Thin Air Resulting in High Pressure: Mountain Sickness and Hypoxia-Induced Pulmonary Hypertension. (2024)

1. The Importance of High Altitude Medicine

With rising altitude, atmospheric pressure falls. The percentage ofoxygen in the air (20.9%) is mostly independent of region and height[1], but since gases (in contrast to liquids) are compressible, thepartial pressure of oxygen (P[O.sub.2]) falls with rising altitude,resulting in hypobaric hypoxia at high altitude [2,3]. P[O.sub.2] at sealevel is approximately 159 mm Hg, whereas on the peak of Mount EverestP[O.sub.2] is only about 53 mm Hg [4,5]. Acute exposure to hypoxicconditions, dependent on the severity, may lead to acute mountainsickness (AMS) and even life-threatening conditions such as highaltitude cerebral edema (HACE, which can occur as the end-stage of AMS)and high altitude pulmonary edema (HAPE) [6,7]. Long-term exposure tohypobaric hypoxia may also lead to health problems in the form ofchronic mountain sickness (CMS) [8]. Pulmonary hypertension (PH) occursin several altitude-associated diseases including CMS and is a keyfeature of HAPE [9-11]. AMS as well as CMS occur at heights above 2500 m[6-8,12], and altitude is categorized based on such physiologicalchanges (Table 1) [13].

With approximately 35 million people traveling to high altitudeeach year, as well as military and rescue personnel, the latter oftenwithout adequate time to acclimatize, knowledge of the acute forms ofmaladaptation to hypoxia as well as their treatment is important [14].CMS as the chronic form of maladaptation to high altitude conditions isalso not to be neglected as a healthcare problem, because there arecurrently more than 140 million people permanently living at altitudesabove 2500 m [15].

2. Acute Reactions of the Cardiopulmonary System to Hypoxia

2.1. Physiologic Response. Within the first seconds after exposureto hypoxia, the resting cardiac output (CO) is increased. In 1982,Naeije et al. [26] demonstrated that this phenomenon was entirely basedon the rise of heart rate and that stroke volume remained unchanged[26]. Furthermore, the increase in CO matched the decrease in arterialoxygen concentration. This phenomenon only lasts for a few days. CO thenreturns almost to sea-level values, with heart rate remaining elevatedand stroke volume decreasing [27,28]. One reason for this adaptation isan increase in sympathetic nervous system activity along with decreasedparasympathetic activity [29, 30]. An additional response to hypoxia isa rise in breathing frequency as well as tidal volume, also known as thehypoxic ventilatory response (HVR). This mechanism can increase alveolarventilation by as much as 5-fold. HVR is triggered throughchemoreceptors located in the bifurcation of the carotid arteries and isa direct response to the decreased partial pressure of arterial oxygen[4,31]. Resting ventilation returns to low-altitude levels after severaldays [32].

Within the first hours of exposure to hypobaric hypoxia at highaltitude, erythrocyte concentration increases because of a reduction inplasma volume due to dehydration [31]. The latter is caused by tachypneain dry high-altitude air [33] and by increased diuresis [34,35]. Afterthis immediate response, circulating erythropoietin levels become vastlyelevated within the first 24-48 hours of exposure to hypoxia and returnto baseline values by the end of the first week [36]. The resultingelevation in erythrocyte concentration can be seen after 3-4 weeks [37].

In order for all these compensatory mechanisms to work adequately,acclimatization to high altitude is necessary. It is thereforerecommended that people traveling above 3000 m ascend only about 300-500m per day with a day of rest every third to fourth day [7].

2.2. Hypoxic Pulmonary Vasoconstriction: Clinical Significance andMolecular Mechanisms. Acute and prolonged exposure to hypoxia, forexample, during a stay at high altitude, results in increased pulmonaryvascular resistance and increased afterload of the right ventricle dueto a mechanism termed hypoxic pulmonary vasoconstriction (HPV), alsoknown as the von-Euler-Liljestrand mechanism. HPV is induced below aP[O.sub.2] of about 100 mm Hg (depending on species) and has two phases:an initial pulmonary vasoconstriction occurs within seconds after theonset of hypoxia, peaks after several minutes, and then decreases; thisis followed by a second prolonged phase of vasoconstriction whichreaches a maximum after several hours and cannot be completely reversedafter reexposure to normoxia, in contrast to the first acute phase[38,39]. Von Euler and Liljestrand described this effect in 1946 in thecat and were the first to speculate that this mechanism may beresponsible for ventilation-perfusion matching during regional hypoxiain the lung [40]. Indeed, regional alveolar hypoxia (e.g., due toalveolar hypoventilation) results in constriction of precapillaryvessels at the entrance of the pulmonary acinus [41], which serves toredistribute blood from poorly ventilated to well ventilated alveoli andthus decreases pulmonary shunt flow, in order to optimize arterialoxygenation. Despite many years of research, the underlying mechanismsof HPV are not completely understood. The trigger for acute HPV seems tobe located in the pulmonary arterial smooth muscle cells (PASMC), whileinitiation of sustained HPV may also depend on the presence of theendothelium [42] which is also a major modulator of HPV (e.g., viarelease of nitric oxide [NO]). Although the role of the endothelium isnot completely resolved, it is commonly accepted that HPV is an adaptivephysiologic mechanism attributed to the lung itself, because HPV ispreserved in patients after lung transplantation [43].

Mitochondria or other oxygen-consuming organelles or enzymes in thePASMC, such as reduced nicotinamide adenine dinucleotide phosphate(NADPH) oxidases, may sense hypoxia and transfer the signal viaalteration of the level of reactive oxygen species (ROS) or the cellularredox state to sarcoplasmic and plasmalemmal ion channels, such aspotassium channels, transient receptor potential channels, and L-typecalcium channels, which cause an intracellular calcium increase andvasoconstriction. Prolonged HPV may also be regulated by calciumsensitization via rho kinase and an alteration in the adenosinetriphosphate (ATP)/adenosine monophosphate (AMP) ratio. However, theexact sequence of signal transduction and the primary oxygen sensorremain unknown (see reviews [56-59]). Particularly, the exact role ofROS as mediators in HPV, the effect of hypoxia on their levels, and theidentities of their interaction partners (e.g., phospholipases andprotein kinases) are not completely understood. Although chronichypoxia-induced alterations of the pulmonary vasculature involve otherpathologic mechanisms in addition to HPV, the identification ofmechanisms regulating HPV has helped to uncover novel therapeuticapproaches for PH (e.g., targeting the NO-cyclic guanosine monophosphate[cGMP] pathway with sildenafil) [60].

