High-Altitude Cardiopulmonary Diseases

Updated: Oct 20, 2021
  • Author: Ronald L Morton, MD; Chief Editor: Girish D Sharma, MD, FCCP, FAAP  more...
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Physiologic Effects of Altitude

Moderate, high, very high, and extreme high altitude are defined as follows [1] :

  • Moderate altitude = 5000-8000 ft (1524-2438 m) above sea level

  • High altitude = 8000-14,000 ft (2438-4267 m)

  • Very high altitude = 14,000-18,000 ft (4267-5486 m)

  • Extreme high altitude = 18,000-29,028 ft (5486-8847 m)

In America, migration to the Western Mountain states has increased the number of children living at moderate-to-high altitudes. In isolated geographic areas of the world, adaptation to altitude has occurred over many generations. However, the population living in the United States is genetically mixed and has varied responses to the added stress of altitude-induced hypoxia.

As the altitude increases, barometric pressure decreases. This decrease in barometric pressure affects the partial pressure of alveolar oxygen (PAO2). The percentage of oxygen remains stable at about 21%. At sea level, the partial pressure of oxygen available in the environment is equal to 0.21 times the barometric minus the water vapor pressure (ie, (760 - 47 mm Hg)* 0.21, or 149 mm Hg). PAO2 is 103 mm Hg.

PAO2 is calculated by using the alveolar gas equation, as follows:

PAO2 = FiO2 (PB - PH2 O) - PACO2 [FiO2 + (1 - FiO2/R)],

In this equation, FiO2 is the fraction of inspired oxygen, PB is the ambient barometric pressure, PH2 O is the pressure exerted by water vapor at body temperature, PACO2 is the alveolar partial pressure of carbon dioxide, and R is the respiratory exchange quotient. The decrease in barometric pressure with increasing altitude reduces PAO2. PAO2 decreases from 103 mm Hg at sea level to 81 mm Hg in Denver, Colorado (5280 ft [1609 m]) and to 48 mm Hg at the top of Pikes Peak (14,110 ft [4301 m]). In mountain areas popular with vacationers, such as Leadville, Colorado (10,200 ft [3109 m]), the PAO2 is 61 mm Hg. [2]

Pneumonia, asthma, bronchiolitis, neonatal lung disease, pulmonary edema and various other pulmonary diseases impair the efficiency of oxygen transfer from the alveolus to the pulmonary capillaries through ventilation-perfusion (V/Q) mismatch. Therefore, infants and children with pulmonary disease may have lower partial pressure of arterial oxygen (PaO2).

Further decrements in PAO2 due to altitude result in proportionate decreases in the PaO2. Thus, infants and children with pulmonary disease may have a PaO2 on the steep slope of the oxygen dissociation curve. As a result, small changes in the PaO2 cause large changes in arterial oxygen saturation (SaO2). In infants and children with pulmonary disease who live at moderate altitudes, changes in oxygen saturation can be observed, even as the barometric pressure falls with passing storm systems.

Newborns living at moderate altitudes have remarkably similar oxygen saturations during the first 24-48 hours of life. In Denver, Colorado, newborns younger than 48 hours have saturations of 85-97%; in Leadville, Colorado, saturations during the first 24 hours are 85-93%. Afterwards, the range widens. This change probably reflects a variable adaptive response to the transition from a fetal circulation to an adult circulation.

In Leadville, saturations in 1-week-old newborns are 83-93% during wakefulness and decrease to 75-86% during quiet sleep. By age 4 months, these values increase to 89-93% and 81-91% during waking and sleeping periods, respectively. Oxygen saturation values for healthy awake infants younger than 2 years are 89-94% in Colorado's Summit County ski area (9000 ft [2743 m]) and 90-99% in Denver. [3, 4]

Newborns living at moderate altitudes are often sent home from the hospital with low-flow oxygen (25-50 mL/min given by nasal cannula) for 2-6 weeks to keep their oxygen saturations at an arbitrary level (>90%) for more than 90% of the time. This treatment may be unnecessary, but it is given to mimic sea-level oxygenation and to promote the transition from fetal to adult physiology.

