed to intermittent hypoxia. Moreover, Zong et al. (2005) demonstrated robust cardioprotection in a novel canine model of chronic intermittent normobaric hypoxia (FIO2 10%): 20-day program of 58 daily cycles of short hypoxia (510 min), with intervening 4-min periods of normoxia prevented development of ventricular tachycardia and brillation upon reperfusion. In contrast to protective effects of adaptation to chronic HAH, Joyeux-Faure et al. (2005) have recently observed that an extreme model of chronic intermittent hypoxia (FIO2 5%, 40-s cycles of hypoxia followed by 20 s of normoxia, 8 h/day, a total of 35 days) makes the heart more sensitive to ischemic injury, probably through the excess of reactive oxygen species (ROS) production. In addition, persistent systemic hypertension is a common maladaptation to severe intermittent hypoxia (e.g. Kolar et al., 1989) and in models of obstructive sleep apnea, obviously as a result of increased sympathetic activity and oxidative stress (Fletcher, 2001, Zoccal et al., 2007). 3.2. Effect of age The cardioprotective effect of adaptation to HAH is markedly inuenced by the age of experimental animals. In a recent study, La Padula and Costa (2005) examined the effect of aging: they submitted 7-week-old rats to sustained simulated altitude of 5000 m for their entire lifetime. They have found that whereas cardiac tolerance to acute hypoxia was in adult animals (up to 18 months) signicantly increased, it was lost in senescent rats (25 months). Loss of adaptation involving an exaggeration of pulmonary hypertension (chronic mountain sickness) is frequent in aged people living at high altitude in the Andes. Whereas an increasing number of data is available concerning the protective effect of adaptation to HAH on the adult myocardium, much less is known about the possible cardioprotective effect on the immature heart. In this connection it is necessary to mention that

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healthy immature myocardium is more tolerant to ischemia than that of the adult (for review see Ostadal et al., 1999). However, only a few studies compared the tolerance to oxygen deprivation in chronically hypoxic versus normoxic immature hearts. We observed (Ostadal et al., 1995) that chronic HAH, simulated in the barochamber, results in a similarly enhanced recovery of the contractile function in rats exposed to chronic hypoxia either from the fourth day of postnatal life or in adulthood. Similarly, Baker et al. (1995) demonstrated that adaptation to hypoxia increased the tolerance of the developing rabbit heart (day 7 to day 28 of postnatal life). Our experiments (Ostadalova et al., 2002) have shown that the protective effect of chronic hypoxia is absent in newborn rats. Prenatal exposure (i.e. pregnant mothers) to simulated HAH fails to further increase ischemic tolerance in 1-day-old hearts; this protective phenomenon develops only during the rst postnatal week. As far as the clinical relevance of this developmental approach is concerned, metabolic adaptation to chronic hypoxia and activation of protective pathways has been observed in the myocardium of children with cyanotic congenital cardiac malformations (Samanek et al., 1989; Ferreiro et al., 2001; Raee et al., 2002). Recent experimental studies have shown that perinatal exposure to chronic HAH can change the susceptibility of the adult heart to ischemia/reperfusion (I/R) injury. Li et al. (2003) and Xu et al. (2006) have found that prenatal chronic hypoxia signicantly increased the sensitivity of the adult male rat heart to oxygen deprivation as indicated by increased infarct size, decreased postischemic recovery of LV function and increased LV stiffness. Similarly, Hampl and Herget (1990) and Hampl et al. (2003) have shown that perinatal hypoxia increases the susceptibility to hypoxic pulmonary hypertension later in life. Our study (Netuka et al., 2006) demonstrated that the late effect of perinatal exposure to intermittent hypobaric hypoxia is sexdependent: it increased cardiac tolerance in adult female rats; the effect in males, as judged from the incidence of ischemic ventricular arrhythmias, was quite opposite. These results support the hypothesis that chronic perinatal hypoxia is a primary programming stimulus in the heart that may lead to sex-dependent changes in cardiac tolerance to acute ischemia in later adult life. This fact would have important implications for patients who have experienced prolonged hypoxemia in early life. 4. Molecular mechanisms of cardioprotection Although the cardioprotective effect of chronic HAH against various manifestations of acute I/R injury has been known for half a century, its molecular mechanism did not receive major attention until recently and thus it remains far from being understood. Among numerous potentially protective factors associated with chronic hypoxia, only a few have been addressed experimentally so far. The situation is further complicated by the fact that various experimental models of hypoxia, animal species and methodological approaches employed as well as various end points of injury examined do not allow to compare data from different research laboratories and extrapolate them to a common picture. It cannot be excluded that the detailed involvement of individual factors is species-dependent