Moreover, HPV is of clinical significance, because decreased HPV(which can occur, for example, during anesthesia [61], pulmonaryinflammation [e.g., sepsis [62]], or the hepatopulmonary syndrome [63])can lead to arterial hypoxemia. By contrast, exaggerated global HPV canaggravate PH, and inhom*ogeneous HPV may contribute to the development ofHAPE as described in a later section.

2.3. Acute Maladaptation. AMS is a combination of unspecificsymptoms typically occurring in nonacclimatized individuals travelingabove 2500 m. Its onset is within the first 6-12 hours after arrival athigh altitude [6,7,12]. Typical symptoms are headache followed by atleast one more of the following symptoms: loss of appetite, nausea,vomiting, dizziness, insomnia, and fatigue [6,7]. Hitherto there are twohypotheses on the underlying pathogenesis.

(1) The fall in arterial oxygen concentration that accompanies anascent to high altitude leads to an increase in the perfusion of thecentral nervous system (CNS) [64-66]. At the same time, autoregulationof the cerebral vessels is impaired [67,68] and concentrations ofcirculating radicals [67,69-71] and vascular endothelial growth factor(VEGF) [72] are increased.These circ*mstances may lead to increasedpermeability of the blood-brain barrier and thus result in extracellularedema. This hypothesis was supported by magnetic resonance imagingstudies of healthy volunteers exposed to normobaric hypoxia [73,74].

(2) Other data suggest that AMS is not associated with disruptionof the blood-brain barrier [67]. Within the magnetic resonance imagingstudies described above, asymptomatic individuals and those whodeveloped AMS showed similar degrees of extracellular edema [73,74],whereas those with AMS presented with an additional intracellular fluidaccumulation, the quantity of which correlated with the degree ofsymptoms. In skeletal muscle cells, hypoxia-induced intracellular liquidaccumulation has been shown to be related to impaired function of the[Na.sup.+][K.sup.+]-ATPase [75]. The same impairment could be the causeof the previously mentioned intracellular fluid retention within the CNS[73]. Free circulating radicals are thought to reduce the activity ofthe [Na.sup.+][K.sup.+]-ATPase, leading to an osmolarity-triggered fluidshift and thus swelling of astrocytes [73,74]. The latter, via variousmechanisms, is thought to lead to elevated NO synthesis [76] which,together with plasma membrane-destabilizing free radicals as well asVEGF, would result in irritation of the sensory trigeminal fibers,triggering the typical headache [77].

AMS itself is benign but severe cases may, if countermeasures arenot undertaken or if further ascent is undertaken, result in HACE [7].Typical signs of the latter are awareness alteration and/or ataxia.Without therapy, death may occur through cerebral herniation. On apathophysiological basis, extravasation due to hyperperfusion is thoughtto contribute [6]. However, keeping the known pathomechanism of AMS inmind, cytotoxic edema will also be present in HACE [78]. The majorcontributor to the increased intracranial pressure is thought to be theextracellular fluid shift [79].

Exposure to hypoxia (normobaric or hypobaric) leads toinhom*ogeneous HPV, resulting in an uneven perfusion of the lung withnonperfused areas next to hyperperfused areas [80]. The high capillarypressure in the latter may result in exudation, indicating the beginningof HAPE [11,81,82]. Chest X-rays and computerized axial tomography scansconducted in the early stages of HAPE show patchy pulmonary infiltrate,sometimes with peripheral predominance. With progression of HAPE theseareas grow and merge to produce a hom*ogeneous distribution [83], andbronchoalveolar lavage fluid contains exudate rich in proteins as wellas erythrocytes as a sign of mild hemorrhage [82,84].

Typical symptoms of HAPE are breathlessness, initially dry coughthat eventually becomes productive with sputum turning from white topink, tachycardia, and sometimes cyanosis [1,7]. These symptoms developin susceptible individuals within the first 2-4 days after arrival ataltitudes above 2500 m. The incidence depends on the ascent velocity andfinal altitude as well as individual susceptibility [7, 11]. Individualsat risk typically exhibit a marked rise in pulmonary arterial pressure(PAP) when exposed to hypoxia as a result of an exaggerated HPV [7], aswell as a greater rise in PAP on exercise under normoxic conditions [7]and a reduced HVR compared with nonsusceptible controls [6, 85,86].

2.4. Treatment of Acute Complications. AMS is typically aself-limiting condition that will resolve after 3-4 days [87]. However,if symptoms persist, descent to a lower altitude is recommended.Furthermore, supplemental oxygen (2-4 L/min) will reduce the symptomswithin 15-30 min [87, 88]. Besides prevention through slow ascent andinclusion of resting days between ascents [89,90], AMS can also beprevented effectively by acetazolamide or dexamethasone [91-93], andthese two medications are each recommended by the Wilderness MedicalSociety with an evidence level of 1A [91-94]. However, acetazolamide hasto be started the day before the ascent and is thus unsuitable forpeople who need to make unplanned, excessively rapid ascents, forinstance, emergency rescue personnel [94,95]. Dexamethasone should beconsidered first in such cases [96]. In 2014, Zheng et al. [97] showedthat inhaled budesonide is able to prevent AMS to the same extent asoral dexamethasone [97]. As peak serum levels of budesonide are muchlower than those of orally administered dexamethasone [98-100] theeffect of budesonide is thought to be more focused on the lung tissue.The mechanisms underlying the effects of dexamethasone as well asinhaled budesonide are not fully understood, but dexamethasone isthought to increase the concentration of apical alveolar membrane[Na.sup.+] channels as well as basal[ Na.sup.+][K.sup.+]-ATPase [101],stimulate surfactant secretion [102], and prevent protein exudation[103].

