cardiac adaptation to chronic high-altitude hypoxia

7/30/2019 Cardiac Adaptation to Chronic High-Altitude Hypoxia

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Respiratory Physiology & Neurobiology 158 (2007) 224236

Cardiac adaptation to chronic high-altitude hypoxia:Beneficial 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 beneficial 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 causesare undoubtedly (i) ischemic hypoxia (often described as car-

diac ischemia), induced by the reduction or interruption of the

coronary blood flow, and (ii) systemic (hypoxic) hypoxia, char-

acterized by a drop in PO2 in the arterial blood but adequate

perfusion. For the sake of completeness we could add (iii) ane-

mic hypoxia, in which the arterial PO2 is normal but the oxygen

transport capacity of the blood is decreased. In terms of rele-

vant chronic clinical syndromes, ischemic hypoxia is manifested

primarily in chronic ischemic heart disease whereas systemic

hypoxia is associated with chronic cor pulmonale of varying ori-

gin, sleep apnea, cyanosis due to a hypoxemic congenital heart

disease, and changes in the cardiopulmonary system inducedby 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 cor-

responding to an altitude of 8000 m and (ii) the myocardium

of subjects living permanently at high altitudes. In both situ-

ations the myocardium is significantly more resistant to acute

Corresponding author. Tel.: +420 296 442 553; fax: +420 296 442 125.

E-mail address: [email protected] (B. Ostadal).

oxygen deficiency but in populations in lowlands this prop-

erty 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 ofchronic 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 adapta-

tion 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. Definition, experimental model

It should be pointed out that the term adaptation has been

described in different ways, which occasionally leads to seman-

tic 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 phys-

iological strain produced by a stressful component of the total

environment. In contrast, the definition by Adolph (1956) dis-

cards the notion of benefit: adaptations are modifications of

organisms that occur in the presence of particular environ-

ments and circumstances . . . not limited, as is often done, to

1569-9048/$ see front matter 2007 Elsevier B.V. All rights reserved.

doi:10.1016/j.resp.2007.03.005
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B. Ostadal, F. Kolar / Respiratory Physiology & Neurobiology 158 (2007) 224 236 225

Table 1

Experimental models of chronic hypoxia

Model Human relevance

Hypobaric hypoxia

Permanent Life at high altitude

Intermittent Repeated ascents in mountains (mountaineering,

tourism, pilgrims), high-altitude training

Normobaric hypoxia

Permanent Hypoxemic congenital heart disease, severe chronic

obstructive lung disease, severe chronic ischemic

heart disease

Intermittent Exacerbations of chronic obstructive lung disease,

ischemic heart disease (acute coronary syndrome,

exercise), sleep apnea

modifications 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 beneficial. Functional adap-

tive changes require time to materialize; they occur through

(i) genotypic adaptations, which result from genetically fixedattributes 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 structureand function that resultfrom 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 hypo-

baric chamber (Table 1). This model permits the study of thetime-course of development of beneficial and adverse adap-

tive changes, the possibility of their spontaneous reversibility

when the animals are removed from the hypoxic atmosphere,

and/or the pharmacological protection against unwanted mani-

festations. 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 perma-

nent; 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. Like-

wise, hypoxia is not continual in myocardial ischemia, when

it depends on the actual regional coronary blood flow (Ostadaland 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, cur-

rent 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 fac-

tors are critical in determining whether intermittent hypoxia is

beneficial or harmful (Beguin et al., 2005). Another interesting

methodological problem is the difference between effects of nor-

mobaric 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 satu-

ration (myocardial parameters were not investigated).