and may differ in the protective mechanisms induced by, e.g. sustained or intermittent, mild or severe, hypoxia, etc. Nevertheless, it seems that various protective phenomena, including both short-lived preconditioning and long-lasting effects of chronic hypoxia, utilize essentially the same endogenous pool of protective pathways, although with different efciency (Neckar et al., 2002a,b). In contrast to classic preconditioning, chronic hypoxia not only activates these signaling pathways but it also affects the expression of their components and other proteins associated with maintaining oxygen homeostasis via transcription factors such as, e.g. hypoxia-inducible factor 1 (HIF-1, for rev. see Semenza, 2004). As molecular mechanisms of cardiac protection by adaptation to chronic hypoxia were recently reviewed elsewhere (Kolar and Ostadal, 2004), here we present only a brief updated overview. It is well known that exposure to chronic intermittent hypoxia is initially associated with oxidative stress (Yoshikawa et al., 1982; Herget et al., 2000; Chen et al., 2005; Kolar et al., 2007) and increased adrenergic stimulation (Ostadal et al., 1984a). Both events were traditionally considered as injurious but now it appears that they are also involved in the development of cardiac ischemia-resistant phenotype. Recent observations suggest that increased sympathetic activity results from the elevated caroptid chemoreceptor response to hypoxia that is mediated by ROSdependent signaling and HIF-1 (for rev. see Prabhakar et al., 2007). The experiments of Mallet et al. (2006) demonstrated that robust cardioprotection in terms of infarct size-limitation and elimination of life-threatening ischemic ventricular arrhythmias in a dog model of intermittent hypoxia was completely prevented by administration of the 1 -adrenoceptor antagonist metoprolol before each hypoxic session. In our experiments on rats, antioxidant interventions (administration of N-acetylcysteine or exposure to hypercapnia) during adaptation of rats to intermittent (Kolar et al., 2007) or sustained (Neckar et al., 2003) hypoxia, respectively, signicantly attenuated the protective effect on infarct size reduction. Milano et al. (2002) suggested that repeated reoxygenation is crucial for the induction of protective response: the recovery of contractile function was better in hearts isolated from rats that had been reoxygenated for 1 h/day throughout the hypoxic adaptation protocol compared to those maintained under sustained hypoxia. These data suggest that both ROS and catecholamines contribute to the induction of cardioprotection by chronic hypoxia but the mechanism is unknown. It should be mentioned that adaptation to hypoxia decreases cardiac adrenergic responsiveness by inhibition of myocardial -adrenoceptor-adenylyl cyclase signaling system (e.g. Voelkel et al., 1981; Hrbasova et al., 2003) that may protect the heart against excessive stimulation by catecholamines in the setting of I/R. It seems likely that chronic 1 -adrenoceptor antagonism could prevent this benecial adaptation in the study of Mallet et al. (2006). Based on the effects of nitric oxide (NO) synthase inhibitors or NO donors, it has been proposed that increased generation of NO plays a positive role in the protective mechanism induced by chronic hypoxia in neonatal rabbit (Baker et al., 1999) and rat hearts (Ostadalova et al., 2002). It remains unclear whether NO produced by the hypoxic myocardium originates from con-

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stitutive NO synthase (eNOS; Baker et al., 1999) or inducible NOS (iNOS; Rouet-Benzineb et al., 1999; Ferreiro et al., 2001; Grilli et al., 2003; Ding et al., 2005). However, it should be perceived that there is an optimal concentration of NO for protection: too little or too much may be detrimental. The role of NO in myocardial I/R injury and in adaptive protective responses of chronically hypoxic heart is extremely complex (for rev. see Manukhina et al., 2006; Zaobornyj et al., 2007). Both adrenergic stimulation and increased production of ROS and NO can change the activity and/or expression of numerous signaling and effector molecules. Among them, various protein kinases were studied regarding their role in protection of chronically hypoxic hearts. Several reports demonstrated up-regulation and permanent activation of protein kinase C (PKC) in the myocardium following adaptation to chronic hypoxia (RouetBenzineb et al., 1999; Morel et al., 2003; Ding et al., 2004). Our experiments revealed that, unlike PKC isoform-, PKC- was strongly upregulated in chronically hypoxic rat myocardium and redistributed mainly to mitochondria and nuclear/perinuclear