Physicians who care for infants and children with borderline oxygen saturations at their local altitude must consider these changes when they advise parents about travel to a high elevation. [5]

Pregnant women may also benefit from discussing travel to high altitude with their physician. Acetazolamide should generally be avoided and travel may be contraindicated in situations such as preeclampsia. While the low number of studies done in this population make specific recommendations difficult, a recent review by Jean et al provides an excellent overview of the available data. [6]

Physicians who practice at altitude should be aware of the normal for their population. When practicing medicine at altitude with limited supplies of oxygen, children with saturations of < 85% may be those who benefit most from limited resources. [7]

For excellent patient education resources, visit eMedicineHealth's First Aid and Injuries Center. Also, see eMedicineHealth's patient education article Mountain Sickness.


Effects of Chronic Hypoxia

The chronic hypoxia associated with moderate altitudes can affect the fetus. Birth weights and uterine blood flow are decreased, placental morphology may be different. Moreover, the incidence of prematurity and pregnancy -induced hypertension is increased at high altitudes. Maternal smoking at high altitudes can have an additive effect. Travel by pregnant women from low to high altitude, and vice versa, can initiate premature labor because of the effects of changing barometric pressures on the amniotic sac. [8]

Oxygen transport can be affected by exposure to high-altitude induced hypoxia. After ascending to high altitudes, lowlanders with metabolic syndrome exhibit an increase in erythropoietin and shift of the oxygen-hemoglobin dissociation curve to the right. [9] After ascending to high altitude, 2,3-diphosphoglycerate (2,3 DPG) is increased, and the oxygen-hemoglobin affinity is decreased, causing increased oxygen release at the tissues. [10] In one report, after 5 days exposure to high altitude (14,957 ft [4559 m]), despite the increase in the 2,3 DPG levels (3.5 μm/g hemoglobin) and decreased erythrocyte age, the P50 value (blood PO2 at 50% hemoglobin oxygen saturation at actual pH) remained unchanged in 11 mountaineers. [11]

Research into the body's response to hypoxia has been altered dramatically by the recent discovery of hypoxia-inducible factors (HIFs). HIFs are proteins called transcription factors, which bind to specific DNA sequences to promote certain genetic information being transcribed into messenger RNA. When cells are exposed to hypoxia, there is an increase in HIF-1α. This starts a cascade with wide-ranging effects on multiple genes, which results in induction of erythropoiesis, angiogenesis, and modified energy use, among other effects. [12]

In some infants, the normal decrease in pulmonary vascular resistance is delayed. In addition, echocardiographic evidence of elevated right-sided pressures persists for several days, or sometimes weeks, without the clinical findings of primary pulmonary hypertension of the newborn. In addition, the frequency of delayed closure of the ductus arteriosus increases. ECG findings of right ventricular hypertrophy often persist during the first months of life. Alteration of the normal transition from fetal to adult pulmonary circulation after exposure to high altitude can also result in symptomatic high-altitude pulmonary hypertension. [13, 14]

High-altitude dwellers may experience loss of adaptation to hypoxia (chronic mountain sickness [CMS]), characterized by increased red cell counts and pulmonary hypertension. One study evaluated 55 patients with CMS in Peru (altitude 4,300 m) by echocardiography. The investigators found that patients with CMS did not show any symptoms or echocardiographic changes of heart failure, despite the pulmonary hypertension. [15]

Another study also demonstrated marked increase in pulmonary hypertension in patients with CMS compared with well-matched controls. Both groups responded to nitric oxide, though the CMS group still had significantly higher pulmonary hypertension. The authors concluded these findings were a result of a structural pulmonary vascular defect in those with CMS, possibly caused by vascular remodeling induced by chronic hypoxemia. [16] Recent research has also indicated those with CMS also have significant systemic vascular dysfunction. [17]


Pulmonary Vascular Hyperreactivity

An estimated 20% of the general population responds to a hypoxic stimulus with a marked increase in the pulmonary vascular resistance; this phenomenon is known as hypoxic pulmonary vasoconstriction. Individuals with these reactions are referred to as hyperreactors. Clinically significant increases in the right ventricular pressure can be measured in individuals who have an elevated pulmonary vascular resistance secondary to the hypoxic environment of increasing altitude. [18]

One study evaluated exhaled nitric oxide and pulmonary artery pressures (by echocardiography) in children living at high altitude (3,600-4,000 m), comparing children of native descent (Aymara children) and children of European ancestry. They found that children of native descent living at high altitude had normal right-sided pressure gradients, with children of European descent having pressure gradients 33% higher than Aymara children. However, the lack of hypoxic pulmonary vasoconstriction (normal pressure gradients) in the Aymara children did not appear to be mediated through inceased nitric oxide synthesis. [19]

Factors that exacerbate hypoxic pulmonary vasoconstriction include acute pulmonary disease, exercise, upper airway obstruction, or congenital heart defects associated with an increase in pulmonary blood flow or restriction of pulmonary venous return.