Sensitivity to hypoxia is characterized by marked interspecies

differences; this raises the question of suitable experimental ani-

mals. 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). Thesig-

nificance of experimental results for clinical practice depends on

the extent to which observed changes are comparable to findings

in humans. Pulmonary hypertension, RV hypertrophy, muscu-

larization 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 tol-

erance to all major deleterious consequences of acute oxygen

deprivation. Furthermore, chronic permanent hypoxia may have

a significant antihypertensive effect, due to decreased periph-eral 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 adap-

tive responses including hypoxic pulmonary hypertension and

RV hypertrophy, which may under excessive hypoxia result in

congestive heart failure. We shall, therefore, deal with the devel-

opment of both beneficial 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 genotypi-

cal 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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226 B. Ostadal, F. Kolar / Respiratory Physiology & Neurobiology 158 (2007) 224236

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 protectiveeffects of living at high altitude.

Epidemiological observations on the protective effect of high

altitude were confirmed in experimental studies using a model

of HAH simulated in a hypobaric chamber. In this connection,

it should be pointed out that the first 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 func-

tion during reoxygenation following a period of acute anoxia

to a higher level than that of control animals. These results

were later confirmed 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 significant

sex difference was demonstrated in the resistance of isolated car-

diac muscle to oxygen deficiency; 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 findings were later repeatedly confirmed in studies

using various experimental models, adaptation protocols, and

different end points of injury. It has been found that the heartof animals adapted to HAH develop smaller myocardial infarc-

tion (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 ofMilano et al. (2002), comparing

the cardioprotective effect of permanent (5500 m, 2 weeks) andintermittent(1 h/dayexposure to normoxia) normobaric hypoxia

in rats; they have found significantly better protection upon

reoxygenation in rats exposed to intermittent hypoxia. More-

over, 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

fibrillation 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.

Kolaretal.,1989) andin modelsof obstructivesleepapnea, obvi-

ously as a result of increased sympathetic activity and oxidative

stress (Fletcher, 2001, Zoccal et al., 2007).

3.2. Effect of age

Thecardioprotective effect of adaptation to HAHis markedly

influenced 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) significantly increased, it was lost in senescent rats (25

months). Loss of adaptation involving an exaggeration of pul-

monary 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 depriva-

tion 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 phenomenondevelops only dur-

ingthe first postnatal week. As faras theclinicalrelevanceof 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 congeni-

tal cardiac malformations (Samanek et al., 1989; Ferreiro et al.,2001; Rafiee et al., 2002).

Recent experimental studies have shown that perinatal expo-

sure 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 sig-

nificantly 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 effectof perinatal exposure to intermittent hypobaric hypoxia is sex-

dependent: it increased cardiac tolerancein adult female rats; the

effect in males, as judged from the incidence of ischemic ven-

tricular arrhythmias, was quite opposite. These results support

the hypothesis that chronic perinatal hypoxia is a primary pro-

gramming 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 againstvarious 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 fac-

tors associated with chronic hypoxia, only a few have been

addressed experimentally so far. The situation is further compli-

cated 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 extrapo-

late 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. Neverthe-

less, 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 protec-

tive pathways, although with different efficiency (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 protec-

tion 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 itappears 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 ROS-

dependent signaling and HIF-1 (for rev. see Prabhakar et al.,

2007). The experiments ofMallet et al. (2006) demonstrated that

robust cardioprotection in terms of infarct size-limitation and

elimination of life-threatening ischemic ventricular arrhythmias

in a dogmodelof intermittenthypoxia was completely prevented

by administration of the 1-adrenoceptor antagonist metopro-

lol before each hypoxic session. In our experiments on rats,

antioxidant interventions (administration ofN-acetylcysteine orexposure to hypercapnia) during adaptation of rats to inter-

mittent (Kolar et al., 2007) or sustained (Neckar et al., 2003)

hypoxia, respectively, significantly attenuated the protective

effect on infarct size reduction. Milano et al. (2002) suggested

that repeated reoxygenation is crucial for the induction of pro-

tective 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 ofmyocardial -adrenoceptor-adenylyl cyclase signaling system

(e.g. Voelkel et al., 1981; Hrbasova et al., 2003) that may pro-

tect the heart against excessive stimulation by catecholamines in

the setting of I/R. It seems likely that chronic 1-adrenoceptor

antagonism could prevent this beneficial adaptation in the study

ofMallet 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 pro-

tection: too little or too much may be detrimental. The role of

NO in myocardial I/Rinjuryand in adaptive protective responses

of chronically hypoxic heart is extremely complex (for rev. see

Manukhina et al., 2006; Zaobornyj et al., 2007).