area (Neckar et al., 2005). These effects were ROS-dependent as they were prevented by antioxidant treatment during the hypoxic adaptation (Kolar et al., 2007). Cardioprotective effects of chronic hypoxia were inhibited by the general PKC inhibitor chelerythrine or PKC--selective inhibitor rottlerin (Ding et al., 2004; Neckar et al., 2005) suggesting the involvement of this enzyme in the protective mechanism. Another study demonstrated that PKC- and members of the family of mitogenactivated protein kinases, p38 MAPK and JNK, were activated and translocated from the cytosolic to the particulate fractions in chronically hypoxic infant human and rabbit myocardium, and inhibitors of these kinases abolished cardioprotection in hypoxic rabbits (Raee et al., 2002). Limited evidence suggests that many other protein kinases such as phosphatidylinositol 3-kinase (Crawford et al., 2003; Ravingerova et al., 2007), protein kinase A, Ca2+ -calmodulin-dependent protein kinase (Xie et al., 2005), cGMP-dependent protein kinase (Baker et al., 1999) or extracellular signal-regulated kinase (Crawford et al., 2003) may contribute to the protective mechanism of various types of chronic hypoxia. Signicance of these pathways, their regulation and mutual interactions remain to be elucidated. Activated protein kinases may exert their protective effects by phosphorylation of numerous target proteins. Concerning chronic hypoxia, the identity of these proteins is a matter of debate, and the evidence available so far is mostly indirect and not sufciently conclusive. One of the potential candidates is the ATP-sensitive K+ channel (KATP ), which was studied by several groups. It was demonstrated that chronic hypoxia led to the activation of KATP in various tissues (Cameron and Baghdady, 1994) and already 24 h of mild hypoxia in culture increased transcription of the channel subunit SUR2A in rat heart-derived H9c2 cells (Crawford et al., 2003). Several recent reports point to the role of KATP in the cardioprotective mechanism of chronic hypoxia though certain controversy exists regarding the importance of the channel type that is localized either on the sarcolemma (sKATP ) or the mitochondrial inner membrane (mKATP ). Because the molecular identity of mKATP is unknown, the majority of these studies rely on pharmaco-

logical tools in order to distinguish which of the two types are involved in protection. Thus, experiments performed mostly on rats using selective mKATP blockers, 5-hydroxydecanoate or MCC-134, and openers, diazoxide or BMS-191095, suggest that mitochondrially located KATP plays a crucial role in the protection of chronically hypoxic hearts against all major end points of I/R injury (Asemu et al., 1999; Neckar et al., 2002b; Ostadalova et al., 2002; Zhu et al., 2003; Kolar et al., 2005). Activation of both mKATP and sKATP seems to contribute to improved postischemic recovery of the contractile function of chronically hypoxic immature rabbit hearts (Baker et al., 1997; Kong et al., 2001). As pharmacology of KATP does not seem to be sufciently discriminative, novel methodological approaches are needed to resolve this issue. Recent reports demonstrated that chronic hypoxia protects cardiac myocytes against I/R-induced cytosolic Ca2+ overload by preserving functions of transport and regulatory proteins that are involved in maintaining intracellular Ca2+ homeostasis, such as Na+ /Ca2+ exchanger, sarcoplasmic reticulum Ca2+ pump, ryanodine receptors (Chen et al., 2006) and phospholamban (Xie et al., 2005). Another study from the same group showed that chronic hypoxia protected mitochondria against Ca2+ overload, and delayed mitochondrial permeability transition and cytochrome c release upon reperfusion (Zhu et al., 2006). The latter effect, together with increased expression of antiapoptotic factor Bcl-2 and decreased expression of proapoptotic Bax, can be responsible for the reduced rate of cardiac myocyte apoptosis induced by I/R insult in chronically hypoxic hearts (Dong et al., 2003). However, it should not be neglected that chronic hypoxia per se can stimulate apoptosis (Bianciardi et al., 2006). Studies of Cai et al. (2003) showed that production of erythropoietin, dependent on activation of HIF-1 pathway, plays an important role not only in the stimulation of hematopoiesis but also in the increased ischemic tolerance of chronically hypoxic mouse heart. Angiotensin II type 1 receptor-mediated effects seem to underlie the improved postischemic recovery of the contractile function afforded by chronic hypoxia in neonatal rat heart (Rakusan et al., 2007). Last but not least, opioid peptides seem to contribute to the antiarrhythmic protection in chronically hypoxic rats (Lishmanov et al., 1998). Obviously, the list of factors and molecular pathways mentioned above is far from complete and many others (stress proteins, antioxidant enzymes, thyroid hormones, prostanoids, etc.) can be expected to play a role in the complex cardioprotective mechanism of chronic hypoxia. Better understanding to this phenomenon is the subject of further focused research. 5. Other benecial adaptive responses 5.1. Blood oxygen transport An increased oxygen-carrying capacity of the blood by elevated hematocrit and concentration of hemoglobin was traditionally considered as an effective adaptive mechanism to chronic HAH. Indeed, birds and mammals (including human subjects) introduced to high altitude develop a variable degree