The first line of defence against HACE lies in its preventionthrough adequate acclimatization by slow ascent [90]. Dexamethasone is apossible treatment option but, in contrast to acetazolamide,dexamethasone does not facilitate acclimatization and thus may lead to afalse sense of security. Its real potential lies in its possiblestabilizing effect as a rescue drug for patients with HACE prior todescent [104,105].

HAPE may be prevented by slow ascent and allowing adequate time toacclimatize, as mentioned above [7]. In addition, there are severalmedical options for the reduction of HAPE incidents: thephosphodiesterase type 5 (PDE5) inhibitor tadalafil (10 mg twice daily[BID]) and dexamethasone (8 mg BID) have been well evaluated [106] ashas slow-release nifedipine (30 mg BID) [9]. When HAPE is evolving, thepatient should descend to lower altitudes and receive immediatesupplemental oxygen therapy (2-4 L/min) if possible [7,107]. In terms ofpharmacological therapy, adjunctive treatment with nifedipine is thecurrent standard, while the use of PDE5 inhibitors requires furtherevaluation [94].

In cases of HACE and HAPE where descent is not possible,alternative options are supplemental oxygen and a portable inflatablehyperbaric chamber that is able to increase air pressure to the levelfound at an altitude of approximately 1500 m [108, 109].

3. Long-Term Changes of the Cardiopulmonary System due to Hypoxia

3.1. Hypoxia-Induced PH: Pathomechanisms and Preclinical Studies.Exposure to chronic hypoxia results in pulmonary vascular remodelingwhich is characterized by specific alterations of the large and smallpulmonary vessels. These changes lead to PH and increased rightventricular (RV) afterload which can be further aggravated by increasedblood viscosity [110]. Large pulmonary vessels show increasedstiffening, while small pulmonary vessels exhibit thickening of theadventitial and medial layer and muscularization of formerlynonmuscularized precapillary vessels ("de novo"muscularization). Chronic hypoxia-induced vascular alterations arecompletely reversible after reexposure to normoxia.

On a cellular level, the remodeling of the small vessels is causedby increased proliferation and migration and decreased apoptosis ofPASMC (Figure 1) [16], and the affected cells seem to comprise aspecific subpopulation of PASMC that are not well differentiated.Additional alterations include increased proliferation and migration offibroblasts that have the ability to differentiate into smooth musclecell-like cells and secrete matrix proteins. It is possible thatpericytes and circulating bone marrow cells also contribute to thepathogenesis of vascular remodeling; however, species-specificdifferences exist [111,112]. Compared with human forms of pulmonaryarterial hypertension and other nonhypoxia-induced forms of PH, chronichypoxia induces less alteration of the intima, specifically no formationof neointima and plexiform lesions [111]. However, alterations ofendothelial cells also play a prominent role in chronic hypoxia-inducedPH, as they release increased levels of vasoconstrictive,proproliferative factors (e.g., endothelin [ET]-1, angiotensin II, VEGF,and platelet-derived growth factor-[PDGF-] B) and reduced levels ofvasodilatory, antiproliferative mediators (NO and prostaglandin[I.sub.2]), as well as increased amounts of adhesion molecules,cytokines, procoagulatory factors, and matrix proteins, which interactwith adjacent cells and attract circulating immune and progenitor celltypes [112,113].

Hypoxia-induced endothelial stimuli and circulating systemicfactors, as well as hypoxia per se, activate intracellular signalingcascades in PASMC involving tyrosine kinases, mitogen activated proteinkinases, protein kinase C, phosphatidylinositol 3 kinase, SMADphosphorylation, calcium inflow, and rho kinases, which all regulatecellular contractility, proliferation, and differentiation, as well assynthesis of matrix proteins. By contrast, antiproliferative signalingpathways which are regulated by cGMP or cyclic AMP become less active.Development of hypoxia-induced PH is further promoted by intrinsicgenetic, epigenetic, and acquired factors, such as bone morphogeneticprotein receptor-2 mutations and hormones [112].

Many of these factors have been targeted with investigationaltherapies in animal models of chronic hypoxia-induced PH, and beneficialeffects have been shown. However, only a few targets have made thetransition into clinical trials (for hypoxia-induced and/or other formsof PH), such as the PDGF pathway which was addressed by tyrosine kinaseinhibitors [114,115] and the NO-cGMP pathway which was addressed byactivators/stimulators of the soluble guanylate cyclase [116,117].Further details of clinical studies in hypoxiainduced PH are provided inSection 3.3.

Mediators between the aforementioned intracellular signalingpathways and hypoxia, which may act as chronic hypoxic oxygen sensingmechanisms, include the activation of hypoxia-inducible factor (HIF) 1,inhibition of mitochondria, and alterations in the release of ROS. HIF1regulates transcription of proteins such as erythropoietin, VEGF, andET1, as well as proteins that regulate cellular glycolytic andmitochondrial metabolism [118]. In accordance with the prominent role ofHIF in hypoxia-induced PH, mice with inducible PASMC-specificHIF1[alpha] knock-out showed decreased development of PH [119]. Theinhibition of mitochondrial metabolism and increased glycolytic ATPproduction (the so-called "metabolic switch") that has beenobserved in PH results in altered ROS release, antiapoptotic effects,activation of proliferative transcription factors, increased supply ofcomponents for protein synthesis, and altered cellular calciumhomeostasis [120,121]. Inhibition or reversal of mitochondrialalterations at several levels of interaction with the cellular signalingpathways could inhibit development of hypoxia-induced PH in mice andrats [121-124]. ROS can interact with a plethora of redox-sensitiveproliferative and antiapoptotic pathways and their role in conditions ofchronic hypoxia is as controversial as their role in acute hypoxia. Inthis regard, both an increase [59, 125] and a decrease of ROS have beenshown to stabilize HIF [126]. Animal studies suggest that ROS scavengingmay be beneficial in chronic hypoxia-induced PH under certaincirc*mstances [127-129].