Clinical Presentation

Acute mountain sickness

Each winter, millions of people ski at altitudes of 8202-11,483 ft (2500-3500 m) in Colorado. Each summer, more than 250,000 people visit the summit of Pikes Peak (14,110 ft [4301 m]). On arriving at high altitude, most individuals note a sensation of breathlessness secondary to the hypoxia-induced hyperventilation and palpitations from an increased heart rate. These are normal physiologic responses. However, within 6-96 hours after their arrival, many individuals notice having a headache, insomnia, anorexia, nausea, vomiting, dizziness, dyspnea, and loss of coordination. [20]

These symptoms represent acute mountain sickness (AMS), a spectrum that, in its severest form, can manifest as high-altitude pulmonary edema (HAPE) or high-altitude cerebral edema. Fortunately, for most individuals, the symptoms are annoying but not incapacitating. The duration of these symptoms is brief, usually only several days.

The development of AMS is directly related to the speed and height of the ascent and inversely related to age, as AMS is most common in the young. Symptoms observed in preverbal children include increased fussiness, decreased appetite, poor sleep patterns, and decreased playfulness.

High-altitude pulmonary edema

Healthy children and active young adults exposed to moderate altitudes are at risk for HAPE. This is an unusual form of noncardiogenic pulmonary edema that develops after an ascent to altitudes generally above 8000 ft (2438 m). The ascent is often rapid and is accomplished by means of either automobile or aircraft. In this situation, exposure to high altitude typically lasts several hours, most commonly after an overnight stay. Fatigue, dyspnea, nausea, and sleeplessness progress to visible cyanosis, tachypnea, and cough productive of copious sputum. Shock and death can result if the symptoms are not recognized and treated. Chest radiographs reveal patchy infiltrates consistent with pulmonary edema.

Chest radiograph in a child with infiltrates shows Chest radiograph in a child with infiltrates shows findings consistent with high-altitude pulmonary edema (HAPE). Courtesy of Dr Bibhuti Das.

A study done in La Paz, Bolivia (11,975 ft [3650 m]) showed echocardiographic evidence of small (< 5 mm) pericardial effusions in approximately half of the subjects after an ascent to altitude. [21] When investigators analyzed bronchoalveolar lavage (BAL) fluid obtained from patients with HAPE, they found increased levels of protein and albumin with a mild increase in RBCs, compared with HAPE-resistant and low-altitude values. [22] Another study examined lung function changes after ascent to high altitude in 26 unacclimatized subjects in Switzerland. They found individual lung function responses to high altitude widely varied and did not predict the development of HAPE. [23]

Findings presented at the World Congress of Mountain and Wilderness Medicine suggested that HAPE can be misdiagnosed as pneumonia in children residing at high altitude due to the overlap in radiographic findings and physical exam. [24, 25]

Pathophysiology of high-altitude pulmonary edema

Current thinking regarding the pathophysiology of HAPE centers around the increased pulmonary edema secondary to increased alveolar-capillary permeability and elevated hydrostatic pressures. [26, 27]

Investigators observed protein-rich transudative fluid in the BAL fluid of 3 patients who developed HAPE. In patients who were susceptible to HAPE, BAL samples appeared to contain normal numbers and differential values of leukocytes, arachidonic acid metabolites, and proinflammatory cytokines (interleukin-1 and tumor necrosis factor). These findings indicated that the primary event leading to the changes observed in HAPE is increased capillary hydrostatic pressures and not a proinflammatory cascade. [22]

HAPE-susceptible individuals have been shown to have significantly increased hypoxic pulmonary vasoconstriction, as well as elevated pulmonary artery pressures, prior to the onset of HAPE. Those with restricted pulmonary vascular beds (ie, absent pulmonary artery) are at higher risk. These findings, combined with animal studies, suggest these high pressures result in mechanical failure at the thin blood-gas barrier, leading to leakage into the alveolar spaces and the observed HAPE phenomena. [12]