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of polycythemia associated with a shift of the oxygen dissociation curve to the right due to an increased concentration of 2,3-diphosphoglycerate (Monge and Leon-Velarde, 1991). This response mainly results from the stimulation of the erythroid precursor cells in the bone marrow by erythropoietin produced in hypoxic kidney. Modern understanding of the biology of erythropoietin has made it clear that hypoxia initiates erythropoietin gene transcription and that hypoxia-inducible factor (HIF)-1 is the pivotal oxygen-regulated transcription factor responsible for this pathway (Semenza, 2004). Gore et al. (2006) have, however, observed that chronic intermittent hypobaric hypoxia did not accelerate erythropoiesis despite the transient increase in serum erythropoietin. This alludes to the requirement of a larger and more sustained critical level of erythropoietin to yield a substantial effect on the red-cell compartment. Interestingly, mammals and birds genotypically adapted to high altitude show modest or no increase in hematocrit (Banchero et al., 1971). This avoids the potentially harmful inuence of increased blood viscosity due to polycythemia and suggests that increased blood oxygen content is not essential for the adaptation. The role of myoglobin consists in storing oxygen and facilitating its transport to tissue. Several studies demonstrated an increased concentration of myoglobin in chronically hypoxic myocardium, but signicant differences exist depending upon species and age (Moret, 1980). 5.2. Tissue oxygen transport The cardiovascular system provides the supply of oxygen to the tissues at high altitude by changes in the cardiac output and by alterations in the distribution of blood in the body. As mentioned in Section 4, exposure to HAH be initially associated with increased adrenergic activity and elevated plasma concentration of catecholamines, which results in positive chronotropic and inotropic stimulation of the heart leading to increase in cardiac output. The data on the response of the systemic circulation to the prolongation of hypoxic exposure are, however, rather controversial. Whereas according to Heath and Williams (1995), the overall effect of the chronic HAH in humans is to reduce cardiac output, Calbet (2003) has found no change in cardiac output in lowlanders after 9 weeks of exposure to HAH, despite persisting elevation of catecholamines. Similar heterogenous result can be observed also in animal studies. For the explanation of these discrepancies, the type, degree and duration of hypoxic exposure have to be taken into consideration. Coronary blood ow in high-altitude residents (Moret et al., 1972) as well as in healthy subjects transferred to high altitude (Grover and Alexander, 1971) is lower. There are, however, disagreements with respect to the coronary ow and development of myocardial capillaries in animals exposed to hypobaric hypoxia. For example, Turek et al. (1975) and Scheel et al. (1990) found a greater coronary ow in rats and dogs, whereas functional measurements in dogs did not reveal any effect of chronic hypoxia on coronary collateral ow. Whereas Rotta (1943), Clark and Smith (1978) and Smith and Clark (1979) found a decrease in the capillary density in chronically hypoxic guinea pigs and rats, Miller and Hale (1970) and Zhong et al. (2002) found an increased capillary density in both ventricles. Rakusan et al. (1981) as well as

Pietschmann and Bartels (1985) found no evidence of increased myocardial capillary density in adult animals exposed to high altitude. Mutual comparison of these studies is difcult due to variations in experimental models and other factors. Among these, the interspecies differences in adaptation to hypoxia may play an important role. Rodents, for example have been shown to have a relatively higher capacity for myocardial vascular growth than other mammals. Another important factor may be the age at which the animals were exposed to HAH, since the degree of angiogenesis decreases with the age of animals (for rev. see Rakusan, 1999; Tomanek et al., 2003). Recently, Rakusan et al. (2007) have found that chronic intermittent hypoxia of relatively short duration stimulated angiogenesis in both RV and LV of the immature rat heart. Moreover, caveolin-1 level, a good marker of capillarization, increased parallel to the vessel density. On the other hand, this angiogenic response was completely prevented by angiotensin II type 1 receptor blockade, suggesting that the AT1 receptor pathway plays an important role in coronary angiogenesis. Hypoxia-induced myocardial angiogenesis is undoubtedly inuenced by extracellular matrix environment, increased expression of basic broblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and other signaling molecules (for rev. see Tomanek, 1999). Nevertheless, it seems that coronary angiogenesis and increased coronary ow are effective compensatory mechanisms at the beginning of the adaptation process; later their importance may decrease. This view is supported by normal or even decreased coronary blood ow in residents living at high altitude (see above). 