3.2. Long-Term Adaptations in High-Altitude Populations. Studies ofnative high-altitude populations have also provided informationregarding the mechanisms involved in (mal) adaptation to long-termhypobaric hypoxia. At varying times in history, humans colonizedmultiple high-altitude locales, including the Tibetan Plateau, theAndean Altiplano, and the Semien Plateau of Ethiopia [130]. Theadaptation of these large populations to chronic hypoxia has beenextensively studied (Figure 2). The Tibetan population has been aparticular focus of research, because Tibetans are believed to havemoved to the Tibetan Plateau (average elevation of 4000 m) almost 25,000years ago, which would have given them more time to adapt to chronichypoxia than other high-altitude human populations such as the nativeinhabitants of the Andean Altiplano (settled 11,000 years ago) and theAmhara population in Ethiopia (settled 5000 years ago [20]).

3.2.1. Pulmonary Vascular System. Interestingly, high-altitudepopulations show relevant differences in their pulmonary vascularresponse to chronic hypoxia. Of note, Tibetans exhibit almost normalPAP, show minimal hypoxic PH [23], and lack the typical pathologicalfindings of vascular remodeling [24]. By contrast, PH and CMS, includingpathophysiological remodeling of the pulmonary arteries, are evidentamong Andeans [22]. These differences are most probably the result ofthe Tibetan population living above 3000 m for thousands of years longerthan the Andean population.

In general, it is believed that increases in hematocrit andhemoglobin (hb) concentration negatively influence pulmonary pressuresand resistance [131]. In this context, it is noteworthy that Tibetanhighlanders have significantly lower hb concentrations than Andeanhighlanders or Han Chinese migrants to high altitude [132]. Highlandersundergoing right heart catheterization while being physically challengedwere also found to have reduced pulmonary vascular distensibility withimpaired and inadequate response of the CO to exercise [133,134].However, subsequent studies of highlanders showed a wide range ofresponses of the pulmonary vascular system to exercise [135,136].Overall, results indicate that pulmonary vascular distensibility and COresponse are impaired in highlanders, with individual and ethnicvariability.

Interestingly, manifest hypoxic PH in highlanders is almostreversible after two years of low-altitude exposure [137]. Substantialalterations in the release of vasodilatory factors, especially NO, arebelieved to contribute to the high-altitude phenotypes. Compared withlowland inhabitants, Tibetan highlanders exhibit higher levels ofcirculating NO [138], as well as a higher NO transfer rate within thepulmonary circulation (implying an enhanced pulmonary vasodilatation)[139].

3.2.2. Genomic Studies. The local variability in the response tochronic hypoxia raised the question whether different genes might havebeen influenced by natural selection in the three major high-altitudepopulations. The HIF system has been described as the major geneticpathway [132], and HIF is believed to control hundreds of genes inresponse to cellular hypoxia.

In Tibetan highlanders, variants in several major HIF upstreamgenes such as EPAS1 (HIF-2[alpha]) and EGLN1 (HIF prolyl 4-hydroxylase2) have been identified. It is believed that these variants contributeto the low hb concentrations in Tibetans [25,140,141]. In particular, amissense mutation in EGLN1 prevents hypoxia-induced and HIF-mediatedenhancement of erythropoiesis [142]. Moreover, HMOX2 (heme oxygenase 2;downstream of HIF) has recently been identified as a relevant modifierof hb metabolism and contributor to high-altitude adaptation in Tibetanhighlanders [143]. In addition, variants of the major upstreamtranscriptional regulator EPAS1 were also significantly associated withlow hb concentrations in Tibetan highlanders [144]. The low hbconcentration and concomitant reduction of blood viscosity compared withacclimatized lowlanders might be an important mechanism to maintaincardiopulmonary circulation in Tibetan highlanders [16].

Genome-wide studies of Andean highlanders showed an overlap withTibetan highlanders for variation in EGLN1 but not EPAS1 [25].Nevertheless, no relevant association between EGLN1 genotype and hblevels was evident in Andean highlanders. In addition, variants in EGLN1and EPAS1 did not significantly contribute to Ethiopian hbconcentrations [20]. However, high-altitude adaptation in Ethiopianhighlanders is believed to be regulated via several different genesinvolved in vascular physiology such as CXC17 (CXC chemokine 17) andPAFAH1B3 (platelet activating factor acetylhydrolase 1b catalyticsubunit 3) [145,146]. Although the large highland populations havedeveloped different genetic variants, some major pathways show arelevant overlap. Many other variants in major genetic pathways havebeen discovered, but these genetic variants alone might not besufficient to explain fully the adaptation to chronic hypoxia. It ispossible that other pathways will be discovered from studies in largercohorts.

3.3. Clinical Studies. An overview of clinical studies of potentialtreatments for high altitude PH is presented in Table 2. The 2005consensus statement on high altitude PH included results from twostudies [8]. The effect of nifedipine was assessed in a case-controlstudy that included 31 patients with high altitude PH diagnosed andtreated in Bolivia at an altitude of 3600 m [44]. A 20% decrease inpulmonary arterial systolic pressure (PASP) was noted in two-thirds ofthe patients (classed as responders). In terms of limitations, it shouldbe noted that the study was based on echocardiography only. In addition,although CO increased to a greater extent in responders than innonresponders, heart rate and systemic systolic blood pressure did notshow responses consistent with the pulmonary vascular response (heartrate increased to a similar extent in responders and nonresponders, andsystemic systolic blood pressure showed a greater decrease innonresponders than in responders) [44]. In another study in Bolivia(also at an altitude of 3600 m), the effect of isovolemic hemodilutionwas assessed in eight native residents [45]. Three of the eightparticipants had high altitude PH. Isovolemic hemodilution led to anincrease in CO in all three participants with PH but had no consistenteffect on mean PAP. Based on the data available at the time, the 2005consensus statement recommended migration to low altitude as the idealtreatment for high altitude PH and noted that there was an urgent needfor randomized controlled trials of possible alternatives such ascalcium-channel blockers, ET receptor antagonists, prostaglandins, andPDE5 inhibitors [8].