Bothadrenergic stimulation and increasedproductionof 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 chroni-

callyhypoxic hearts. Severalreports demonstrated up-regulation

and permanent activation of protein kinase C (PKC) in the

myocardium following adaptation to chronic hypoxia (Rouet-

Benzineb 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-dependentas 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- andmembersof thefamily of mitogen-

activated 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 (Rafiee et al., 2002). Limited evidence suggeststhat many other protein kinases such as phosphatidylinositol

3-kinase (Crawford et al., 2003; Ravingerova et al., 2007), pro-

tein kinaseA, Ca2+-calmodulin-dependent protein kinase (Xieet

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. Significance 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 sufficiently conclusive. One of the potential candidatesis 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 mech-

anism 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 sufficiently 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+ homeosta-

sis, such as Na+/Ca2+ exchanger, sarcoplasmic reticulum Ca2+

pump, ryanodine receptors (Chen et al., 2006) and phospho-lamban (Xie et al., 2005). Another study from the same group

showed that chronic hypoxia protected mitochondria against

Ca2+ overload, and delayed mitochondrial permeability tran-

sition 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 proapop-

totic 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 ery-thropoietin, dependent on activation of HIF-1 pathway, plays

an importantrole notonly in thestimulationof 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 chroni-

cally hypoxic rats (Lishmanov et al., 1998). Obviously, the list

of factors and molecular pathways mentioned above is far from

complete and manyothers(stress proteins, antioxidant enzymes,

thyroid hormones, prostanoids, etc.) can be expected to play

a role in the complex cardioprotective mechanism of chronichypoxia. Better understanding to this phenomenon is the subject

of further focused research.

5. Other beneficial adaptive responses

5.1. Blood oxygen transport

An increased oxygen-carrying capacity of the blood by

elevated hematocrit and concentration of hemoglobin was tra-

ditionally 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 disso-

ciation 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 ery-

thropoietin 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 substan-

tial 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 influence of increased blood viscosity due to

polycythemia and suggests that increased blood oxygen content

is notessential for theadaptation.The role of myoglobinconsistsin storing oxygen and facilitating its transport to tissue. Several

studies demonstrated an increased concentration of myoglobin

in chronically hypoxic myocardium, but significant 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 men-

tioned in Section 4, exposure to HAHbe initially associated with

increased adrenergic activity and elevated plasma concentrationof 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 con-

troversial. 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 dis-

crepancies, the type, degree and duration of hypoxic exposure

have to be taken into consideration.

Coronary blood flow 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, dis-

agreements with respect to thecoronaryflow anddevelopment of

myocardial capillaries in animals exposed to hypobaric hypoxia.

For example, Turek et al. (1975) and Scheel et al. (1990) found a

greater coronary flow in rats and dogs, whereas functional mea-

surementsin dogs did not reveal any effect of chronic hypoxia on

coronary collateral flow. Whereas Rotta (1943), Clark and Smith

(1978) and Smith and Clark (1979) found a decrease in the cap-

illary density in chronically hypoxic guinea pigs and rats, Miller

and Hale (1970) and Zhong et al. (2002) found an increased cap-

illary 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 difficult 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 pre-

vented by angiotensin II type 1 receptor blockade, suggesting

that the AT1 receptor pathway plays an important role in coro-

nary angiogenesis. Hypoxia-induced myocardial angiogenesis

is undoubtedly influenced by extracellular matrix environment,increased expression of basic fibroblast growth factor (bFGF),

vascular endothelial growth factor (VEGF) and other signaling

molecules (for rev. see Tomanek, 1999).