In an intriguing study, researchers measured differences in nasal potentials among individuals susceptible to HAPE and among control subjects who were not susceptible to HAPE after an ascent to high-altitude (14,957 ft [4559 m]). In both groups, the total nasal potential and the chloride-sensitive portion of nasal potential increased at high altitude. However, after the subjects were treated with normobaric hypoxia for 6 hours at high altitude, the investigators observed no change in total or chloride-sensitive nasal potentials in individuals who were susceptible to HAPE compared with control subjects. The researchers postulated that abnormal transepithelial ion transport (increased secretion of chloride ions) may help compensate for the drying or crusting of the nasal mucosa seen in individuals at high altitude. [28]

Risk factors for high-altitude pulmonary edema

Altitude may adversely affect chronic illnesses such as sickle cell disease, cystic fibrosis, bronchopulmonary dysplasia, restricted pulmonary vascular bed, and type 1 diabetes mellitus. Effects of altitude on individuals with type I diabetes include decreased glycemic control, poor appetite or anorexia, and poor reliability with glucose meters. [29]

Recurrent episodes of HAPE in children with Down syndrome and obstructive sleep apnea (OSA) secondary to obesity have been seen at relatively low elevations (7000 ft [2134 m]) and probably reflect worsened desaturations during sleep. [30]

The incidence of a patent foramen ovale is 4 times greater in alpine climbers who have had high-altitude pulmonary edema compared with those who have not developed symptoms at high altitude. [31]

In Denver, Colorado, 10 children living at high-altitude (5282-10,006 ft [1610-3050 m]) underwent cardiac catheterization after fully recovering from HAPE. Five patients had undetected cardiac defects before the onset of HAPE, and one had OSA secondary to obesity. [32]


Prophylaxis and Treatment of High-Altitude Illness

Staged and graded ascent

To prevent acute mountain sickness (AMS), one may use the techniques of staged and graded ascent. Staged ascent involves the person becoming acclimatized at a base camp over 2-3 days before ascending. Graded ascent involves ascent over limited elevation per day. Guidelines suggest that, once a person is above 8000 ft (2438 m) elevation, he or she should ascend at a rate of 1000-2000 ft/d (305-610 m/d). [33]  According to guidelines from the Wilderness Medical Society on planning the rate of ascent, the altitude at which a person sleeps is more important than the altitude reached during waking hours. [34]

Physiologic mechanisms that lead to acclimatization to high altitude include hyperventilation, increased RBC concentrations in the blood (polycythemia), increased cellular oxidative enzyme levels, and a rightward shift of the oxygen dissociation curve at moderate altitudes (which improves loading of oxygen in the venous blood). [2] At high altitudes, a leftward shift of the oxygen-hemoglobin dissociation curve (caused by the respiratory alkalosis) results in the loading of oxygen in the pulmonary capillaries.

When a person has symptoms of AMS (headache, fatigue, dizziness, nausea, insomnia), treatment involves descent to lower altitude and oxygenation. Symptoms, oxygenation saturations, and chest radiographic findings usually dramatically improve. [35, 36, 37, 38]

Environmental modifications

Two methods have been used to make certain environments more suitable for occupants by lowering the physiologic altitude. The first method increases the barometric pressure of an enclosed, airtight space and is well known for its use in commercial aircraft. The other method involves oxygen enrichment of room air. Generally, a 1% increase in oxygen has an equivalent altitude reduction of about 300 m. Rooms do not need to be air tight for this method to work. This technique has been used successfully at high-altitude radiotelescope sites and in train passenger cars in China. While there has been some concern about possible fire hazards, this issue has been studied in depth and charts have been produced to indicate levels at which oxygen enrichment is safe. [12]

In many situations, environmental modification is not feasible. Emerging data explore using battery-powered, portable continuous positive airway pressure for trekkers as both a means of prevention and treatment for AMS. [39, 40]

Pharmacologic therapies to prevent and treat high-altitude illness

Tables 1 and 2 summarize the pharmacologic therapies used to prevent and treat high-altitude illness. The Wilderness Medical Society has also released updated consensus guidelines for prevention and treatment of acute altitude illness, which include pharmacologic dosing information. [34] Successful prophylaxis has been reported with acetazolamide (Diamox) and nifedipine for individuals with recurrent episodes. [41] A review article provides an excellent summary of acetazolamide research in AMS and discusses dosing strategies for optimal prophylaxis depending on the clinical situation. [42] Another study suggests that 5-lipoxygenase inhibitor (5-LO) is beneficial in preventing AMS. [43]

One study showed no difference in the incidences of AMS between subjects treated with ginkgo biloba and those given placebo. [44] However, other studies have shown a beneficial effect of ginkgo biloba in the prevention of AMS. [45]