In 2005, a randomized controlled trial of the PDE5 inhibitorsildenafil in 22 patients with high altitude PH in Kyrgyzstan waspublished [46]. The patients were randomly assigned to receivesildenafil 25 mg or 100 mg three times daily or placebo. Right heartcatheterization was carried out at baseline and after 12 weeks oftreatment. The patients receiving active treatment had a significantlygreater reduction in PAP (-6 mm Hg) than those receiving placebo (+1 mmHg). Changes in pulmonary vascular resistance and CO showed nodifference between the sildenafil and placebo groups, but the higherdose of sildenafil increased CO and decreased pulmonary vascularresistance much more than the lower dose. The placebo-corrected increasein six-minute walking distance was more than 40 m for both sildenafildoses [46]. A 2010 meta-analysis of ten trials came to the conclusionthat PDE5 inhibitors reduce PASP and have beneficial effects in patientswith high altitude PH [47]. The NO-cGMP pathway has also been targetedby the soluble guanylate cyclase stimulator riociguat, which reduced PAPand pulmonary vascular resistance in volunteers during exercise at asimulated altitude of ~4600 m [48].

Measures of high altitude PH were followed as secondary endpointsin a study of acetazolamide in 55 patients with CMS in Peru [49]. Aftera double-blind, randomized, placebo-controlled phase, all patientsreceived open-label acetazolamide. The increased hematocrit improvedsignificantly with acetazolamide compared with placebo. Noechocardiographic measures of high altitude PH improved withacetazolamide compared with placebo. However, CO improved significantlyfrom baseline in the open-label phase (+1 L/min). The patients treatedin this study most likely had no PH at baseline (echocardiographic PASP:34 mm Hg plus right atrial pressure) [49].

The rho kinase inhibitor fasudil showed impressive effects in anacute hemodynamic study in 19 Kyrgyz patients living at altitudes above3200 m with high altitude PH [50]. The placebo-controlled cross-overdesign allowed two acute echocardiographic evaluations of the rightheart before and after infusion of fasudil (1 mg/min) or placebo over 30min. Following fasudil infusion, PASP decreased by 10 mm Hg from abaseline of 52 mm Hg and CO increased by 0.5 L/min from a baseline of6.1 L/min; neither parameter showed any change from baseline followingplacebo infusion [50].

Bosentan, an ET receptor antagonist approved for the treatment ofpulmonary arterial hypertension, was tested as prophylaxis in healthyvolunteers (maximal oxygen uptake: 52 mL/kg x min) taken by motorvehicle to an altitude of 3800 m for evaluation of echocardiographicparameters and exercise capacity [51]. Compared with placebo, bosentanwas associated with a greater increase from sea-level baseline in PASP(+15 mm Hg [bosentan] versus +8 mm Hg [placebo]) and lower oxygensaturation during exercise (78% versus 85%). Other relevant measures didnot differ [51]. However, an acute hemodynamic study showed a beneficialeffect of bosentan on PASP (measured by echocardiography) in 15 Kyrgyzpatients with invasively proven high altitude PH: a single oral dose ofbosentan led to a decrease in PASP from 46 to 37 mm Hg after 3 h, whileCO and pulsoxymetric saturation remained stable [52]. Anotherechocardiography study in healthy volunteers showed that a single doseof bosentan blunted the rise in PASP caused by acute (90 min) hypoxiaexposure [53].

The effect of inhaled iloprost, a prostanoid therapy approved forthe treatment of pulmonary arterial hypertension, was assessed in anechocardiography study of 12 healthy volunteers at an altitude of 5050m. The results suggested that a prolonged stay at high altitude led toimpairment of RV systolic and diastolic function which was not reversedby inhalation of a single dose of iloprost (5 [micro]g) [54].

The effect of iron depletion or supplementation on PASP wasevaluated in two randomized, controlled, echocardiography studies,albeit not in patients with high altitude PH: one study assessed healthyvolunteers ascending to 4340 m and the other study enrolled patientswith CMS and PASP within the normal range (mean: 37 mm Hg) [55]. Theestimated increase in PASP in healthy volunteers after ascent was partlyreversed by iron supplementation (reduction by 6 mm Hg), but neverreached pathological levels. In patients with CMS, progressive irondeficiency (induced by venesection and isovolemic donation of 2 L ofblood) increased the estimated PASP by 9 mm Hg. Subsequent ironreplacement did not change the PASP [55].

3.3.1. (Possible) Treatment Options. As for other conditions athigh altitude, descent is life saving for severe cases [16]. However, ifdescent is not possible, pharmacologic treatment can be considered. PDE5inhibitors have the broadest evidence base to date, and high doses(e.g., 100 mg three times daily) of sildenafil could be considered.Further studies of pharmacologic treatments for high altitude PH areneeded.

4. The Right Ventricle in Hypoxia

In hypoxic conditions such as in high altitude, right sided heartfailure due to HPV and pulmonary vascular remodeling with the resultingincrease in afterload is one of the most feared life-threateningdiseases. Only 1% of previously healthy individuals with pulmonaryvascular hyperreactivity to hypoxia and severe hypoxic PH are at risk ofdeveloping right heart failure in high altitude [131,147]. The incidenceof right heart failure in hypoxic conditions, for instance, at highaltitude, is by no means proportional to high pulmonary pressure. Itremains to be elucidated why some high-altitude residents with high PAPare able to live "normal" lives with no restrictions in theiractivities [148], whereas others develop right heart failure.

4.1. How Does the Right Ventricle React to Hypoxic Conditions? Themost illuminating studies in this context are those conducted at highaltitude or in conditions similar to the hypoxic conditions of highaltitude. Huez et al. [149] exposed 25 healthy volunteers to hypoxia for90 min (fraction of inspired O2: 0.12) or dobutamine (titrated toproduce the same effect on heart rate without changing pulmonaryvascular tone) and explored the effects on RV and left ventricularfunction using standard Doppler echocardiography, pulsed tissue Dopplerimaging, and longitudinal systolic strain and strain-rate imaging.Hypoxia and dobutamine both increased CO and correspondingly tricuspidregurgitation velocity as an index for PAP. Conventionalechocardiography and tissue Doppler imaging revealed that dobutamineincreased RV indices of systolic function (such as RV area shorteningfraction, tricuspid annular plane systolic excursion [TAPSE], orsystolic ejection wave velocity [S] at the tricuspid annulus), whereashypoxia did not. Accordingly, longitudinal wall motion analysis revealedthat S, systolic strain, and strain rate on the RV free wall andinterventricular septum were increased by dobutamine but were notaffected by hypoxia. These results indicate that systolic function ofthe right ventricle is not altered in hypoxia. Instead, early diastolicfunction appears to be affected; tissue Doppler imaging revealed thathypoxia increased the isovolumic relaxation time relative to the RRinterval and delayed the onset of the E wave at the tricuspid annulus.