5.3. Energy metabolism Bert (1878) was the rst to postulate that tissues may gradually alter their cellular metabolism during adaptation of the body to high altitude. According to Moret (1980) this effect may involve increased capacity of cardiac anaerobic metabolism, increased energy utilization capacity, and possibly selection of metabolic pathways or substrates with a higher energy efciency, which would decrease the oxygen requirements. This view is supported by the ndings in chronically hypoxic rats in which both ventricles had a signicantly increased glucose-utilizing capacity (hexokinase) as well as the capacity for the synthesis and degradation of lactate (lactate dehydrogenase). On the other hand, the ability to break down fatty acids (3-hydroxyacyl-CoA-dehydrogenase) signicantly decreased (Bass et al., 1989; Deindl et al., 2003). Many ATP-dependent processes, such as ion pumping or protein synthesis, are down regulated during exposure to chronic hypoxia (Hochachka and Lutz, 2001). This regulation allows the ATP level to remain constant even while the ATP turnover rate greatly declines (Nouette-Gaulain et al., 2005). Pissarek et al. (1997) found that chronic hypoxia induces an increased expression of B-creatine kinase subunit, which could represent an efcient adaptation in cellular energy transport, because of the colocalization of glycolytic enzymes and cytosolic creatine kinase isozymes. The experiments of McGrath and Bullard (1968) showing that the protective effect of adaptation was lost after treatment of the animals with the

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glyceraldehyde-3-phosphate dehydrogenase inhibitor, iodoacetate, suggested that the protective inuence of adaptation might be due to the increased glycolytic capacity. Furthermore, adaptation to chronic hypoxia induces an increased expression of cardiac myosin isoform with low myobrillar ATPase activity in both RV and LV (Pelouch et al., 1985; Pissarek et al., 1997). Recently, Letout et al. (2005) found, that this chronic hypoxiainduced shift (i.e. from myosin heavy chain with high ATPase activity to -myosin heavy chain with low ATPase activity) was similar in rats adapted or native to high altitude. In addition, adaptation to high altitude lowers the specic activities of several sarcolemmal ATPases and at the same time increases their afnity for ATP (Ziegelhoffer et al., 1987). These effects can be considered as an adaptive mechanism at the enzyme level that permits more efcient utilization of ATP and helps to prevent changes in membrane transport under conditions of low energy production. Chronic hypobaric hypoxia increased the number of cardiac mitochondria and slightly decreased their mean volume (Costa et al., 1988; Novel-Chate et al., 1995). Mitochondrial metabolism is involved in the adaptation to high altitude via energy regulation, generation of ROS, and apoptosis (Chandel et al., 2000). Nouette-Gaulain et al. (2005) have shown that chronic HAH decreased ATP synthesis as a consequence of an alteration in mitochondrial respiratory chain complexes in both ventricles but that this effect is delayed in the RV. However, when RV hypertrophy was fully developed, mitochondrial energy metabolism was decreased as in the LV, suggesting some specic, but transient, adaptive processes at the onset of the RV hypertrophy. The results concerning the time-course of high altitude-induced alteration in energy metabolism in the RV deserve further discussion. It should be mentioned, however, that it is often impossible to distinguish the direct effects of hypoxia from those of hypertrophy and other factors, including the decrease in food utilization associated with exposure to high altitude (Barrie and Harris, 1976). 6. Right ventricular hypertrophy 6.1. High altitude-induced pulmonary hypertension and right ventricular hypertrophy Sustained hypoxia exerts opposite effects on the systemic and pulmonary vascular smooth muscle, bringing about vasodilatation in the systemic circulation but vasoconstriction and consequent structural remodeling in the pulmonary circulation. Pulmonary hypertension develops as a result of chronic hypoxia, whereas the systemic blood pressure is normal or even below normal in well-adapted subjects (Heath and Williams, 1995). Reliable investigations of the effect of high altitude on the cardiopulmonary system started some 50 years ago. Rotta et al. (1956) rst reported that healthy men and women living at high altitude have some degree of pulmonary hypertension and RV hypertrophy. These observations in people living in the Peruvian Andes were later conrmed by Penaloza et al. (1962) and Sime et al. (1963) for the same geographical region as well as by Vogel et al. (1962) for residents living at high altitude in the