Researchers performed a double-blind placebo-controlled trial in mountain climbers at low altitude while they were breathing hypoxic gas and while they were at an elevation of (17,716 ft [5400 m]). Sildenafil, a selective phosphodiesterase-5 inhibitor, reduced hypoxic pulmonary hypertension at rest and during exercise and increased maximum exercise capacity and cardiac output. The increase in performance was hypothesized to be secondary to increased cardiac output due to reduced right ventricular afterload, which increased oxygen transport to the exercising muscles. [46]

Some have suggested that the improvement may have been secondary to factors other than an improvement in altitude-induced right ventricular dysfunction. Examples are decreased lung interstitial edema due to the inhibition of hypoxic pulmonary venous constriction and the attenuation of hypoxia-induced depression of left ventricular diastolic function.

A more recent double blind, randomized controlled trial, however, has called into question the efficacy of sildenafil as an effective routine prophylactic therapy for AMS. [47]

Limited data regarding prophylaxis and treatment of high-altitude illness are available for children.

Table 1. Therapies to Prevent and Treat Acute Mountain Sickness [48] (Open Table in a new window)


Prophylactic Dosage

Treatment Dosage

Adverse Reactions



2-4 L/min by nasal cannula or mask, then 1-2 L/min or titrate to keep SaO2 >90%


Hyperbaric oxygen


2-4 psi for at least 2 h

Potential rebound


Adult: 125-250 mg orally (PO) q12h for 24 h before ascent and for first 2 days at high altitude

250 mg PO q12h until symptoms resolve

Paresthesias, altered taste, polyuria

Child: 5 mg/kg/d PO divided q8-12h

Not established

Paresthesias, altered taste, polyuria

Dexamethasone [49]

Adults: 2 mg PO q6h or 4 mg q12h

4 mg PO/intramuscularly (IM)/intravenously (IV) q6h

Mood change, hyperglycemia, dyspepsia

Ginkgo biloba

Adults: 80-120 mg PO q12h

Not established

Headaches; conflicting evidence with clinical trials

Table 2. Therapies to Prevent and Treat High-Altitude Pulmonary Edema [48] (Open Table in a new window)


Prophylactic Dosage

Treatment Dosage

Adverse Reactions



2-4 L/min by nasal cannula or mask, then 1-2 L/min or titrate to keep SaO2 >90%


Hyperbaric oxygen


2-4 psi for at least 2 h

Potential rebound


Adults: 20-30 mg extended-release PO q12h

10 mg PO initially, then 20-30 mg extended-release PO q12h

Reflex tachycardia, hypotension (uncommon)


Adults: 40 mg PO q6-8h on day 1, then 40 mg PO tid on days 2-6

Not established

Dyspepsia, facial flushing, muscle aches


Adults: 10 mg PO q12h

Not established

Dyspepsia, facial flushing, muscle aches

Salmeterol [50]

Adults: 125 mcg (1 inhalation) q12h for 1 day before and during ascent

Not established

Worsening asthma if not used with an inhaled corticosteroid


Congenital Heart Disease

The murmur from a ventricular septal defect is caused by flow disturbance as blood moves from the high-pressure left ventricle through the defect into the low-pressure right ventricle. At high altitudes, delayed reduction in fetal pulmonary vascular resistance and a genetic predisposition to hyperreactivity may maintain an elevated pulmonary vascular resistance and result in right-sided pressure near systemic levels. Therefore, even with a large ventricular septal defect, atrial septal defect, or patent ductus arteriosus, little or no left-to-right shunting may occur, and no typical cardiac murmur may be detected.

A child with such findings may not have the typical symptoms associated with increased pulmonary blood flow, such as sweating, tachypnea, and delayed growth. Therefore, large defects can be missed in this group of patients. One must maintain a high index of suspicion and exclude an increased right ventricular impulse when a single loud second heart sound is detected during clinical examination.

The incidence of patent ductus arteriosus and atrial septal defect is reported to be highest in populations living at moderate altitudes. Patients with cardiac defects who depend on a low pulmonary vascular resistance, such as those who have received a caval-pulmonary or Glenn shunt or undergone a Fontan operation, may be adversely affected by altitude-induced hypoxia and its effect on pulmonary vascular resistance.