Echocardiographic measurements were performed by the same group[150] in 15 healthy lowlanders at different altitudes (sea level; <24h after arrival in La Paz, Bolivia, at 3750 m; and after 10 days ofacclimatization and ascent to Huayna Potosi, at 4850 m), and the resultswere compared with those obtained in 15 age- and body size-matchedinhabitants of Oruro, Bolivia, at 4000 m. Acute exposure to highaltitude in lowlanders caused an increase in mean PAP to 20-25 mm Hg,altered RV diastolic function (indicated by a decreased E/A ratio aswell as a prolonged isovolumic relaxation time contributing to anincreased RV Tei index), and maintained RV systolic function (measuredby TAPSE and S at the tricuspid annulus). Compared with the lowlandersexposed to high altitude, the native highlanders had lower PAP butgreater alteration in diastolic function, decreased TAPSE and S at thetricuspid annulus, and an increased RV Tei index. The cardiacadaptations to high altitude appeared qualitatively similar between bothgroups, but with significant deterioration of indices of systolic anddiastolic function in high-altitude dwellers. According to the authors,these results could be an effect of a lesser degree of sympatheticnervous system activation in the native highlanders.

Allemann and colleagues [151] assessed the effects of rapid ascentto high altitude on PAP and right and left ventricular function byechocardiography in 118 nonacclimatized healthy children andadolescents. The echocardiography was performed at low altitude and 40 hafter rapid ascent to 3450 m. PAP, estimated by measuring the systolicRV to right atrial pressure gradient, was significantly higher at highaltitude than at low altitude. There was no depression in RV systolicfunction even in children with the most severe altitude-induced PH. RVsystolic function even increased in the latter group. Naeije andcolleague discussed another possible mechanism of right heart failure.Chronic hypoxia and relative hypercapnia could be a cause of salt andwater retention in the mildly afterloaded right heart. This would leadto congestion, but remains to be proven in large studies [131].

Recently Crnkovic and colleagues [152] used a mouse model ofchronic hypoxia to describe RV function in hypoxia. In this model, TAPSEwas significantly decreased in hypoxia, whereas invasive measurementsdemonstrated a significantly increased maximal rate of rise in RVpressure (RV max dP/dt) and an unchanged RV contractility index. Theauthors concluded that RV systolic function is maintained in hypoxia,despite the decreased TAPSE. Due to its pressure-dependency, dP/dt [153]is a very vague parameter to describe RV contractility and therefore weneed studies (in humans as well as animals) that investigate RVcontractility and RV-arterial coupling using the accepted parametersEes/Ea (ventricular end-systolic elastance/arterial elastance), in orderto be able to measure the "correct" systolic function.

Recently Stembridge et al. [154] performed twodimensional, Doppler,and speckle-tracking echocardiography on adolescent highland Sherpa(altitude: 3840 m; n = 26) compared with age-matched lowland Sherpa(altitude: 1400 m; n = 10) and lowland Caucasian controls (sea level; n= 30). The RV diastolic area showed no significant difference betweenthe groups, whereas RV longitudinal strain and strain rate (reflectingcontractile function) were lower in highland Sherpa compared withlowland Sherpa, with no difference between highland Sherpa and lowlandCaucasian controls.

In conclusion, most of the studies investigating RV function inhypoxia are small and the majority of them used echocardiographicmeasurements to assess diastolic or systolic RV function. Furtherinvestigations should be done in order to assess the load-independent(as far as systolic function is concerned) parameter Ees and itsrelationship to Ea. All the other parameters mentioned above areindirect parameters, which at least give us some evidence that thesystolic function of the right ventricle in most studies is notimpaired, whereas the diastolic function is slightly reduced due to theincreasing afterload. Investigations of Ees/Ea would enable us tomeasure directly the contractility of the right ventricle, providing uswith more information about the reaction of the right ventricle tohypoxia.

5. Summary

Acute responses to hypobaric hypoxia include increased heart rate,increased erythrocyte concentration, increased breathing frequency andtidal volume (HVR), and HPV leading to increased pulmonary vascularresistance and right ventricular afterload. Acute maladaptation resultsin increased CNS perfusion and intracellular fluid accumulation (AMS,which can lead to potentially fatal HACE), as well as inhom*ogeneous HPVleading to hyperperfusion of some areas of the lung with subsequentexudation (HAPE). Acute maladaptation may be prevented by slow ascentand/or by administration of acetazolamide or dexamethasone; tadalafiland nifedipine are also options for reduction of HAPE events. Treatmentof acute maladaptation involves descent to a lower altitude and/oradministration of supplemental oxygen; dexamethasone may be used tostabilize patients with HACE prior to descent, and nifedipine is used asadjunctive therapy in HAPE.

Chronic hypoxia leads to pulmonary vascular remodeling (and thusPH) via HIF1 activation, mitochondrial inhibition, altered ROS release,and downstream alteration of many signaling pathways in endothelialcells and PASMC. The resulting increase in RV afterload can lead to thedevelopment of life-threatening right heart failure. Despite extensivestudy of physiological adaptations in native high-altitude populationsand the evaluation of multiple potential pharmacological targets inanimal models, few pharmacological treatments for hypoxia-induced PHhave entered clinical trials. PDE5 inhibitors have the most evidence todate, and further studies of pharmacological therapies are needed. Dataon RV function in hypoxia are also limited, and future studies shouldassess RV contractility directly by investigating Ees and Ea.

https://doi.org/10.1155/2017/8381653

Conflicts of Interest

Jan Grimminger has received financial research support by Actelion,speaker fees by MSD, and support for participation ineducation/congresses by Actelion and Bayer Pharma AG. Manuel Richter hasreceived support from United Therapeutics and Bayer Pharma AG andspeaker fees from Actelion, Mundipharma, Roche, and United Therapeutics.Natascha Sommer has declared no conflicts of interest. Henning Gallreceived honoraria for talks and/or consultancy and financial supportfor participation in education/congresses and/or clinical research fromActelion, AstraZeneca, Bayer, BMS, GSK, Janssen Cilag, Lilly, MSD,Novartis, OMT, Pfizer, and United Therapeutics. Khodr Tello has declaredno conflicts of interest. Hossein Ardeschir Ghofrani received honorariafor talks and/or consultancy and financial support for participation ineducation/congresses and/or clinical research from Actelion,AstraZeneca, Bayer, GSK, Janssen Cilag, Lilly, MSD, Novartis, OMT,Pfizer, and United Therapeutics.