Nevertheless, it seems that coronary angiogenesis and

increasedcoronary floware effective compensatory mechanisms

at the beginning of the adaptation process; later their impor-

tance may decrease. This view is supported by normal or even

decreased coronary blood flow in residents living at high altitude

(see above).

5.3. Energy metabolism

Bert (1878) was the first to postulate that tissues may grad-

ually 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

metabolicpathwaysor substrateswith a higher energy efficiency,

which would decrease the oxygen requirements. This view is

supported by the findings in chronically hypoxic rats in which

both ventricles had a significantly increased glucose-utilizing

capacity (hexokinase) as well as the capacity for the synthe-

sis and degradation of lactate (lactate dehydrogenase). On the

other hand, the ability to break down fatty acids (3-hydroxy-

acyl-CoA-dehydrogenase) significantly decreased (Bass et al.,1989;Deindletal.,2003). Many ATP-dependent processes, such

as ion pumping or protein synthesis, are down regulated dur-

ing 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 efficient 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, iodoac-

etate, suggested that the protective influence of adaptation might

be due to the increased glycolytic capacity. Furthermore, adap-

tation to chronic hypoxia induces an increased expression of

cardiac myosin isoform with low myofibrillar ATPase activity

in both RV and LV (Pelouch et al., 1985; Pissarek et al., 1997).

Recently, Letout et al. (2005) found, that this chronic hypoxia-

induced 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 specific activities of sev-

eral sarcolemmal ATPases and at the same time increases their

affinity for ATP (Ziegelhoffer et al., 1987). These effects can be

considered as an adaptive mechanism at the enzyme level that

permits more efficient 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 decreasedtheir meanvolume (Costa et

al., 1988; Novel-Chate et al., 1995). Mitochondrial metabolismis involved in the adaptation to high altitude via energy regula-

tion, 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 respiratorychaincomplexes in both ventricles but

that this effect is delayed in the RV. However, when RV hyper-

trophy was fully developed, mitochondrial energy metabolism

was decreased as in the LV, suggesting some specific, but tran-

sient, adaptive processes at the onset of the RV hypertrophy. The

results concerningthe time-course of highaltitude-induced alter-

ation in energy metabolism in the RV deserve further discussion.

It should be mentioned, however, that it is often impossible todistinguish the direct effects of hypoxia from those of hypertro-

phy 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 vasodi-

latation in the systemic circulation but vasoconstriction andconsequent 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 car-

diopulmonary system started some 50 years ago. Rotta et al.

(1956) first 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 Peru-

vian Andes were later confirmed 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 pul-

monary hypertension and RV hypertrophy in men was specified

to be 3000 m (Hurtado, 1960).

Chronic high altitude-induced RV hypertrophy is a beneficial

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 pul-

monary hypertension and RV hypertrophy in different animal

species including mouse, guinea pig, rat, cow, rabbit, pig, dogand sheep. As mentionedabove, thereare significant 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 pul-

monary 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 mea-

sured in open chest rats were about 25 mm Hg in the control and

43 mm Hg in animals exposed to high altitude. After acute liga-

tion 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 isolatedpreparation of the RV working heart has revealed that mechan-

ical 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 main-

tain 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 ani-

mals exposed to chronic HAH. The explanation of this finding

is not clear since cell shortening and baseline calcium transients

were not changed in LV myocytes isolated from hearts of rats

adaptedtochronicHAH(Chenetal.,2006). Similarly, Cazorlaet

al. (2006) did not observe any increase in the LV stroke volume,

LV end-diastolic diameter, calcium sensitivity of myofilament

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 significant changes in the pro-

tein profiling both in the hypertrophic RV and non-hypertrophic

LV (Ostadal et al., 1978a). Right-to-left differences, character-

istic for animals living in normoxic environment, e.g. highercollagen concentration in the RV and higher concentration of

myofibrillar 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, sug-

gesting 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

influence of age on chronic hypoxia-induced pulmonary hyper-tension and RV hypertrophy is insufficient 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 differ-

ence in pulmonary hypertension and RV hypertrophy was not

significant. We have observed (Kolar et al., 1989) that inter-

mittent 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 ataltitude 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 significantly