As a general rule, patients who have difficulty with postoperative hemodynamics at sea level have even more difficulty at rising altitudes. Patients with primary pulmonary hypertension and Eisenmenger syndrome probably have greater difficulty at moderate altitudes than at sea level, and their disease may more rapidly progress at altitude than at sea level.

Patients with a large ventricular septal defect who have substantially increased pulmonary vascular resistance secondary to the hypoxic environment at moderate altitudes may be at risk for increased symptoms when they travel to relatively low altitudes. Improved oxygenation may decrease pulmonary vascular resistance and increase pulmonary blood flow and related symptoms. These changes can be controlled by increasing diuretic therapy while such patients are at low altitudes. [18, 51]

A study that investigated the direct effects of short-term high altitude exposure on pulmonary blood flow and exercise capacity in Fontan patients found that short-term high altitude exposure has no negative impact on pulmonary blood flow and exercise capacity in Fontan patients when compared with controls. [52]


Air Travel

Traveling by means of a commercial aircraft is equivalent to visiting Colorado Springs, Colorado (6200 ft [1890 m]); Santa Fe, New Mexico (7000 ft [2134 m]); or any location with an altitude of 6000-8500 ft (1828-2438 m) for the duration of the flight.

Studies in adults have confirmed the expected 6-8% decrease in baseline saturations. [53] Furthermore, the duration is brief, and the journey is not associated with prolonged sleep-induced hypopnea. As expected, patients with cyanosis who tolerate living at moderate altitudes also tolerate commercial air travel, whereas patients who require oxygen supplementation at moderate altitudes should continue to receive oxygen during travel to relatively low altitudes. In addition, increasing oxygen-flow prescriptions during air travel is reasonable for patients receiving long-term oxygen therapy at sea level. [54]

Some argue that patients with underlying risk factors for in-flight oxygen desaturations (eg, chronic obstructive pulmonary disease [COPD], chronic lung disease of prematurity [CLD]) should undergo a hypoxia altitude simulation test prior to air travel (simulating the maximum cabin pressure of 8000 mm Hg). [55, 56] One study found that, in patients with COPD (n=13), the hypoxia inhalation test (HIT) was able to accurately predict in-flight hypoxemia and the need for supplemental oxygen. [57] However, in a pediatric population with neonatal CLD, a cutoff value of 90% supplemental oxygen during the hypoxia test was unable to discriminate between patients with CLD and healthy control subjects. The role of the preflight hypoxia test remains controversial in the pediatric patient with CLD. [58]

Patients at risk because of air travel include those who were previously intolerant to brief decreases in oxygenation. In the authors' experience, patients at greatest risk are those with an elevated pulmonary vascular resistance who do not meet the criteria for surgery (eg, a Fontan procedure) at a moderate altitude and who are referred to an institution at sea level for surgery. The authors' postoperative recommendations include transfer of these patients back to a moderate altitude with supplemental oxygenation and close observation during the first 72 hours of their return.

Regulations of most airlines do not allow patients to use their own oxygen sources. Therefore, air travelers must make arrangements with the airline and obtain clearance from the airline's medical director before they fly.

The Aerospace Medical Association lists the following cardiovascular contraindications to commercial air travel: [59]

  • Uncomplicated myocardial infarction occurring within 3 weeks of flight

  • Complicated myocardial infarction occurring within 6 weeks of flight

  • Unstable angina

  • Severe decompensated congestive heart failure

  • Uncontrolled hypertension

  • Coronary artery bypass grafting performed within 2 weeks of flight

  • Cardiovascular accident occurring within 2 weeks of flight

  • Uncontrolled ventricular or supraventricular tachycardia

  • Severe symptomatic valvular heart disease

Additional information can be found from Aviation Health Guide for General Practitioners and Medical Advice for Commercial Air Travelers. [60, 61]



Recent research centers around different genetic polymorphisms in patients with high-altitude illness in an attempt to determine whether genetic makeup determines susceptibility. Endothelial nitric oxide synthase (NOS3) is an endogenous regulator of pulmonary vasodilatation. Patients with certain heterozygous polymorphisms for the NOS3 gene may be more susceptible to the effects of high altitude and the development of high-altitude pulmonary edema (HAPE). [62]

A recent review identifies a number of genes that may have an impact on developing altitude illness, though research is still in an early stage. Growing data seem to suggest that altitude illness is a polygenic condition strongly influenced by environmental factors. Further research, including genome-wide association studies and epigenetic analysis, should help shed light on these complex interactions. [63, 64]