Authors' Contributions

Jan Grimminger and Manuel Richter contributed equally to this work.

Acknowledgments

The authors thank Claire Mulligan, Ph.D. (Beacon MedicalCommunications Ltd, Brighton, UK) for editorial support, funded by theUniversity of Giessen.

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Jan Grimminger, (1,2,3) Manuel Richter, (2,3,4) Khodr Tello, (2,3)Natascha Sommer, (2,3) Henning Gall, (2,3) and Hossein ArdeschirGhofrani (2,3,4,5)

(1) Department of Internal Medicine, University Clinic HamburgEppendorf, University of Hamburg, Martinistrasse 52, 20246 Hamburg,Germany

(2) Department of Internal Medicine, Justus Liebig UniversityGiessen, Universities of Giessen and Marburg Lung Center (UGMLC),Klinikstrasse 33, 35392 Giessen, Germany

(3) German Center for Lung Research (DZL), Giessen, Germany

(4) Department of Pneumology, Kerckhoff Heart and Thoracic Center,Bad Nauheim, Germany

(5) Department of Medicine, Imperial College London, London, UK

Correspondence should be addressed to Jan Grimminger;[emailprotected]

Received 17 November 2016; Revised 15 February 2017; Accepted 28February 2017; Published 27 March 2017

Academic Editor: Stylianos Orfanos

Table 1: Categorization of altitude.Altitude category Height above sea level(I) Moderate altitude 1500-2500 m(II) High altitude 2500-3500m(III) Very high altitude 3500-5800m(IV) Extremely high altitude >5800 mTable 2: Clinical studies of potential treatments for high altitudePH.Trial[reference] Design Study population (n)Antezana Uncontrolled, open-label Native residents at highet al. trial with case-control altitude (n = 311998 [44] analysis (high versus low [14 with PH]) baseline Hb and PASP; responders versus nonresponders)Manier et Uncontrolled, open-label Native residents at highal. 1988 trial altitude (n = 8[45] [3 with PH])Aldashev et Double-blind, randomized, Patients with highal. 2005 placebo-controlled trial altitude PH (n = 22)[46]Jin et al. Meta-analysis of Patients with high2010 [47] randomized, controlled altitude PH (n = 218 trials [in 10 trials])Andrews et Open-label trial Volunteersal. 2016 (hemodynamics evaluated (n not reported)[48] during incremental exercise tests before and after administration of study drug)Richalet et Double-blind, randomized, Patients with CMSal. 2008 placebo-controlled trial, (n = 55)[49] followed by an open-label trial after a 4-week washout periodKojonazarov Double-blind, randomized, Patients with highet al. placebo-controlled, altitude PH (n = 19)2012a [50] crossover trialSeheult et Double-blind, randomized, Nonacclimatizedal. 2009 placebo-controlled, volunteers (n = 8)[51] crossover trialKojonazarov Uncontrolled, open-label Patients with highet al. trial altitude PH (n = 15)2012b [52]Pham et al. Double-blind, randomized, Volunteers (n = 15)2012 [53] placebo-controlled, crossover trialKortekaas Double-blind, randomized, Volunteers (n = 12)et al. 2009 placebo-controlled,[54] crossover trialSmith et Two double-blind, Native sea levelal. 2009 randomized, placebo- volunteers (n = 22)[55] controlled trials, one in Native high altitude healthy volunteers and one residents with CMS in patients with CMS (the (n = 11) latter also had a crossover phase)Trial[reference] Location (altitude) TreatmentsAntezana La Paz, Bolivia Nifedipine 10 mg (1-3 doseset al. (3500-4100 m) at 30 min intervals;1998 [44] sublingual)Manier et La Paz, Bolivia Isovolemic hemodilutional. 1988 (3600-4200m)[45]Aldashev et Naryn region, Kyrgyzstan Sildenafil 25 or 100 mg oral. 2005 (2500-4000 m) placebo every 8 h for 12[46] weeks (tablets)Jin et al. (>2500-5400m) PDE5 inhibitors2010 [47]Andrews et Simulated altitude Riociguat 1 mgal. 2016 of ~4600 m (single oral dose)[48]Richalet et Cerro de Pasco, Peru Randomized phase:al. 2008 (4300 m) acetazolamide 250 mg or[49] placebo daily for 12 weeks (oral) Open-label phase: acetazolamide 250 mg daily for 12 weeks (oral)Kojonazarov Tien-Shan Mountains, Fasudil hydrochlorideet al. Kyrgyzstan (3200-3600 m) hydrate 30 mg or placebo2012a [50] (IV infusion)Seheult et White Mountains, CA, Bosentan 125 mg or placeboal. 2009 USA (3800 m) twice daily for 5 days[51] before ascent and 2 days at high altitude (oral)Kojonazarov Tien-Shan Mountains, Bosentan 125 mg (singleet al. Kyrgyzstan (2500-3800 m) oral dose)2012b [52]Pham et al. Acute (90 min) normobaric Bosentan 250 mg or placebo2012 [53] hypoxia equivalent to (single oral dose) altitude of ~4300mKortekaas Dhaulagiri, Nepal Iloprost 5 [micro]g oret al. 2009 (5050 m) placebo (single inhaled[54] dose) at sea level and after 14-day trek to high altitude Sea level volunteers: Fe(III)- hydroxide sucrose 200 mg orSmith et Cerro de Pasco, Peru placebo (IV infusion) onal. 2009 (4340 m) third day after ascent to[55] high altitude by road Patients with CMS: isovolemic hemodilution followed by Fe(III)- hydroxide sucrose 400 mg or placebo (IV infusion)Trial[reference] Main hemodynamic resultsAntezana Two-thirds of participants overall showedet al. response to nifedipine (>20% decrease in1998 [44] PASP), but systemic systolic blood pressure showed greater decrease in nonresponders than respondersManier et Isovolemic hemodilution led to an increaseal. 