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 end-

point of injury: in contrast to persisting infarct size-limitation,

the antiarrhythmic protection had already disappeared during

the first week after the hypoxic exposure. The attenuation of

systemic hypertension in adapted spontaneously hypertensive

rats dissipated when the rats returned to normoxic conditions

(Henleyet al., 1992). As highaltitude-inducedcardiac protection

against acute I/R injury lasts markedly longer that any form ofischemic 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 hypertro-

phy and alterations in cardiac function and metabolism) were

completely reversible after removal of rats from the hypoxic

atmosphere for a sufficiently 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 first 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 com-

position of the ventricular myocardium of rats exposed to HAH

remained, however, significantly 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 car-

dioprotection it would be ideal to reduce the development of

adverse changes and simultaneously preserve the beneficial

signs of the process of adaptation. From the relatively nar-

row spectrum of promising drugs, calcium antagonists were

investigated for their combined vasodilatatory and cardiopro-

tective effects (Ostadal et al., 1981). Preventive administration

of verapamil (before each of the hypoxic exposures) signifi-

cantly reduced the degree of pulmonary hypertension and RV

hypertrophy and partially prevented hypertensive changes in

the pulmonary vasculature. Unfortunately, the beneficial sign

of adaptation (i.e. cardiac resistance to acute hypoxia) was also


9/13


diminished. Therapeutic administration of calcium antagonists

when the cardiopulmonary changes were already developed was

without effect. For an explanation of these findings, the rela-

tionship 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 fibrosis 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-inducedpulmonaryhypertension (Pelouch et al., 1997).

It was shown that enalapril significantly 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 regres-

sion of cardiac fibrosis due to enalapril may be independent of

changes in the hemodynamic load. In addition, the inhibitionof ACE attenuated the process of morphological reconstruc-

tion of pulmonary vasculature (Herget et al., 1996). Recently,

Rakusan et al. (2007) found that the AT1 receptor pathway plays

an importantrole in coronary angiogenesis and improvedcardiac

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 block-

ers propranolol (Moret and Duchosal, 1976) or metipranolol

(Ostadal et al., 1978b) to high altitude-exposed rats significantly

reduced the values of RV systolic pressure and RV hypertrophy.

These results were later confirmed by Ostman-Smith (1995) and

Tual et al. (2006), suggesting that the adrenergic system partic-

ipates in the development of HAH-induced cardiopulmonary

changes. Moreover, beta-blockade significantly reduced also

the polycythemic response of hypoxic animals (Ostadal et al.,

1978b; Voelkel et al., 1980), probably by its effect on the pro-

duction of erythropoietin (Zivny et al., 1983).

8. Conclusions

It maybe concludedthat adaptation to chronic HAHincreases

cardiac tolerance to all major deleterious consequences of acute

oxygen deprivation in both adult and immature heart. In addi-

tion 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 (perma-

nent versus intermittent, normobaric versus hypobaric), duration

and severity of hypoxia and frequency of hypoxic episodes are

critical factors determining whether chronic hypoxia is bene-

ficial or harmful. Unfortunately, despite the fact that the first

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 pro-

posed. Although many potential factors have been suggested

to play a role in the cardioprotective effect, the available

data are not sufficiently conclusive and its detailed molecular

mechanism remains unknown. As compared with the tempo-

ral character of ischemic preconditioning, cardiac protection by

adaptation to chronic HAH may persist even after the regres-

sion of other hypoxia-induced changes, such as pulmonary

hypertension and RV hypertrophy. This fact offers a more opti-

mistic 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 confined

to life at high altitude, but can be found in chronic ischemicheart 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 experi-

mental 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).

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