United States, and by Singh et al. (1965) for temporary residents in Himalayas. The critical altitude for the development of pulmonary hypertension and RV hypertrophy in men was specied to be 3000 m (Hurtado, 1960). Chronic high altitude-induced RV hypertrophy is a benecial adaptation, allowing the RV to cope with an increased afterload and to maintain a normal cardiac output. It has been shown in rats that RV hypertrophy could already be seen at the time when chronic pulmonary hypertension was not yet developed (Widimsky et al., 1973). This suggests that RV hypertrophy can be induced by intermittent pulmonary hypertension present only during the stay of experimental animals in the barochamber. The LV weight remained unchanged and increased only during prolonged exposure to high altitude (Widimsky et al., 1973; La Padula and Costa, 2005; Cazorla et al., 2006). Since hypoxic pulmonary vasoconstriction exists in all adult mammals, it is not surprising that exposure to high altitude, either natural or simulated in a barochamber, may induce pulmonary hypertension and RV hypertrophy in different animal species including mouse, guinea pig, rat, cow, rabbit, pig, dog and sheep. As mentioned above, there are signicant interspecies variations in the pulmonary hemodynamic response to chronic hypoxia. Moreover, native high-altitude mammals including llamas, alpacas, and vicunas have largely lost their hypoxic pulmonary vasoconstriction response (Heath, 1988). They have thin-walled elastic and muscular pulmonary arteries and do not develop muscularization of the pulmonary arterioles. Such a thin-walled vasculature in the lung is associated with low pulmonary artery resistance and pressure; thus, these animals do not develop RV hypertrophy. 6.2. Functional adaptation of the right ventricle Experimental data dealing with the RV function of animals, exposed to HAH are scarce and comparison of the function of the right and left heart is still lacking. This approach would be very useful for the dissociation of the effect of increased workload (RV) and hypoxia (RV and LV). Kolar et al. (1993) have found that the resting values of RV systolic pressure measured in open chest rats were about 25 mm Hg in the control and 43 mm Hg in animals exposed to high altitude. After acute ligation of the pulmonary artery, the RV systolic pressure increased by a maximum of 52 mm Hg in the controls and by 73 mm Hg in hypertrophic ventricles. Similar changes were observed also for the maximum rate of contraction. Analysis of an isolated preparation of the RV working heart has revealed that mechanical performance during the compensated phase of hypertrophy was almost doubled in chronic HAH exposed animals, while the index of contractility remained unchanged; this indicates that the enhanced ventricular performance is merely the consequence of the increased muscle mass. The ability of the RV to maintain cardiac output against increased pulmonary resistance was markedly improved (Kolar and Ostadal, 1991). Interestingly, the RV contractile function is also generally preserved in patients with chronic obstructive lung disease suffering from pulmonary hypertension and RV hypertrophy. On the other hand, RV failure is observed with prolongation of exposure or degree of hypoxia

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in which worsening of hypoxemia induces a marked increase in afterload. Data dealing with the LV are rather controversial. La Padula and Costa (2005) using isolated rat papillary muscles from the LV have observed increased contractility in adult animals exposed to chronic HAH. The explanation of this nding is not clear since cell shortening and baseline calcium transients were not changed in LV myocytes isolated from hearts of rats adapted to chronic HAH (Chen et al., 2006). Similarly, Cazorla et al. (2006) did not observe any increase in the LV stroke volume, LV end-diastolic diameter, calcium sensitivity of myolament activation as well as transmural gradient of passive tension in single skinned myocytes isolated from the LV in rats exposed to simulated HAH. For the explanation of these controversial results, a different duration of hypoxia and different functional parameters studied have to be taken into consideration. Development of chronic hypoxia-induced RV hypertrophy in adult rats is accompanied by signicant changes in the protein proling both in the hypertrophic RV and non-hypertrophic LV (Ostadal et al., 1978a). Right-to-left differences, characteristic for animals living in normoxic environment, e.g. higher collagen concentration in the RV and higher concentration of myobrillar proteins in the LV did not change. HAH