1988 from baseline in CO but had no consistent[45] effect on mean PAP in participants with high altitude PHAldashev et Sildenafil had a significant treatment effectal. 2005 versus placebo in terms of mean PAP (-6.7 mm[46] Hg [95% CL -11.6 to -1.8]; p = 0.010) and 6MWD (+43.5 m [95% Cl 13.4 to 72.6]; p = 0.007)Jin et al. PDE5 inhibitors had a significant treatment2010 [47] effect versus control in terms of PASP at rest (weighted mean difference -7.5 mm Hg [95% CL -10.9 to -4.2]; p < 0.0001), and no significant effect on systolic blood pressure and heart rate at rest and during exerciseAndrews et Riociguat led to a decrease in PAP and PVR atal. 2016 all levels of exercise intensity[48]Richalet et Randomized phase: acetazolamide had noal. 2008 significant effect on echocardiographic[49] measures of high altitude PH compared with placebo Open-label phase: acetazolamide led to significant improvements from baseline in CO (original placebo and acetazolamide groups both +1 L-min [p < 0.001]) and PVR (original placebo group: -0.12 WU [p < 0.02]; original acetazolamide group: -0.19 WU [p < 0.001])Kojonazarov Fasudil infusion led to improvements fromet al. baseline in PASP (-10 mm Hg) and CO (+0.5 L/2012a [50] min), whereas placebo infusion did not (p < 0.001 for fasudil versus placebo)Seheult et After ascent to high altitude, PASP increasedal. 2009 from sea-level baseline to a greater extent[51] with bosentan (+15 mm Hg) than with placebo (+8 mm Hg)Kojonazarov Bosentan led to a decrease in PASP from 46 toet al. 37 mm Hg after 3 h, while CO remained stable2012b [52]Pham et al. Compared with placebo, bosentan blunted the2012 [53] hypoxia-induced rise in PASP by 6.4 mm Hg (p = 0.063) and 5.2 mm Hg (p = 0.002) in participants with and without a history of high altitude pulmonary edema, respectivelyKortekaas TAPSE and tricuspid inflow peak velocitieset al. 2009 were decreased after trekking from sea level[54] to high altitude, suggesting impaired right ventricular systolic and diastolic dysfunction; a single dose of inhaled iloprost did not reverse these changesSmith et Sea level volunteers: at high altitude, ironal. 2009 infusion reduced PASP by 6 mm Hg (95% CI: 4[55] to 8; p = 0.01) Patients with CMS: iron depletion by hemodilution increased PASP from baseline by 9 mm Hg (95% CI: 4 to 14 mm Hg; p = 0.003); subsequent iron replacement had no acute effect on PASP6MWD: 6-minute walking distance; Cl: confidence interval; CMS: chronicmountain sickness; CO: cardiac output; Hb: hemoglobin; IV: intravenous;PAP: pulmonary arterial pressure; PASP: pulmonary arterial systolicpressure; PDE: phospho diesterase; PH: pulmonary hypertension; PVR:pulmonary vascular resistance; TAPSE: tricuspid annular plane systolicexcursion.Figure 1: Mechanisms of vascular remodeling in chronic hypoxia(from [16], permission granted). AEC: alveolar epithelial cell;CCL: C-C motif chemokine ligand; CD40L: CD40 ligand; CXCL: C-X-Cmotif chemokine ligand; ECAM: endothelial cell adhesion molecule;FGF: fibroblast growth factor; HDAC: histone deacetylase; GM-CSF:granulocyte macrophage colony stimulating factor; HIF:hypoxia-inducible factor; ICAM: intercellular adhesion molecule;IL: interleukin; NO-sGC-cGMP: nitric oxide-soluble guanylatecyclase-cyclic GMP; MCP: monocyte chemoattractant protein; PDGF:platelet-derived growth factor; PGI2: prostacyclin; RANTES:regulated upon activation, normally T-expressed, and presumablysecreted; ROS: reactive oxygen species; SDF: stromal cell-derivedfactor; TRPC6: transient receptor potential cation channel 6; VCAM:vascular cell adhesion molecule.Cellular and molecular mechanismsVasomotor toneROS PG[I.sub.2]TRPC6 NO-sGC-cGMP axisK- and Ca-channels EndothelinRho kinase SerotoninAbnormal proliferationHIFGrowth factors (PDGF, FGF)Metabolic changesMatrix metalloproteinasesInflammation/recruitmentCytokines and chemokines Adhesion moleculesIL-1b and IL-6, ICAMCCL2 (MCP-1), VCAMCXCL12 (SDF-1), ECAMCCL5 (RANTES),GM-CSF,CD40LEpigeneticsHDAC: Class 1MicroRNAs: eg miR17, miR21, miR124, miR145, miR210Figure 2: Map showing populated regions at altitudes of 2500 m orhigher (from [17], permission granted), and characteristics of threemajor high-altitude populations. 'Compared with sea-level populationsat low altitude (see [18,19]). EGLN1: hypoxia-inducible factor prolyl4-hydroxylase 2; EPAS1: hypoxia-inducible factor-2[alpha]; hb:hemoglobin. ([dagger]): [20, 21], ([dagger])([dagger]): [22-24],([dagger])([dagger])([dagger]): [25]. Andean EthiopianCharacteristic Altiplano PlateauDuration of 11,000 years 5000 yearssettlement ([dagger]) (Amhara)Pulmonary hypertension Present --([dagger])([dagger])Hb concentration * Elevated SimilarArterial hb oxygen Low Similarsaturation *EGLN1 variants Yes No([dagger])([dagger])([dagger])EPAS1 variants No No([dagger])([dagger])([dagger])Characteristic Tibetan PlateauDuration of 25,000 yearssettlement ([dagger])Pulmonary hypertension Minimal([dagger])([dagger])Hb concentration * Similar ([less than or equal to] 4000 m) Elevated (>4000 m)Arterial hb oxygen Lowsaturation *EGLN1 variants Yes([dagger])([dagger])([dagger])EPAS1 variants Yes([dagger])([dagger])([dagger])