also modulates qualitative and quantitative changes of collagenous proteins: the proportion of this protein fraction was increased, whereas the collagen I/collagen III ratio is decreased, suggesting an increased synthesis of collagen III (Pelouch et al., 1985). Cardiac enlargement may be the result of both an increase in the number of individual cell elements (hyperplasia), which is limited to the early phases of ontogeny, and an increase in their volume (hypertrophy). The literature concerning the inuence of age on chronic hypoxia-induced pulmonary hypertension and RV hypertrophy is insufcient and not concise. Smith et al. (1974) reported that young rats exposed to chronic hypoxia had a lower RV hypertrophy than adult animals, but the young group was not acclimatized before the 21st day of life. Rabinovitch et al. (1981) compared cardiopulmonary changes in rats exposed to permanent hypoxia starting either from the ninth day of life or in adults. They found that the age difference in pulmonary hypertension and RV hypertrophy was not signicant. We have observed (Kolar et al., 1989) that intermittent HAH-induced chronic pulmonary hypertension and RV enlargement in rats exposed to hypoxia from the fourth day of postnatal life or in adulthood was comparable. Interestingly, rats secondarily adapted to altitude and animals born and living at altitude for many generations exhibit a similar degree of RV enlargement, likely to be related to hypoxia-induced pulmonary hypertension (Letout et al., 2005). In young animals exposed to HAH from the fourth day of postnatal life, the concentration of contractile, collagenous and sarcoplasmic proteins increased in the RV already after the seventh hypoxic exposure, when a RV enlargement was not yet observed (Pelouch et al., 1987). HAH delayed the transformation of to isoforms of myosin heavy chain, which normally occurs during rat ontogeny (Lompre et al., 1981). In young rats high altitude increased both types of collagen, but the elevation of collagen III was signicantly higher.

7. Regression of adaptive changes 7.1. Cardioprotective effects An important feature of adaptation to chronic HAH is that the protective effect may persist for a relatively long period after removal of animals from the hypoxic atmosphere (Ostadal and Widimsky, 1985; Faltova et al., 1987; Neckar et al., 2004; Fitzpatrick et al., 2005). It is unknown at present how long the recovery period is needed to achieve complete reversibility of protection. A recent study (Neckar et al., 2004) has shown that residual protection persists for at least 35 days of normoxic recovery. Duration depends, however, on the measured endpoint of injury: in contrast to persisting infarct size-limitation, the antiarrhythmic protection had already disappeared during the rst week after the hypoxic exposure. The attenuation of systemic hypertension in adapted spontaneously hypertensive rats dissipated when the rats returned to normoxic conditions (Henley et al., 1992). As high altitude-induced cardiac protection against acute I/R injury lasts markedly longer that any form of ischemic preconditioning (for rev. see Ostadal and Kolar, 1999), it suggests some possibilities in the search of clinically relevant protective mechanisms against cardiac ischemia. 7.2. Pulmonary hypertension and right ventricular hypertrophy Even severe chronic hypoxia-induced changes (body weight loss, polycythemia, pulmonary hypertension, RV hypertrophy and alterations in cardiac function and metabolism) were completely reversible after removal of rats from the hypoxic atmosphere for a sufciently long period of time (Ressl et al., 1974; Ostadal et al., 1985; Bass et al., 1989; Kolar and Ostadal, 1991). The regression of muscularization of distal pulmonary arterioles was, however, incomplete (Leach et al., 1977; Herget et al., 1978). The rst fully normalized parameter was the body weight (2 weeks after the end of hypoxic exposure); hemoglobin and RV weight were normalized 2 weeks later. The protein composition of the ventricular myocardium of rats exposed to HAH remained, however, signicantly different from the controls: an increased proportion of the collagenous fraction persisted even when the RV weight was already normal. 7.3. Pharmacological treatment In view of the potential value of chronic hypoxia for cardioprotection it would be ideal to reduce the development of adverse changes and simultaneously preserve the benecial signs of the process of adaptation. From the relatively narrow spectrum of promising drugs, calcium antagonists were investigated for their combined vasodilatatory and cardioprotective effects (Ostadal et al., 1981). Preventive administration of verapamil (before each of the hypoxic exposures) signicantly reduced the degree of pulmonary hypertension and RV hypertrophy and partially prevented hypertensive changes in the pulmonary vasculature. Unfortunately, the benecial sign of adaptation (i.e. cardiac resistance to acute hypoxia) was also

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diminished. Therapeutic administration of calcium antagonists when the cardiopulmonary changes were already developed was without effect. For an explanation of these ndings, the relationship between calcium metabolism in pulmonary vascular smooth muscle and the degree of hypoxia should be taken into consideration. Since ACE inhibitors are known to reduce LV hypertrophy and brosis in experimental systemic hypertension (Weber et al., 1991), an attempt was made to determine whether treatment with ACE inhibitor enalapril could also reduce the increased ventricular concentration of collagen in animals recovering from hypoxia-induced pulmonary hypertension (Pelouch et al., 1997). It was shown that enalapril signicantly decreased the heart rate, systemic arterial pressure and LV weight in both hypoxic and control animals. However, the pulmonary blood pressure and RV hypertrophy remained unchanged. On the other hand, the content of collagen was reduced in both ventricles from the enalapril-treated animals. These data suggest that the regression of cardiac brosis due to enalapril may be independent of changes in the hemodynamic load. In addition, the inhibition of ACE attenuated the process of morphological reconstruction of pulmonary vasculature (Herget et al., 1996). Recently, Rakusan et al. (2007) found that the AT1 receptor pathway plays an important role in coronary angiogenesis and improved cardiac ischemic tolerance induced in neonatal rats by chronic hypoxia. Further studies are required if we are to fully appreciate the role of the renin-angiotensin system in the process of adaptation to chronic hypoxia. Moreover, it would be very interesting to know whether new therapies approved for the treatment of pulmonary hypertension (prostanoids, endothelin-receptor antagonists and phosphodiesterase-5 inhibitors) will be more successful in this respect (for rev. see Ghofrani et al., 2006). Attempts have been made to reduce pulmonary hypertension and RV hypertrophy by blocking the adrenergic pathways. It has been reported that administration of -adrenoceptor blockers propranolol (Moret and Duchosal, 1976) or metipranolol (Ostadal et al., 1978b) to high altitude-exposed rats signicantly reduced the values of RV systolic pressure and RV hypertrophy. These results were later conrmed by Ostman-Smith (1995) and Tual et al. (2006), suggesting that the adrenergic system participates in the development of HAH-induced cardiopulmonary changes. Moreover, beta-blockade signicantly reduced also the polycythemic response of hypoxic animals (Ostadal et al., 1978b; Voelkel et al., 1980), probably by its effect on the production of erythropoietin (Zivny et al., 1983). 8. Conclusions It may be concluded that adaptation to chronic HAH increases cardiac tolerance to all major deleterious consequences of acute oxygen deprivation in both adult and immature heart. In addition to the protective effect, chronic hypoxia also induces other adaptive responses, including hypoxic pulmonary hypertension and RV hypertrophy, which, in the case of an excessive hypoxic stimulus, may result in congestive heart failure. It is evident from experimental studies that the type of hypoxia (permanent versus intermittent, normobaric versus hypobaric), duration

and severity of hypoxia and frequency of hypoxic episodes are critical factors determining whether chronic hypoxia is benecial or harmful. Unfortunately, despite the fact that the rst experimental study on the cardioprotective effect of adaptation to HAH was published almost 50 years ago, no satisfactory explanation of this important phenomenon has yet been proposed. Although many potential factors have been suggested to play a role in the cardioprotective effect, the available data are not sufciently conclusive and its detailed molecular mechanism remains unknown. As compared with the temporal character of ischemic preconditioning, cardiac protection by adaptation to chronic HAH may persist even after the regression of other hypoxia-induced changes, such as pulmonary hypertension and RV hypertrophy. This fact offers a more optimistic view on the future of effective protection of the ischemic myocardium. As far as the clinical relevance of the experimental research on adaptation to high altitude is concerned, it is necessary to stress that chronic hypoxia and hypoxemia are not conned to life at high altitude, but can be found in chronic ischemic heart disease, chronic obstructive lung disease, sleep apnea, and in children with cyanotic congenital heart disease. It may be assumed that elucidation of the mechanisms involved in experimental adaptation to high altitude may be at least partially used for the explanation of mechanisms involved in cardiac effects of chronic hypoxia in humans. Acknowledgements This study was supported by grants from the Ministry of Education of the Czech Republic (1M0510) and from the Grant Agency of the Czech Republic (305/07/0875). References
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